Bioorganic & Medicinal Chemistry

Editorial board ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8
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Design, synthesis and biological evaluation of N,N-3-phenyl-3-benzylaminopropanamide derivatives as novel cholesteryl ester transfer protein inhibitor ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Dongmei Zhao, Honglei Xie, Changlin Bai, Chunchi Liu, Chenzhou Hao, Shizhen Zhao, Hongli Yuan, Changqun Luo, Jian Wang, Bin Lin, Jiang Zheng, Maosheng Cheng A series of N,N-3-phenyl-3-benzylaminopropanamide derivatives were identified as novel CETP (cholesteryl ester transfer protein) inhibitors. In our previous study, lead compound L10 was discovered by pharmacophore-based virtual screening (Dong-Mei Zhao et al., 2014). Based on L10 (IC50 8.06μM), compound HL6 (IC50 10.7μM) was discovered following systematic structure variation and biological tests. Further optimization of the structure–activity relationship (SAR) resulted in N,N-3-phenyl-3-benzylaminopro panamides derivatives as novel CETP inhibitors. They were synthesized and evaluated against CETP by BODIPY-CE fluorescence assay. Among them, HL16 (IC50 0.69μM) was a highly potent CETP inhibitor in vitro. In addition, HL16 exhibited favorable HDL-C enhancement and LDL-C reduction in vivo by hamster. The molecular docking of HL16 into the CETP was performed. The binding mode demonstrated that HL16 occupied the CETP binding site and formed interactions with the key amino acid residues. Graphical abstract image
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Synthesis, and anticonvulsant activity of new amides derived from 3-methyl- or 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetic acids ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Jolanta Obniska, Anna Rapacz, Sabina Rybka, Małgorzata Góra, Krzysztof Kamiński, Kinga Sałat, Paweł Żmudzki This paper describes the synthesis of the library of 22 new 3-methyl- and 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetamides as potential anticonvulsant agents. The maximal electroshock (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models were used for screening all the compounds. The 6Hz model of pharmacoresistant limbic seizures was applied for studying selected derivatives. Six amides were chosen for pharmacological characterization of their antinociceptive activity in the formalin model of tonic pain as well as local anesthetic activity was assessed in mice. The pharmacological data indicate on the broad spectra of activity across the preclinical seizure models. Compounds 10 (ED50 =32.08mg/kg, MES test) and 9 (ED50 =40.34mg/kg, scPTZ test) demonstrated the highest potency. These compounds displayed considerably better safety profiles than clinically relevant antiepileptic drugs phenytoin, ethosuximide, or valproic acid. Several molecules showed antinociceptive and local anesthetic properties. The in vitro radioligand binding studies demonstrated that the influence on the sodium and calcium channels may be one of the essential mechanisms of action. Graphical abstract image
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Compound profiling and 3D-QSAR studies of hydrazone derivatives with activity against intracellular Trypanosoma cruzi ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Lívia Bandeira Costa, Marcos Veríssimo de Oliveira Cardoso, Gevanio Bezerra de Oliveira Filho, Paulo André Teixeira de Moraes Gomes, José Wanderlan Pontes Espíndola, Thays Gabrielle de Jesus Silva, Pedro Henrique Monteiro Torres, Floriano Paes Silva, Julio Martin, Regina Célia Bressan Queiroz de Figueiredo, Ana Cristina Lima Leite Chagas disease is a tropical disease caused by the parasite Trypanosoma cruzi, which is endemic in Central and South America. Few treatments are available with effectiveness limited to the early (acute) stage of disease, significant toxicity and widespread drug resistance. In this work we report the outcome of a HTS-ready assay chemical library screen to identify novel, nontoxic, small-molecule inhibitors of T. cruzi. We have selected 50 compounds that possess hydrazone as a common group. The compounds were screened using recombinant T. cruzi (Tulahuen strain) expressing beta-galactosidase. A 3D quantitative structure–activity relationship (QSAR) analysis was performed using descriptors calculated from comparative molecular field analysis (CoMFA). Our findings show that of the fifty selected hydrazones, compounds LpQM-19, 28 and 31 displayed the highest activity against T. cruzi, leading to a selectivity index (SI) of 20-fold. The 3D-QSAR analysis indicates that a particular electrostatic arrangement, where electron-deficient atoms are aligned along the molecule main axis positively correlates with compound biological activity. These results provide new candidate molecules for the development of treatments against Chagas disease. Graphical abstract image
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1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Fabrizio Micheli, Andrea Bernardelli, Federica Bianchi, Simone Braggio, Laura Castelletti, Palmina Cavallini, Paolo Cavanni, Susanna Cremonesi, Michele Dal Cin, Aldo Feriani, Beatrice Oliosi, Teresa Semeraro, Luca Tarsi, Silvia Tomelleri, Andrea Wong, Filippo Visentini, Laura Zonzini, Christian Heidbreder A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pK i =8.4, DA D2 pK i =6.0 and hERG fpK i =5.2) showed a balanced profile and further refinements are in progress around this molecule. Graphical abstract image
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Novel nicotine analogues with potential anti-mycobacterial activity ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Paresh T. Gandhi, Thimmasandra Narayanappa Athmaram, Gundaiah Ramesh Arunkumar Tuberculosis (TB) is the second leading lethal infectious disease in the world after acquired immuno deficiency (AIDs). We have developed a series of twenty-five novel nicotine analogues with de-addiction property and tested them for their activity against Mycobacterium tuberculosis (MTB). In an effort to increase the specificity of action and directing nicotine analogues to target MTB, four promising compounds were further optimized via molecular docking studies against the Dihydrofolate reductase of MTB. After lead optimization, one nicotine analogue [3-(5-(3fluorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one] exhibited minimum inhibitory concentration of 1μg/mL (2.86nM) against M. tuberculosis (H37Rv strain), a human pathogenic strain of clinically significant importance. Pharmacokinetic analysis of [3-(5-(3fluorophenyl)nicotinoyl)-1methylpyrrolidin-2-one] with lowest MIC value via oral route in Wistar rats revealed that at a dosage of 5mg/kg body weight gave a maximum serum drug concentration (C max) of 2.86μg/mL, T max of one hour and a half-life (T 1/2) of more than 24h and Volume of distribution (V d) of 27.36L. Whereas the parenteral (intra venous) route showed a C max of 3.37μg/mL, T max of 0.05h, T 1/2 of 24h and V d equivalent to 23.18L. The acute oral toxicity and repeated oral toxicity studies in female Wistar rats had an LD50 >2000mg/kg body weight. Our data suggests that nicotine derivatives developed in the present study has good metabolic stability with tunable pharmacokinetics (PK) with therapeutic potential to combat MTB. However, further in vivo studies for anti-tuberculosis activity and elucidation of mode of action could result in more promising novel drug for treating MTB. To the best of our knowledge this is the first report revealing the anti-mycobacterial potential of nicotine analogue at potential therapeutic concentrations. Graphical abstract image
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Isatin analogs as novel inhibitors of Candida spp. β-carbonic anhydrase enzymes ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Atilla Akdemir, Özlen Güzel-Akdemir, Nilgün Karalı, Claudiu T. Supuran Enzyme inhibition data of structurally novel isatin-containing sulfonamides were determined for two carbonic anhydrases (CAs, EC 4.2.1.1) from pathogenic Candida species (CaNce103 from C. albicans and CgNce103 from C. glabrata). The compounds show K I values in the low nanomolar range for the fungal CAs, while they have significantly higher K I values for the human CAs. Homology models were constructed for the CaNce103 and CgNce103 and subsequently the ligands were docked into these models to rationalize their enzyme inhibitory properties. Graphical abstract image
