Archiv der Pharmazie

Synthesis and Evaluation of Thiazolidine Amide and N-Thiazolyl Amide Fluoroquinolone Derivatives ()
In an effort to develop new fluoroquinolones, we synthesized eight compounds and tested them against a panel of bacteria. The design of these compounds was guided by the introduction of the isothiazoloquinolone motif. The three most active compounds in this series, 8–10, demonstrated good antibacterial activity against methicillin-sensitive Staphylococcus aureus and healthcare-acquired methicillin-resistant Staphylococcus aureus (MIC 0.62–6.3 µg/mL). Further, when these three active compounds were tested for their inhibitory effects on bacterial enzymes, compound 9 was the most effective agent exhibiting IC50 values of 33.9 and 116.5 μM in the S. aureus deoxyribonucleic acid (DNA) gyrase supercoiling and topoisomerase IV decatenation assays, respectively. A series of non-carboxylic acid fluoroquinolone analogs containing thiazolidine and N-thiazolyl amides were synthesized. All compounds were evaluated for their in vitro minimum inhibitory concentrations against clinically relevant bacteria. In addition, the three most active compounds were tested for their enzyme-inhibitory activity against Staphylococcus aureus DNA gyrase and topoisomerase IV.
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Evaluation of Biological Activity and Computer-Aided Design of New Soft Glucocorticoids ()
Soft glucocorticoids are compounds that are biotransformed to inactive and non-toxic metabolites and have fewer side effects than traditional glucocorticoids. A new class of 17β-carboxamide steroids has been recently introduced by our group. In this study, local anti-inflammatory activity of these derivatives was evaluated by use of the croton oil-induced ear edema test. Glucocorticoids with the highest maximal edema inhibition (MEI) were pointed out, and the systemic side effects of those with the lowest EC50 values were significantly lower in comparison to dexamethasone. A 3D-QSAR model was created and employed for the design of 27 compounds. By use of the sequential combination of ligand-based and structure-based virtual screening, three compounds were selected from the ChEMBL library and used as a starting point for the design of 15 derivatives. Molecular docking analysis of the designed derivatives with the highest predicted MEI and relative glucocorticoid receptor binding affinity (20, 22, 24-1, 25-1, 27, VS7, VS13, and VS14) confirmed the presence of interactions with the glucocorticoid receptor that are important for the activity. Local anti-inflammatory activity and systemic side effects were evaluated for a group of novel 17β-carboxamide steroids, indicating that these compounds are potentially new soft glucocorticoids. Using 3D-QSAR analysis of these results and virtual screening of the ChEMBL library, novel derivatives were designed and eight compounds with the highest predicted local anti-inflammatory activity and relative glucocorticoid receptor binding affinity (20, 22, 24-1, 25-1, 27, VS7, VS13, and VS14) were selected.
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Benzodioxole–Pyrazole Hybrids as Anti-Inflammatory and Analgesic Agents with COX-1,2/5-LOX Inhibition and Antioxidant Potential ()
Two series of benzodioxole–pyrazole hybrids were synthesized and the IC50 values for in vitro inhibition of the enzymes cyclooxygenase 1/2 (COX-1, COX-2) and 5-lipoxygenase (5-LOX) were investigated. All compounds were tested for their in vivo anti-inflammatory and analgesic potentials using diclofenac sodium as a reference standard. Compounds 4, 11, 17, 20, 21, 26, and 27, which showed good analgesic and/or anti-inflammatory activities, were also evaluated for their ability to inhibit tumor necrosis factor (TNF)-α production, myeloperoxidase and proteinase, beside their antioxidant activity. Collectively, compounds 11, 17, and 26 displayed significant anti-inflammatory, analgesic, and antioxidant activities, beside dual COX-2 and 5-LOX inhibition. Among these, compound 26 showed high selectivity for in vitro COX-1/COX-2 inhibition, whereas the analogs 11 and 17 noticeably ameliorated the TNF-α level by 85.19 and 97.71%, respectively. A molecular docking study was performed to investigate the possible binding mode of compounds 11, 17, and 26 with the active sites of the COX-2 and 5-LOX enzymes, where they showed nearly the same binding pattern as that of celecoxib and meclofenamic acid, respectively. In two series of benzodioxole–pyrazole hybrids, compounds 11, 17, and 26 displayed significant anti-inflammatory, analgesic and antioxidant activities, beside dual cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibition. Compound 26 showed strong dual COX-2/5-LOX inhibition (IC50 = 0.33 and 3.11 µM, respectively), whereas analogs 11 and 17 noticeably ameliorated the tumor necrosis factor-α level by 85.19 and 97.71%, respectively.
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Synthesis and Evaluation of 5-(o-Tolyl)-1H-tetrazole Derivatives as Potent Anticonvulsant Agents ()
A series of 5-(o-tolyl)-1H-tetrazole derivatives were synthesized and evaluated for their anticonvulsant activities. 1-(2-Methylbenzyl)-5-(o-tolyl)-1H-tetrazole (3h) showed important anticonvulsant activity against the MES-induced seizures, as well as lower neurotoxicity with an ED50 value of 12.7 mg/kg and a TD50 value of over 500 mg/kg after intraperitoneal injection into mice, providing 3h with a high protective index (TD50/ED50) of over 39.4. The achieved results prove that the distinctive compounds could be valuable as a model for future development, adaptation, and investigation to construct more active analogues. In a series of 5-(o-tolyl)-1H-tetrazole derivatives, 1-(2-methylbenzyl)-5-(o-tolyl)-1H-tetrazole (3h) showed significant anticonvulsant activity against MES-induced seizures and lower neurotoxicity after intraperitoneal injection into mice, providing 3h with a high protective index (TD50/ED50) of over 39.4. Some compounds could be valuable as a model to construct more active analogues.
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Synthesis, Characterization, and Biological Evaluation of Some Novel Quinoxaline Derivatives as Antiviral Agents ()
Ethyl (6,7-dimethyl-2-oxo-3,4-dihydroquinoxalin-3-yl)acetate and ethyl (6-methyl-2-oxo-3,4-dihydroquinoxalin-3-yl)acetate (1a,b), 3-methylquinoxalin-2(1H)-one (4) and 1,4-dihydroquinoxaline-2,3-dione (11) were the starting precursors for nine novel quinoxaline compounds, 3a, 6, 10, 13, 15, 16, 17, 18, and 20, via adopting different nucleophilic reactions. The synthesized compounds were tested for their antiviral activity against HCV, HBV, HSV-1, and HCMV. Concomitantly, their safety profile was investigated as well as their selectivity against the viral strains. The Virology Unit at the University of Alabama recorded that two compounds, i.e., 1a and 20, exhibited highly potent activity against HCMV with lower IC50 values (<0.05 μM) compared to ganciclovir (IC50 = 0.59 μM). Compounds 1a and 20 also exhibited low cytotoxicity together with a high selectivity index. A four-step preparation method comprising hydrazinolysis, reaction with triethylorthoformate, nucleophilic attack of 2-aminopyridine on hydrazonoderivatives, then intramolecular cyclization was applied to transform compound 1a to 20. The quinoxaline derivative 20 exhibited higher activity against human cytomegalovirus (EC50 < 0.05 µM) compared to ganciclovir as the reference standard (EC50 = 0.59 µM).
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Synthesis and Evaluation of Novel [1,2,4]Triazolo[5,1-c][1,2,4]-triazines and Pyrazolo[5,1-c][1,2,4]triazines as Potential Antidiabetic Agents ()
Inhibition of the dipeptidyl peptidase-4 (DPP4) enzyme activity and prevention of advanced glycation end (AGE) products formation represents a reliable approach to achieve control over hyperglycemia and the associated pathogenesis of diabetic vascular complications. In the frames of this research study, several triazolo- and pyrazolotriazines were synthesized and evaluated as inhibitors of AGE products formation, DPP4, glycogen phosphorylase and α-glucosidase activities, as well as AGE cross-link breakers. From the two considered classes of heterocyclic compounds, the pyrazolotriazines showed the highest potency as antiglycating agents and DPP4 inhibitors. Structure–activity relationships (SAR) for these compounds, which can be considered as potential drugs for the treatment of type 2 diabetes, were evaluated. A series of novel azolo[5,1-c][1,2,4]triazines were synthesized and evaluated as inhibitors of advanced glycation end (AGE) products formation, dipeptidyl peptidase 4, glycogen phosphorylase and α-glucosidase activities, and as AGE cross-link breakers. One of the most active compounds (16a) inhibits methylglyoxal-mediated AGE products formation with an IC50 value of 186.8 μM.