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Antiretroviral (HIV-1) activity of azulene derivatives ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Julia Peet, Anastasia Selyutina, Aleksei Bredihhin The antiretroviral activity of azulene derivatives was detected for the first time. A series of eighteen diversely substituted azulenes was synthesized and tested in vitro using HIV-1 based virus-like particles (VLPs) and infectious HIV-1 virus in U2OS and TZM-bl cell lines. Among the compounds tested, the 2-hydroxyazulenes demonstrated the most significant activity by inhibiting HIV-1 replication with IC50 of 2–10 and 8–20μM for the VLPs and the infectious virus, respectively. These results indicate that azulene derivatives may be potentially useful candidates for the development of antiretroviral agents. Graphical abstract image
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Novel indole-based melatonin analogues: Evaluation of antioxidant activity and protective effect against amyloid β-induced damage ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Hande Gurer-Orhan, Cigdem Karaaslan, Senem Ozcan, Omidreza Firuzi, Marjan Tavakkoli, Luciano Saso, Sibel Suzen Oxidative stress has been recognized as a contributing factor in ageing and various diseases including cancer and neuropathological disorders. Indole derivatives such as the neurohormone melatonin (MLT) constitute an important class of therapeutic agent in medicinal chemistry. MLT can scavenge different reactive oxygen species and can also stimulate the synthesis of antioxidant enzymes. As a part of our ongoing studies, a series of new indole-based hydrazide/hydrazone derivatives were synthesized as MLT analogues. Their antioxidant activity was investigated in human erythrocytes by evaluating their reducing effect against oxidation of a redox-sensitive fluorescent probe. Possible inherent cytotoxicity of the compounds was investigated in CHO-K1 cells by lactate dehydrogenase leakage test. Protection of neuronal PC12 cells against amyloid β-induced damage was examined by MTT assay and their ability in reduction of ROS generation induced by amyloid β was tested. MLT analogues having an o-halogenated aromatic moiety exhibited effective antioxidant properties without having any membrane-damaging effect. Moreover, derivatives having o-halogenated and dihalogenated aromatic side chain significantly protected neuronal cells at concentrations of 10 and 100μM. In conclusion, MLT derivatives represent promising scaffolds for discovery of effective antioxidant and neuroprotective agents. Graphical abstract image
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In vivo phase II-enzymes inducers, as potential chemopreventive agents, based on the chalcone and furoxan skeletons ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Mauricio Cabrera, Ignacio Mastandrea, Gabriel Otero, Hugo Cerecetto, Mercedes González Cancer chemoprevention involves prevention/delay/reverse of the carcinogenic process through administration of cancer chemopreventive agents (CCA). Compounds which are able to induce detoxification-enzymes, especially monofunctional phase II enzymes, have become in excellent approaches for new CCA. Herein, we report the synthesis of new furoxanyl chalcone-like hybrid compounds as CCA. In vitro studies showed that phenylfuroxanyl derivatives 6 and 9 displayed the best activities being 9 the greatest monofunctional-inducer. Additionally, compounds were non-mutagenic against TA98 Salmonella typhimurium strain (Ames test) and could be used in the prevention of the progression of pre-malignant lesions for their cytotoxic activity against tumoral cells. In vivo proof of concept showed increment on phase II-enzymes activities in liver, colon and mammary gland having derivative 9 the best induction profiles. We probed Nrf2 nuclear translocation is operative for both compounds allowing to exert protective effects via expression of downstream phase-II enzymes. Graphical abstract image
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A concise synthesis and evaluation of new malonamide derivatives as potential α-glucosidase inhibitors ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Mohammad Shahidul Islam, Assem Barakat, Abdullah M. Al-Majid, Hazem A. Ghabbour, A.F.M. Motiur Rahman, Kulsoom Javaid, Rehan Imad, Sammer Yousuf, M. Iqbal Choudhary A series of new malonamide derivatives were synthesized by Michael addition reaction of N 1,N 3-di(pyridin-2-yl)malonamide into α,β-unsaturated ketones mediated by DBU in DCM at ambient temperature. The inhibitory potential of these compounds in vitro, against α-glucosidase enzyme was evaluated. Result showed that most of malonamide derivatives were identified as a potent inhibitors of α-glucosidase enzyme. Among all the compounds, 4K (IC50 =11.7±0.5μM) was found out as the most active one compared to standard drug acarbose (IC50 =840±1.73μM). Further cytotoxicity of 4a–4m were also evaluated against a number of cancer and normal cell lines and interesting results were obtained. Graphical abstract image
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Development of a potent 2-oxoamide inhibitor of secreted phospholipase A2 guided by molecular docking calculations and molecular dynamics simulations ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Sofia Vasilakaki, Efrosini Barbayianni, Georgios Leonis, Manthos G. Papadopoulos, Thomas Mavromoustakos, Michael H. Gelb, George Kokotos Inhibition of group IIA secreted phospholipase A2 (GIIA sPLA2) has been an important objective for medicinal chemists. We have previously shown that inhibitors incorporating the 2-oxoamide functionality may inhibit human and mouse GIIA sPLA2s. Herein, the development of new potent inhibitors by molecular docking calculations using the structure of the known inhibitor 7 as scaffold, are described. Synthesis and biological evaluation of the new compounds revealed that the long chain 2-oxoamide based on (S)-valine GK241 led to improved activity (IC50 =143nM and 68nM against human and mouse GIIA sPLA2, respectively). In addition, molecular dynamics simulations were employed to shed light on GK241 potent and selective inhibitory activity. Graphical abstract image
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Donor substrate promiscuity of bacterial β1–3-N-acetylglucosaminyltransferases and acceptor substrate flexibility of β1–4-galactosyltransferases ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Yanhong Li, Mengyang Xue, Xue Sheng, Hai Yu, Jie Zeng, Vireak Thon, Yi Chen, Musleh M. Muthana, Peng G. Wang, Xi Chen β1–3-N-Acetylglucosaminyltransferases (β3GlcNAcTs) and β1–4-galactosyltransferases (β4GalTs) have been broadly used in enzymatic synthesis of N-acetyllactosamine (LacNAc)-containing oligosaccharides and glycoconjugates including poly-LacNAc, and lacto-N-neotetraose (LNnT) found in the milk of human and other mammals. In order to explore oligosaccharides and derivatives that can be synthesized by the combination of β3GlcNAcTs and β4GalTs, donor substrate specificity studies of two bacterial β3GlcNAcTs from Helicobacter pylori (Hpβ3GlcNAcT) and Neisseria meningitidis (NmLgtA), respectively, using a library of 39 sugar nucleotides were carried out. The two β3GlcNAcTs have complementary donor substrate promiscuity and 13 different trisaccharides were produced. They were used to investigate the acceptor substrate specificities of three β4GalTs from Neisseria meningitidis (NmLgtB), Helicobacter pylori (Hpβ4GalT), and bovine (Bβ4GalT), respectively. Ten of the 13 trisaccharides were shown to be tolerable acceptors for at least one of these β4GalTs. The application of NmLgtA in one-pot multienzyme (OPME) synthesis of two trisaccharides including GalNAcβ1–3Galβ1–4GlcβProN3 and Galβ1–3Galβ1–4Glc was demonstrated. The study provides important information for using these glycosyltransferases as powerful catalysts in enzymatic and chemoenzymatic syntheses of oligosaccharides and derivatives which can be useful probes and reagents. Graphical abstract image
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Development of a fluorescent cardiomyocyte specific binding probe ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Lara Pes, Young Kim, Ching-Hsuan Tung Cardiomyocytes are the major component of the heart. Their dysfunction or damage could lead to serious cardiovascular diseases, which have claimed numerous lives around the world. A molecule able to recognize cardiomyocytes would have significant value in diagnosis and treatment. Recently a novel peptide termed myocyte targeting peptide (MTP), with three residues of a non-natural amino acid biphenylalanine (Bip), showed good affinity to cardiomyocytes. Its selectivity towards cardiac tissues was concluded to be due to the ability of Bip to bind cardiac troponin I. With the aim of optimizing the affinity and the specificity towards cardiac myocytes and to better understand structure–activity relationship, a library of MTP derivatives was designed. Exploiting a fluorescent tag, the selectivity of the MTP analogs to myocardium over skeletal and stomach muscle tissues was assayed by fluorescence imaging. Among the tested sequences, the peptide probe Bip2, H-Lys(FITC)-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Gly-Ser-Gly-Ser-Bip-Bip-NH2, displayed the best selectivity for cardiomyocytes. Graphical abstract image
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Design and synthesis of small molecule-sulfotyrosine mimetics that inhibit HIV-1 entry ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Cajetan Dogo-Isonagie, Su-Lin Lee, Katheryn Lohith, Hongbing Liu, Sivakoteswara R. Mandadapu, Sabrina Lusvarghi, Robert D. O’Connor, Carole A. Bewley In the absence of a cure or vaccine for HIV/AIDS, small molecule inhibitors remain an attractive choice for antiviral therapeutics. Recent structural and functional studies of the HIV-1 surface envelope glycoprotein gp120 have revealed sites of vulnerability that can be targeted by small molecule and peptide inhibitors, thereby inhibiting HIV-1 infection. Here we describe a series of small molecule entry inhibitors that were designed to mimic the sulfated N-terminal peptide of the HIV-1 coreceptor CCR5. From a panel of hydrazonothiazolyl pyrazolinones, we demonstrate that compounds containing naphthyl di- and tri-sulfonic acids inhibit HIV-1 infection in single round infectivity assays with the disulfonic acids being the most potent. Molecular docking supports the observed structure activity relationship, and SPR confirmed binding to gp120. In infectivity assays treatment with a representative naphthyl disulfonate and a disulfated CCR5 N-terminus peptide results in competitive inhibition, with combination indices >2. In total this work shows that gp120 and HIV-1 infection can be inhibited by small molecules that mimic the function of, and are competitive with the natural sulfated CCR5 N-terminus. Graphical abstract image
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Design, synthesis of phenstatin/isocombretastatin-oxindole conjugates as antimitotic agents ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): G. Bharath Kumar, V. Lakshma Nayak, Ibrahim Bin Sayeed, Vangala Santhosh Reddy, Anver Basha Shaik, Rasala Mahesh, Mirza Feroz Baig, Mohd Adil Shareef, A. Ravikumar, Ahmed Kamal A series of phenstatin/isocombretastatin-oxindole conjugates was synthesized and tested for their cytotoxic activity against five human cancer cells such as prostate (DU-145), lung (A549), colon (HT-29), breast (MCF-7), liver (HepG2) cancer cells with IC50 values ranging from 0.049 to 38.90μM. Amongst them, two conjugates (5c and 5d) showed broad spectrum of antiproliferative efficacy on lung cancer cells with an IC50 value of 79nM and 93nM, respectively, whereas on colon cancer cells with an IC50 values 45nM and 49nM, respectively. In addition, cell cycle assay revealed that these conjugates (5c and 5d) arrest at the G2/M phase and leads to apoptotic cell death which was confirmed by Annexin V-FITC and mitochondrial membrane depolarization. Further, the tubulin polymerization assay analysis results suggest that these conjugates particularly 5c and 5d exhibit significant inhibitory effect on the tubulin assembly with an IC50 value of 1.23μM and 1.01μM, respectively. Molecular docking studies indicated that these compounds (5c and 5d) occupy the colchicine binding site of the tubulin. Graphical abstract image
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Novel tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one: Design, synthesis, model and use as hMAO-B inhibitors ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Rui Chen, Jie Xiao, Yong Ni, Han-Fei Xu, Min Zheng, Xu Tong, Tong-Tian Zhang, Chenzhong Liao, Wen-Jian Tang Based on our recently reported selective hMAO-A inhibitors, on which, the intramolecular cyclization led to a very interesting change of isoform selectivity. A series of selective hMAO-B inhibitors (3a–3u) with novel scaffold of tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one were designed and synthesized. Compound 3u (IC50 =221nM) exhibited the best inhibitory activity and isoform selectivity against hMAO-B, superior to selegiline (IC50 =321nM), which is a commercial selective hMAO-B inhibitor used to Parkinson’s disease. Modeling study indicated that the selectivity of our compounds to hMAO-B is determined by at least two residues, i.e., Ile 199 and Cys 172 (or corresponded Phe 208 and Asn 181 of hMAO-A). These data support further studies to assess rational design of more efficiently selective hMAO-B inhibitors. Graphical abstract image
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Synthesis, and docking studies of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Wufu Zhu, Wenhui Wang, Shan Xu, Jianqiang Wang, Qidong Tang, Chunjiang Wu, Yanfang Zhao, Pengwu Zheng Four series of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (14a–e, 15a–g, 16a–e and 17a–g) were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, PC-3 and MCF-7). Four selected compounds (15e, 16a–b and 17a) were further evaluated for the activity against c-Met kinase, HepG2 and Hela cell lines. Most of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 valuables in single-digit μM to nanomole range. Eleven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15e showed superior activity to Foretinib against A549, PC-3 and MCF-7 cell lines, with the IC50 values of 0.14±0.08μM, 0.24±0.07μM and 0.02±0.01μM, which were 4.6, 1.6 and 473.5 times more active than Foretinib (0.64±0.26μM, 0.39±0.11μM, 9.47±0.22μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that the replacement of phenylpicolinamide scaffold with phenylpyrimidine fragment of the target compounds was benefit for the activity. What’s more, the introduction of fluoro atom to the aminophenoxy part played no significant impact on the activity and any substituent group on aryl group is unfavourable for the activity. Graphical abstract image
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C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Zheng Liu, Jacob J. Swidorski, Beata Nowicka-Sans, Brian Terry, Tricia Protack, Zeyu Lin, Himadri Samanta, Sharon Zhang, Zhufang Li, Dawn D. Parker, Sandhya Rahematpura, Susan Jenkins, Brett R. Beno, Mark Krystal, Nicholas A. Meanwell, Ira B. Dicker, Alicia Regueiro-Ren A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3′3′-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies. Compound 9a exhibits comparable cell culture potency toward wt virus as 1 (WT EC50 =16nM for 9a compared to 10nM for 1). However, the potency of 9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to 1. Hence 9a, the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2nd generation MI. Graphical abstract image
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Investigation of 4-amino-5-alkynylpyrimidine-2(1H)-ones as anti-mycobacterial agents ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Gaurav Garg, Milind Pande, Ambika Agrawal, Jie Li, Rakesh Kumar In vitro anti-mycobacterial activities of novel 4-amino-5-alkynylpyrimidine-2(1H)-ones were investigated. 4-Amino-5-heptynylpyrimidine-2(1H)-one (3) and 4-amino-5-(2-phenylethynyl)pyrimidine-2(1H)-one (7) displayed potent in vitro activity against Mycobacterium bovis and Mycobacterium tuberculosis. Compounds 3 and 7 were also assessed for their in vivo activity in BALB/c mice infected with M. tuberculosis (H37Ra). Both compounds showed promising in vivo efficacy at a dose of 25mg/kg for 2weeks. Importantly, compounds 3 and 7 interacted synergistically with the front-line anti-tuberculosis drug isoniazid in vitro and in vivo. These results suggest that this class of compounds has strong anti-mycobacterial potential. Graphical abstract image
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Molecular simulation of cyclohexanyl nucleic acid (CNA) duplexes with CNA, DNA and RNA and CNA triloop and tetraloop hairpin structures ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Matheus Froeyen, Rania Abu el Asrar, Mikhail Abramov, Piet Herdewijn As part of a selection strategy for artificial nucleic acids (XNA) (to be considered as potential new information systems in vivo), we have carried out a modelling study on cyclohexanyl nucleic acids (CNA) duplexes and hairpins. CNA may form a duplex as well as hairpin structures, having the carbocyclic nucleosides in the 4C1 conformation (with equatorial basis). The geometry of ds CNA is close to that of a HNA:RNA duplex. We demonstrated that CNA triphosphates function as a substrate for polymerases. Modelling experiments indicate that the monomers are probably presented to the polymerase in the 1C4 conformation. Graphical abstract image
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Novel squaramides with in vitro liver stage antiplasmodial activity ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Carlos J.A. Ribeiro, Margarida Espadinha, Marta Machado, Jiri Gut, Lídia M. Gonçalves, Philip J. Rosenthal, Miguel Prudêncio, Rui Moreira, Maria M.M. Santos A structure–activity relationship study was performed with ten 8-aminoquinoline-squaramides compounds active against liver stage malaria parasites, using human hepatoma cells (Huh7) infected by Plasmodium berghei parasites. In addition, their blood-schizontocidal activity was assessed against chloroquine-resistant W2 strain Plasmodium falciparum. Compound 3 was 7.3-fold more potent than the positive control primaquine against liver-stage parasites, illustrating the importance of the squarate moiety to activity. Graphical abstract image
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Design, physico-chemical properties and biological evaluation of some new N-[(phenoxy)alkyl]- and N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols as anticonvulsant agents ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): A.M. Waszkielewicz, A. Gunia-Krzyżak, B. Powroźnik, K. Słoczyńska, E. Pękala, M. Walczak, M. Bednarski, E. Żesławska, W. Nitek, H. Marona A series of thirty N-(phenoxy)alkyl or N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols has been designed, synthesized and evaluated for anticonvulsant activity in MES, 6Hz test, and pilocarpine-induced status epilepticus. Among the title compounds, the most promising seems R-(−)-2N-{2-[2-(2,6-dimethylphenoxy)ethoxy]ethyl}aminopropan-1-ol hydrochloride (22a) with proved absolute configuration with X-ray analysis and enantiomeric purity. The compound is effective in MES test with ED50 =12.92mg/kg b.w. and its rotarod TD50 =33.26mg/kg b.w. The activity dose is also effective in a neurogenic pain model—the formalin test. Within high throughput profile assay, among eighty one targets, the strongest affinity of the compound is observed towards σ receptors and 5-HT transporter and the compound does not bind to hERG. It also does not exhibit mutagenic properties in the Vibrio harveyi test. Moreover, murine liver microsomal assay and pharmacokinetics profile (mice, iv, p.o., ip) indicate that the liver is the primary site of biotransformation of the compound, suggesting that both 22a and its metabolite(s) are active, compensating probably low bioavailability of the parent molecule. Graphical abstract image
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Discovery of novel N,N-3-phenyl-3-benzylaminopropionanilides as potent inhibitors of cholesteryl ester transfer protein in vivo ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Honglei Xie, Yiqun Li, Changlin Bai, Ruifeng Wang, Chunchi Liu, Chenzhou Hao, Bin Lin, Maosheng Cheng, Dongmei Zhao Epidemiological studies have identified that the risk of cardiovascular events increases due to the decreased levels of high density lipoprotein-cholesterol and the elevated levels of low density lipoprotein-cholesterol. Herein, we report a novel series of N,N-3-phenyl-3-benzylaminopropionanilide derivatives, which were identified as potent cholesteryl ester transfer protein (CETP) inhibitor. The initial lead compound L10 (IC50 8.06μM) was found by pharmacophore-based virtual screening (Dong-Mei Zhao et al., Chin. Chem. Lett. 2014, 25, 299). After systematic structure variation and biological testing against CETP, two different series were identified as scaffolds for potent CETP inhibitors. One is N,N-3-phenyl-3-benzylaminopropanamide derivatives, which were investigated in our previous paper (Bioorg. Med. Chem. 2015, doi: http://dx.doi.org/10.1016/j.bmc.2015.12.010). The most potent compound HL16 in that series has the IC50 of 0.69μM. The other series is N,N-3-phenyl-3-benzylaminopropionanilide derivatives, which was investigated in current study. Further optimization of the structure–activity relationship (SAR) resulted in H16 (IC50 0.15μM), which was discovered as a potent CETP inhibitor in vitro by BODIPY-CE fluorescence assay. In addition, the results of pharmacodynamics studies showed that H16 exhibited both favorable HDL-C enhancement and LDL-C reduction in vivo by hamster. It also has an excellent stability in rat liver microsomal. Graphical abstract image
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Design and evaluation of novel glutaminase inhibitors ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Lee A. McDermott, Prema Iyer, Larry Vernetti, Shawn Rimer, Jingran Sun, Melissa Boby, Tianyi Yang, Michael Fioravanti, Jason O’Neill, Liwei Wang, Dylan Drakes, William Katt, Qingqiu Huang, Richard Cerione A novel set of GAC (kidney glutaminase isoform C) inhibitors able to inhibit the enzymatic activity of GAC and the growth of the triple negative MDA-MB-231 breast cancer cells with low nanomolar potency is described. Compounds in this series have a reduced number of rotatable bonds, improved C log Ps, microsomal stability and ligand efficiency when compared to the leading GAC inhibitors BPTES and CB-839. Property improvements were achieved by the replacement of the flexible n-diethylthio or the n-butyl moiety present in the leading inhibitors by heteroatom substituted heterocycloalkanes. Graphical abstract image
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Quinoxalinone (Part II). Discovery of (Z)-3-(2-(pyridin-4-yl)vinyl)quinoxalinone derivates as potent VEGFR-2 kinase inhibitors ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Leilei Shi, Jianfeng Zhou, Jifeng Wu, Junya Cao, Yuemao Shen, Hua Zhou, Xun Li Inhibition of VEGFR-2 kinase has been highlighted as one of the well-defined strategies to suppress tumor growth via blockade of angiogenesis. Guided by the principles of bioisosteric replacement and pharmacophoric fragment migration, a series of novel quinoxalinone derivates were designed, synthesized and evaluated for their VEGFR-2 inhibitory potencies. Among them, compounds 7c, 8b, 8c, 8e and 10b displayed antiangiogenic abilities via the in vitro tube formation assay (cellular level) and ex vivo rat aortic ring assay (tissue level) at a low concentration (0.1μM). By means of in vivo zebrafish embryo model, two (Z)-3-(2-(pyridin-4-yl)vinyl)quinoxalinone derivates 8c and 8e showed significant antiangiogenesis effects, suggesting they have potentials to be developed into antiangiogenesis agents via further structural optimization. Moreover, these two compounds also demonstrated potent inhibition toward VEGFR-2 and B-raf kinases in a low concentration (1μM). A possible interpretation of our evaluation result has been presented by a molecular docking study by docking representative compound 8c with VEGFR-2. Graphical abstract image
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Design, synthesis, and evaluation of 2-piperidone derivatives for the inhibition of β-amyloid aggregation and inflammation mediated neurotoxicity ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Lei Li, Ming Chen, Feng-Chao Jiang A series of novel multipotent 2-piperidone derivatives were designed, synthesized and biologically evaluated as chemical agents for the treatment of Alzheimer’s disease (AD). The results showed that most of the target compounds displayed significant potency to inhibit Aβ1–42 self-aggregation. Among them, compound 7q exhibited the best inhibition of Aβ1–42 self-aggregation (59.11% at 20μM) in a concentration-dependent manner. Additionally, the compounds 6b, 7p and 7q as representatives were found to present anti-inflammation properties in lipopolysaccharide (LPS)-induced microglial BV-2 cells. They could effectively suppress the production of pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6. Meanwhile, compound 7q could prevent the neuronal cell SH-SY5Y death by LPS-stimulated microglia cell activation mediated neurotoxicity. The molecular modeling studies demonstrated that compounds matched the pharmacophore well and had good predicted physicochemical properties and estimated IC50 values. Moreover, compound 7q exerted a good binding to the active site of myeloid differentiation factor 88 (MyD88) through the docking analysis and could interfere with its homodimerization or heterodimerization. Consequently, these compounds emerged as promising candidates for further development of novel multifunctional agents for AD treatment. Graphical abstract image
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Design and synthesis of thiourea derivatives with sulfur-containing heterocyclic scaffolds as potential tyrosinase inhibitors ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Pingping Liu, Chen Shu, Lujie Liu, Qingchun Huang, Yanqing Peng Tyrosinase is a key enzyme during the production of melanins in plants and animals. A class of novel N-aryl-N′-substituted phenylthiourea derivatives (3a–i, 6a–k) were designed, synthesized and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed some 4,5,6,7-tetrahydro-2-[[(phenylamino)thioxomethyl]amino]-benzo[b]thiophene-3-carboxylic acid derivatives (3a–i) exhibited moderate inhibitory potency on diphenolase activity of tyrosinase. When the scaffold of 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid was replaced with 2-(1,3,4-thiadiazol-2-yl)thio acetic acid, the inhibitory activity of compounds (6a–k) against tyrosinase was improved obviously; especially, the inhibitory activity of compound 6h (IC50 =6.13μM) is significantly higher than kojic acid (IC50 =33.3μM). Moreover, the analysis on inhibition mechanism revealed that compound 6h might plays the role as a noncompetitive inhibitor. Graphical abstract image
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Exploration of 2-benzylbenzimidazole scaffold as novel inhibitor of NF-κB ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): PullaReddy Boggu, Eeda Venkateswararao, Manoj Manickam, Dajin Kwak, Youngsoo Kim, Sang-Hun Jung For finding the novel inhibitor of nuclear factor κB activity, a series of benzimidazole derivatives were rationally designed, synthesized and systematically studied for their in vitro activities against LPS induced NF-κB inhibition in RAW 264.7 cells using the SEAP assay based on the flexible chalcone JSH ((E)-1-(2-hydroxy-6-(isopentyloxy)phenyl)-3-(4-hydroxy phenyl)prop-2-en-1-one) which was previously reported. Although most of the benzimidazole derivatives showed strong inhibitory activity in low micromolar potency, 2-(4-methoxybenzyl)-1H-benzo[d]imidazole (3m; IC50 =1.7μM) and 2-(2-methoxybenzyl)-1H-benzo[d]imidazole (3n; IC50 =2.4μM) showed the best inhibition. The structure activity relationship revealed that 2-benzylbenzimidazole scaffold with hydrogen bonding acceptor on phenyl ring appears as a pharmacophore. Graphical abstract image
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Rational design, synthesis and biological evaluation of 1,3,4-oxadiazole pyrimidine derivatives as novel pyruvate dehydrogenase complex E1 inhibitors ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Haifeng He, Wei Wang, Yuan Zhou, Qin Xia, Yanliang Ren, Jiangtao Feng, Hao Peng, Hongwu He, Lingling Feng On the basis of previous study on 2-methylpyrimidine-4-ylamine derivatives I, further synthetic optimization was done to find potent PDHc-E1 inhibitors with antibacterial activity. Three series of novel pyrimidine derivatives 6, 11 and 14 were designed and synthesized as potential Escherichia coli PDHc-E1 inhibitors by introducing 1,3,4-oxadiazole-thioether, 2,4-disubstituted-1,3-thiazole or 1,2,4-triazol-4-amine-thioether moiety into lead structure I, respectively. Most of 6, 11 and 14 exhibited good inhibitory activity against E. coli PHDc-E1 (IC50 0.97–19.21μM) and obvious inhibitory activity against cyanobacteria (EC50 0.83–9.86μM). Their inhibitory activities were much higher than that of lead structure I. 11 showed more potent inhibitory activity against both E. coli PDHc-E1 (IC50 <6.62μM) and cyanobacteria (EC50 <1.63μM) than that of 6, 14 or lead compound I. The most effective compound 11d with good enzyme-selectivity exhibited most powerful inhibitory potency against E. coli PDHc-E1 (IC50 =0.97μM) and cyanobacteria (EC50 =0.83μM). The possible interactions of the important residues of PDHc-E1 with title compounds were studied by molecular docking, site-directed mutagenesis, and enzymatic assays. The results indicated that 11d had more potent inhibitory activity than that of 14d or I due to its 1,3,4-oxadiazole moiety with more binding position and stronger interaction with Lsy392 and His106 at active site of E. coli PDHc-E1. Graphical abstract image
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Synthesis and biological evaluation of quinoline derivatives as potential anti-prostate cancer agents and Pim-1 kinase inhibitors ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Kun Li, Ying Li, Di Zhou, Yinbo Fan, Hongye Guo, Tianyi Ma, Jiachen Wen, Dan Liu, Linxiang Zhao In this work, a series of quinoline derivatives were designed and synthesized as antitumor agents. Most quinolines showed potent anti-proliferative activity against human prostatic cancer PC-3 cell line. Among which, 9d, 9f and 9g were the most effective compounds with GI50 values of 2.60, 2.81 and 1.29μM, respectively. Structure–activity relationship analysis indicated that the secondary amine linked quinoline and pyridine ring played an important role in the anti-proliferative effects. Mechanistic studies revealed that 9g was a potential Pim-1 kinase inhibitor with abilities of cell cycle arrest and apoptosis induction. Considering of the increased activity of Pim-1 in prostate cancer, such compounds have potential to be developed as anti-prostate cancer agents. Graphical abstract image
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Design, synthesis, topoisomerase I & II inhibitory activity, antiproliferative activity, and structure–activity relationship study of pyrazoline derivatives: An ATP-competitive human topoisomerase IIα catalytic inhibitor ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Pervez Ahmad, Hyunjung Woo, Kyu-Yeon Jun, Adnan A. Kadi, Hatem A. Abdel-Aziz, Youngjoo Kwon, A.F.M. Motiur Rahman A series of pyrazoline derivatives (5) were synthesized in 92–96% yields from chalcones (3) and hydrazides (4). Subsequently, topo-I and IIα-mediated relaxation and antiproliferative activity assays were evaluated for 5. Among the tested compounds, 5h had a very strong topo-I activity of 97% (Camptothecin, 74%) at concentration of 100μM. Nevertheless, all the compounds 5a–5i showed significant topo II inhibitory activity in the range of 90–94% (Etoposide, 96%) at the same concentration. Cytotoxic potential of these compounds was tested in a panel of three human tumor cell lines, HCT15, BT474 and T47D. All the compounds showed strong activity against HCT15 cell line with IC50 at the range of 1.9–10.4μM (Adriamycin, 23.0; Etoposide, 6.9; and Camptothecin, 7.1μM). Moreover, compounds 5c, 5f and 5i were observed to have strong antiproliferative activity against BT474 cell lines. Since, compound 5d showed antiproliferative activity at a very low IC50 thus 5d was then selected to study on their mode of action with diverse methods of ATP competition assay, ATPase assay and DNA-topo IIα cleavable complex assay and the results revealed that it functioned as a ATP-competitive human topoisomerase IIα catalytic inhibitor. Further evaluation of endogenous topo-mediated DNA relaxation in cells has been conducted to find that, 5d inhibited endogenous topo-mediated pBR322 plasmid relaxation is more efficient (78.0±4.7% at 50μM) than Etoposide (36.0±1.7% at 50μM). Graphical abstract image
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Thiadiazole derivatives as New Class of β-glucuronidase inhibitors ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Uzma Salar, Muhammad Taha, Nor Hadiani Ismail, Khalid Mohammed Khan, Syahrul Imran, Shahnaz Perveen, Abdul Wadood, Muhammad Riaz Thiadiazole derivatives 1–24 were synthesized via a single step reaction and screened for in vitro β-glucuronidase inhibitory activity. All the synthetic compounds displayed good inhibitory activity in the range of IC50 =2.16±0.01–58.06±1.60μM as compare to standard d-saccharic acid 1,4-lactone (IC50 =48.4±1.25μM). Molecular docking study was conducted in order to establish the structure–activity relationship (SAR) which demonstrated that thiadiazole as well as both aryl moieties (aryl and N-aryl) involved to exhibit the inhibitory potential. All the synthetic compounds were characterized by spectroscopic techniques 1H, 13C NMR, and EIMS. Graphical abstract image
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Discovery of new low-molecular-weight p53–Mdmx disruptors and their anti-cancer activities ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Shinichi Uesato, Yoshihiro Matsuura, Saki Matsue, Takaaki Sumiyoshi, Yoshiyuki Hirata, Suzuho Takemoto, Yasuyuki Kawaratani, Yusuke Yamai, Kyoji Ishida, Tsutomu Sasaki, Masato Enari Although several p53–Mdm2-binding disruptors have been identified to date, few studies have been published on p53–Mdmx-interaction inhibitors. In the present study, we demonstrated that o-aminothiophenol derivatives with molecular weights of 200–300 selectively inhibited the p53–Mdmx interaction. S-2-Isobutyramidophenyl 2-methylpropanethioate (K-178) (1c) activated p53, up-regulated the expression of its downstream genes such as p21 and Mdm2, and preferentially inhibited the growth of cancer cells with wild-type p53 over those with mutant p53. Furthermore, we found that the S-isobutyryl-deprotected forms 1b and 3b of 1c and S-2-benzamidophenyl 2-methylpropanethioate (K-181) (3c) preferentially inhibited the p53–Mdmx interaction over the p53–Mdm2 interaction, respectively, by using a Flag-p53 and glutathione S-transferase (GST)-fused protein complex (Mdm2, Mdmx, DAPK1, or PPID). In addition, the interaction of p53 with Mdmx was lost by replacing a sulfur atom with an oxygen atom in 1b and 1c. These results suggest that sulfides such as 1b, 3b, 4b, and 5b interfere with the binding of p53–Mdmx, resulting in the dissociation of the two proteins. Furthermore, the results of oral administration experiments using xenografts in nude mice indicated that 1c reduced the volume of tumor masses to 49.0% and 36.6% that of the control at 100mg/kg and 150mg/kg, respectively, in 40days. Graphical abstract image
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Evaluation of the anti-inflammatory action of curcumin analog (DM1): Effect on iNOS and COX-2 gene expression and autophagy pathways ()
Publication date: 15 April 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 8 Author(s): Niraldo Paulino, Amarilis Scremin Paulino, Susana N. Diniz, Sergio de Mendonça, Ivair D. Gonçalves, Fernanda Faião Flores, Reginaldo Pereira Santos, Carina Rodrigues, Paulo Celso Pardi, José Agustin Quincoces Suarez This work describes the anti-inflammatory effect of the curcumin-analog compound, sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate (DM1), and shows that DM1 modulates iNOS and COX-2 gene expression in cultured RAW 264.7 cells and induces autophagy on human melanoma cell line A375. Graphical abstract image
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2-Arylacetamido-4-Phenylamino-5-Substituted Pyridazinones as Formyl Peptide Receptors Agonists ()
Publication date: Available online 8 April 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Claudia Vergelli, Igor A. Schepetkin, Giovanna Ciciani, Agostino Cilibrizzi, Letizia Crocetti, Maria Paola Giovannoni, Gabriella Guerrini, Antonella Iacovone, Liliya N. Kirpotina, Andrei I. Khlebnikov, Richard D. Ye, Mark T. Quinn N-Formyl peptide receptors (FPRs: FPR1, FPR2, and FPR3) are G protein-coupled receptors that play key roles in modulating immune cells. FPRs represent potentially important therapeutic targets for the development of drugs that could enhance endogenous anti-inflammation systems associated with various pathologies, thereby reducing the progression of inflammatory conditions. Previously, we identified 2-arylacetamide pyridazin-3(2H)-ones as FPR1- or FPR2-selective agonists, as well as a large number of FPR1/FPR2-dual agonists and several mixed-agonists for the three FPR isoforms. Here, we report a new series of 2-arylacetamido-4-aniline pyridazin-3(2H)-ones substituted in position 5 as a further development of these FPR agonists. Chemical manipulation presented in this work resulted in mixed FPR agonists 8a, 13a and 27b, which had EC50 values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC50 = 45 nM), while 13a and 27b showed a moderate preference for FPR2 (EC50 = 35 and 61 nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling. Graphical abstract image
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Discovery of pyrazinone based compounds that potently inhibit the drug-resistant enzyme variant R155K of the hepatitis C virus NS3 protease ()
Publication date: Available online 8 April 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Anna Karin Belfrage, Eldar Abdurakhmanov, Eva Åkerblom, Peter Brandt, Anna Oshalim, Johan Gising, Anna Skogh, U. Helena Danielson, Anja Sandström Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminal. Biochemical evaluation was performed against genotype 1a, both the wild-type and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance. Graphical abstract image
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Biological evaluation of synthetic α, β-unsaturatedcarbonylbased cyclohexanone derivatives as neuroprotective novel inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation ()
Publication date: Available online 8 April 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Gao-Feng Zha, Cheng-Pan Zhang, Hua-Li Qin, Ibrahim Jantan, Muhammad Sher, Muhammad Wahab Amjad, Muhammad Ajaz Hussain, Zahid Hussain, Syed Nasir Abbas Bukhari A series of new α, β-unsaturatedcarbonyl-based cyclohexanone derivatives was synthesized by simple condensation method and all compounds were characterized by using various spectroscopic techniques. New compounds were evaluated for their effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds were also screened for in vitro cytotoxicity and for inhibitory activity for self-induced Aβ1–42 aggregation. The effect of these compounds against amyloid β-induced cytotoxicity was also investigated. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against AChE and self-induced Aβ1–42 aggregation. The compound 3o exhibited best AChE (IC50 = 0.037 μM) inhibitory potential. Furthermore, compound 3o disassembled the Aβ fibrils produced by self-induced Aβ aggregation by 76.6%. Compounds containing N-methyl-4-piperidone linker, showed high acetylcholinesterase and self-induced Aβ aggregation inhibitory activities as compared to reference drug donepezil. The pre-treatment of cells with synthetic compounds protected them against Aβ-induced cell death by up to 92%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment and our study suggest the cyclohexanone derivatives as promising new inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases. Graphical abstract image
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Engineered production of cancer targeting peptide (CTP)-containing C-1027 in Streptomyces globisporus and biological evaluation ()
Publication date: Available online 8 April 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Wenli Li, Xiuling Li, Tingting Huang, Qihui Teng, Ivana Crnovcic, Christoph Rader, Ben Shen Conjugation of cancer targeting peptides (CTPs) with small molecular therapeutics has emerged as a promising strategy to deliver potent (but typically nonspecific) cytotoxic agents selectively to cancer cells. Here we report the engineered production of a CTP (NGR)-containing C-1027 and evaluation of its activity against selected cancer cell lines. C-1027 is an enediyne chromoprotein produced by Streptomyces globisporus, consisting of an apo-protein (CagA) and an enediyne chromophore (C-1027). NGR is a CTP that targets CD13 in tumor vasculature. S. globisporus SB1026, a recombinant strain engineered to encode CagA with the NGR sequence fused at its C-terminus, directly produces the NGR-containing C-1027 that is equally active as the native C-1027. Our results demonstrate the feasibility to produce CTP-containing enediyne chromoproteins by metabolic pathway engineering and microbial fermentation and will inspire efforts to engineer other CTP-containing drug binding proteins for targeted delivery. Graphical abstract image
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Design, discovery, modelling, synthesis, and biological evaluation of novel and small, low toxicity s-triazine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors ()
Publication date: Available online 8 April 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Birgit Viira, Anastasia Selyutina, Alfonso T. García-Sosa, Maarit Karonen, Jari Sinkkonen, Andres Merits, Uko Maran A set of top-ranked compounds from a multi-objective in silico screen was experimentally tested for toxicity and the ability to inhibit the activity of HIV-1 reverse transcriptase (RT) in cell-free assay and in cell-based assay using HIV-1 based virus-like particles. Detailed analysis of a commercial sample that indicated specific inhibition of HIV-1 reverse transcription revealed that a minor component that was structurally similar to that of the main compound was responsible for the strongest inhibition. As a result, novel s-triazine derivatives were proposed, modelled, discovered, and synthesised, and their antiviral activity and cellular toxicity were tested. Compounds 18a and 18b were found to be efficient HIV-1 RT inhibitors, with an IC50 of 5.6 ± 1.1 μM and 0.16 ± 0.05 μM in a cell-based assay using infectious HIV-1, respectively. Compound 18b also had no detectable toxicity for different human cell lines. Their binding mode and interactions with the RT suggest that there was strong and adaptable binding in a tight (NNRTI) hydrophobic pocket. In summary, this iterative study produced structural clues and led to a group of non-toxic, novel compounds to inhibit HIV-RT with up to nanomolar potency. Graphical abstract image
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Sulfone-stabilized carbanions for the reversible covalent capture of a posttranslationally-generated cysteine oxoform found in protein tyrosine phosphatase 1B (PTP1B) ()
Publication date: Available online 8 April 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Zachary D. Parsons, Kasi Viswanatharaju Ruddraraju, Nicholas Santo, Kent S. Gates Redox regulation of protein tyrosine phosphatase 1B (PTP1B) involves oxidative conversion of the active site cysteine thiolate into an electrophilic sulfenyl amide residue. Reduction of the sulfenyl amide by biological thiols regenerates the native cysteine residue. Here we explored fundamental chemical reactions that may enable covalent capture of the sulfenyl amide residue in oxidized PTP1B. Various sulfone-containing carbon acids were found to react readily with a model peptide sulfenyl amide via attack of the sulfonyl carbanion on the electrophilic sulfur center in the sulfenyl amide. Both the products and the rates of these reactions were characterized. The results suggest that capture of a peptide sulfenyl amide residue by sulfone-stabilized carbanions can slow, but not completely prevent, thiol-mediated generation of the corresponding cysteine-containing peptide. Sulfone-containing carbon acids may be useful components in the construction of agents that knock down PTP1B activity in cells via transient covalent capture of the sulfenyl amide oxoform generated during insulin signaling processes. Graphical abstract image
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Synthesis and evaluation of 4-(2-hydroxypropyl)piperazin-1-yl) derivatives as Hsp90 inhibitors ()
Publication date: Available online 7 April 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Bahidja Cherfaoui, Tian-kun Guo, Hao Peng Sun, Wei-Lin Cheng, Fang Liu, Fen Jiang, Xiao-Li Xu, Qi-Dong You We previously reported 4-(3-((6-bromonaphthalen-2-yl) oxy)-2-hydroxypropyl)-N,N-dimethylpiperazine-1-sulfonamide (1) as heat shock protein 90 inhibitor with moderate activity. In our ongoing efforts for the discovery of Hsp90 inhibitors, we undertake structural investigations on this class of inhibitors. Series of the titled compound were designed, synthesized and evaluated. We have found that compounds with a hydroxyl group at C-4 of the aryl ring on the piperazine moiety possess Hsp90 inhibition properties. Compound 6f with improved activity could be further developed and optimized as Hsp90 inhibitor. Graphical abstract image
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Amine-Free Melanin-Concentrating Hormone Receptor 1 Antagonists: Novel Non-Basic 1-(2H-indazole-5-yl)pyridin-2(1H)-one Derivatives and Mitigation of Mutagenicity in Ames Test ()
Publication date: Available online 7 April 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Hideyuki Igawa, Masashi Takahashi, Minoru Ikoma, Hiromi Kaku, Keiko Kakegawa, Asato Kina, Jumpei Aida, Shoki Okuda, Yayoi Kawata, Toshihiro Noguchi, Natsu Hotta, Syunsuke Yamamoto, Masaharu Nakayama, Yasutaka Nagisa, Shizuo Kasai, Tsuyoshi Maekawa To develop non-basic melanin-concentrating hormone receptor 1 (MCHR1) antagonists with a high probability of target selectivity and therapeutic window, we explored neutral bicyclic motifs that could replace the previously reported imidazo[1,2-a]pyridine or 1H-benzimidazole motif. The results indicated that the binding affinity of a chemically neutral 2H-indazole derivative 8a with MCHR1 (hMCHR1: IC50 = 35 nM) was comparable to that of the imidazopyridine and benzimidazole derivatives (1 and 2, respectively) reported so far. However, 8a was positive in the Ames test using TA1537 in S9− condition. Based on a putative intercalation of 8a with DNA, we introduced a sterically-hindering cyclopropyl group on the indazole ring to decrease planarity, which led to the discovery of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-{[5-(trifluoromethyl)thiophen-3-yl]methoxy}pyridin-2(1H)-one 8l without mutagenicity in TA1537. Compound 8l exerted significant antiobesity effects in diet-induced obese F344 rats and exhibited promising safety profile. Graphical abstract image
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Screening and target identification of bioactive compounds that modulate cell migration and autophagy ()
Publication date: Available online 7 April 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Etsu Tashiro, Masaya Imoto Cell migration is a fundamental step for embryonic development, wound repair, immune responses, and tumor cell invasion and metastasis. It is well known that protrusive structures, namely filopodia and lamellipodia, can be observed at the leading edge of migrating cells. The formation of these structures is necessary for cell migration; however, the molecular mechanisms behind the formation of these structures remain largely unclear. Therefore, bioactive compounds that modulate protrusive structures are extremely powerful tools for studying the mechanisms behind the formation of these structures and subsequent cell migration. Therefore, we have screened for bioactive compounds that inhibit the formation of filopodia, lamellipodia, or cell migration from natural products, and attempted to identify the target molecules of our isolated compounds. Additionally, autophagy is a bulk, non-specific protein degradation system that is involved in the pathogenesis of cancer and neurodegenerative disorders. Recent extensive studies have revealed the molecular mechanisms of autophagy, however, they also remain largely unclear. Thus, we also have screened for bioactive compounds that modulate autophagy, and identified the target molecules. In the present article, we introduce the phenotypic screening system and target identification of four bioactive compounds. Graphical abstract image
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Amine-Free Melanin-concentrating Hormone Receptor 1 Antagonists: Novel 1-(1H-benzimidazol-6-yl)pyridin-2(1H)-one Derivatives and Design to Avoid CYP3A4 Time-Dependent Inhibition ()
Publication date: Available online 6 April 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Hideyuki Igawa, Masashi Takahashi, Mikio Shirasaki, Keiko Kakegawa, Asato Kina, Minoru Ikoma, Jumpei Aida, Tsuneo Yasuma, Shoki Okuda, Yayoi Kawata, Toshihiro Noguchi, Syunsuke Yamamoto, Yasushi Fujioka, Mrinalkanti Kundu, Uttam Khamrai, Masaharu Nakayama, Yasutaka Nagisa, Shizuo Kasai, Tsuyoshi Maekawa Melanin-concentrating hormone (MCH) is an attractive target for antiobesity agents, and numerous drug discovery programs are dedicated to finding small-molecule MCH receptor 1 (MCHR1) antagonists. We recently reported novel pyridine-2(1H)-ones as aliphatic amine-free MCHR1 antagonists that structurally featured an imidazo[1,2-a]pyridine-based bicyclic motif. To investigate imidazopyridine variants with lower basicity and less potential to inhibit cytochrome P450 3A4 (CYP3A4), we designed pyridine-2(1H)-ones bearing various less basic bicyclic motifs. Among these, a lead compound 6a bearing a 1H-benzimidazole motif showed comparable binding affinity to MCHR1 to the corresponding imidazopyridine derivative 1. Optimization of 6a afforded a series of potent thiophene derivatives (6q–u); however, most of these were found to cause time-dependent inhibition (TDI) of CYP3A4. As bioactivation of thiophenes to form sulfoxide or epoxide species was considered to be a major cause of CYP3A4 TDI, we introduced electron withdrawing groups on the thiophene and found that a CF3 group on the ring or a Cl adjacent to the sulfur atom helped prevent CYP3A4 TDI. Consequently, 4-[(5-chlorothiophen-2-yl)methoxy]-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (6s) was identified as a potent MCHR1 antagonist without the risk of CYP3A4 TDI, which exhibited a promising safety profile including low CYP3A4 inhibition and exerted significant antiobesity effects in diet-induced obese F344 rats. Graphical abstract image
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Characterization and in vitro activity of a branched peptide boronic acid that interacts with HIV-1 RRE RNA ()
Publication date: Available online 5 April 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Jessica E. Wynn, Wenyu Zhang, Denis M. Tebit, Laurie R. Gray, Marie-Louise Hammarskjold, David Rekosh, Webster L. Santos A branched peptide containing multiple boronic acids was found to bind RRE IIB selectively and inhibit HIV-1 p24 capsid production in a dose-dependent manner. Structure-activity relationship studies revealed that branching in the peptide is crucial for the low micromolar binding towards RRE IIB, and that the peptide demonstrates selectivity towards RRE IIB in the presence of tRNA. Footprinting studies suggest a binding site on the upper stem and internal loop region of the RNA, which induces enzymatic cleavage of the internal loops of RRE IIB upon binding. Graphical abstract image
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Synthesis and evaluation of 4-hydroxyl aurone derivatives as multifunctional agents for the treatment of Alzheimer’s disease ()
Publication date: Available online 5 April 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Yan Li, Xiaoming Qiang, Li Luo, Yuxing Li, Ganyuan Xiao, Zhenghuai Tan, Yong Deng A series of 4-hydroxyl aurone derivatives were designed synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease. The results demonstrated that most of the derivatives exhibited good multifunctional properties. Among them, compound 14e displayed good inhibitory activities of self- and Cu2+-induced Aβ 1-42 aggregation with 99.2% and 84.0% at 25 μM respectively, and high antioxidant activity with a value 1.90-fold of Trolox. In addition, 14e also showed remarkable inhibitory activities of both monoamine oxidase A and B with IC50 values of 0.271 μM and 0.393 μM respectively. However the 6-methoxyl aurones 15a-c revealed excellent selectivity toward MAO-B. Furthermore, the representative compounds 14e and 15b displayed good metal-chelating abilities and blood-brain barrier (BBB) permeabilities in vitro. Graphical abstract image
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1,6-Bis[(benzyloxy)methyl]uracil derivatives – novel antivirals with activity against HIV-1 and influenza H1N1 virus ()
Publication date: Available online 5 April 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Alexander N. Geisman, Vladimir T. Valuev-Elliston, Alexander A. Ozerov, Anastasia L. Khandazhinskaya, Alexander O. Chizhov, Sergey N. Kochetkov, Christophe Pannecouque, Lieve Naesens, Katherine L. Seley-Radtke, Mikhail S. Novikov A series of 1,6-bis[(benzyloxy)methyl]uracil derivatives combining structural features of both diphenyl ether and pyridone types of NNRTIs were synthesized. Target compounds were found to inhibit HIV-1 reverse transcriptase at micro- and submicromolar levels of concentrations and exhibited anti-HIV-1 activity in MT-4 cell culture, demonstrating resistance profile similar to first generation NNRTIs. The synthesized compounds also showed profound activity against influenza virus (H1N1) in MDCK cell culture without detectable cytotoxicity. The lead compound of this assay appeared to exceed rimantadine, amantadine, ribavirine and oseltamivir carboxylate in activity. The mechanism of action of 1,6-bis[(benzyloxy)methyl]uracils against influenza virus is currently under investigation. Graphical abstract image
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Discovery and optimization of 1,7-disubstituted-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-ones as potent and selective PKCθ inhibitors ()
Publication date: Available online 4 April 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Taisuke Katoh, Takafumi Takai, Takafumi Yukawa, Tetsuya Tsukamoto, Etsurou Watanabe, Hideyuki Mototani, Takeo Arita, Hiroki Hayashi, Hideyuki Nakagawa, Michael Klein, Hua Zou, Bi-Ching Sang, Gyorgy Snell, Yoshihisa Nakada A high-throughput screening campaign helped us to identify an initial lead compound (1) as a protein kinase C–θ (PKCθ) inhibitor. Using the docking model of compound 1 bound to PKCθ as a model, structure-based drug design was employed and two regions were identified that could be explored for further optimization, i.e., (a) a hydrophilic region around Thr442, unique to PKC family, in the inner part of the hinge region, and (b) a lipophilic region at the forefront of the ethyl moiety. Optimization of the hinge binder led us to find 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one as a potent and selective hinge binder, which resulted in the discovery of compound 5. Filling the lipophilic region with a suitable lipophilic substituent boosted PKCθ inhibitory activity and led to the identification of compound 10. The co-crystal structure of compound 10 bound to PKCθ confirmed that both the hydrophilic and lipophilic regions were fully utilized. Further optimization of compound 10 led us to compound 14, which demonstrated an improved pharmacokinetic profile and inhibition of IL-2 production in a mouse. Graphical abstract image Highlights
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Structure-Activity Relationship of Lipid Core Peptide-based Group A Streptococcus Vaccine Candidates ()
Publication date: Available online 2 April 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Amy Chan, Waleed M. Hussein, Khairunnisa Abdul Ghaffar, Nirmal Marasini, Ahmed Mostafa, Sharareh Eskandari, Michael R. Batzloff, Michael F. Good, Mariusz Skwarczynski, Istvan Toth Infection with Group A Streptococcus (GAS) can result in a range of different illnesses, some of which are fatal. Currently, our efforts to develop a vaccine against GAS focuses on the lipid core peptide (LCP) system, a subunit vaccine containing a lipoamino acid (LAA) moiety which allows the stimulation of systemic antibody activity. In the present study, a peptide (J14) representing the B-cell epitope from the GAS M protein was incorporated alongside a universal T-helper epitope (P25) in four LCP constructs of different spatial orientation or LAA lengths. Through structure-activity studies, it was discovered that while the alteration of the LCP orientation had a weaker effect on immunostimulation, increasing the LAA side chain length within the construct increased antibody responses in murine models. Furthermore, the mice immunised with the lead LCP construct were also able to maintain antibody activity throughout the course of five months. These findings highlight the importance of LAA moieties in the development of intranasal peptide vaccines and confirmed that its side chain length has an effect on the immunogenicity of the structure. Graphical abstract image
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