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Mannich-Benzimidazole Derivatives as Antioxidant and Anticholinesterase Inhibitors: Synthesis, Biological Evaluations, and Molecular Docking Study ()
A series of Mannich bases of benzimidazole derivatives having a phenolic group were designed to assess their anticholinesterase and antioxidant activities. The acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities were evaluated in vitro by using Ellman's method. According to the activity results, all of the compounds exhibited moderate to good AChE inhibitory activity (except for 2a), with IC50 values ranging from 0.93 to 10.85 μM, and generally displayed moderate BuChE inhibitory activity. Also, most of the compounds were selective against BuChE. Compound 4b was the most active molecule on the AChE enzyme and also selective. In addition, we investigated the antioxidant effects of the synthesized compounds against FeCl2/ascorbic acid-induced oxidative stress in the rat brain in vitro, and the activity results showed that most of the compounds are effective as radical scavengers. Molecular docking studies and molecular dynamics simulations were also carried out. A series of Mannich bases of benzimidazole derivatives with a phenolic group were synthesized and assayed for their antioxidant activities and acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory properties. 2-[(Diethylamino)methyl]-4-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol (4b) (IC50 = 0.93 µM) showed the best inhibitory activity toward AChE. Most of the compounds are almost equally active compared to tert-butyl hydroquinone as antioxidant reference.
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Synthesis and Structure–Activity Relationships of Novel Benzylamine-Type Antifungals as Butenafine-Related Antimycotics ()
Benzylamine-type antimycotics like naftifine, butenafine, or terbinafine are a well-known class of antimycotics since the 1980s. The following paper describes the synthesis and biological evaluation of a series of novel benzylamine-type antimycotics characterized by an isooctyl side chain and various substituents at the benzylamine moiety. The compounds were prepared from benzaldehyde derivatives and 2-amino-6-methylheptane by reductive amination with sodium triacetoxyborohydride and subsequent precipitation with hydrogen chloride. The antimycotic activity of the resulting compounds was evaluated in an agar diffusion assay against the yeasts C. glabrata and Yarrowia lipolytica, the mold Aspergillus niger and the dermatophyte H. burtonii. The compounds were also tested in a microdilution assay against the yeast Candida glabrata and the dermatophyte H. burtonii to determine the minimal inhibitory concentrations (MIC). Compounds with an aromatic ether side chain or a short alkyl ether side chain showed significant antimycotic activity against C. glabrata, comparable to terbinafine or clotrimazole. A series of novel benzylamine-type antimycotics characterized by an isooctyl side chain and various substituents at the benzylamine moiety were synthesized and evaluated for their biological activities. Compounds with an aromatic ether side chain or a short alkyl ether side chain showed significant antimycotic activity against Candida glabrata, comparable to terbinafine or clotrimazole.
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Diclofenac-Based Hydrazones and Spirothiazolidinones: Synthesis, Characterization, and Antimicrobial Properties ()
We report here the synthesis, structural characterization, and biological evaluation of novel diclofenac-based hydrazone (4a–f) and spirothiazolidinone (5a–f, 6a–f) derivatives designed as potential antimicrobial agents. The compounds were evaluated in vitro for their antiviral activity against a wide spectrum of DNA and RNA viruses. They were further screened in vitro against different strains of bacteria and fungi. The hydrazone derivatives, 4a and 4c–f, were found to be active against herpesviruses (HSV-1, HSV-2, and HSV-1 TK−), vaccinia virus, and Coxsackie B4 virus, with EC50 values between 6.6 µg/mL and 14.7 μg/mL, and the selectivity index values were greater than 10 for 4a and 4f. The newly synthesized compounds (4–6) were inactive against the bacterial and the fungal strains tested, at levels below 2500, 1250, or 625 μg/mL. Interestingly, the key intermediate 3 with a free hydrazide moiety displayed antifungal properties against Candida albicans and C. parapsilosis at MIC values of 4.88 µg/mL and 78.12 μg/mL, respectively. A new series of diclofenac-based hydrazones (4a–f) and spirothiazolidinones (5a–f, 6a–f) were synthesized and assayed for antimicrobial activity against a wide spectrum of viral, bacterial, and fungal pathogens. The hydrazone derivatives, 4a and 4c–f, were found to be active against herpesviruses (HSV-1, HSV-2, and HSV-1 TK–), vaccinia virus, and Coxsackie B4 virus, with EC50 values between 6.6 µg/mL and 14.7 µg/mL, and the selectivity index values were greater than 10 for 4a and 4f.
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Synthesis, Anti-Inflammatory Activity, and COX-1/2 Inhibition Profile of Some Novel Non-Acidic Polysubstituted Pyrazoles and Pyrano[2,3-c]pyrazoles ()
The synthesis and evaluation of the anti-inflammatory activity of some structure hybrids comprising basically the 5-hydroxy-3-methyl-1-phenyl-4-substituted-1H-pyrazole scaffold directly linked to a variety of heterocycles and functionalities, or annulated as pyrano[2,3-c]pyrazoles, is described. According to the in vivo results and a comprehensive structure–activity relationship study, five analogs (5, 10, 17, 19, and 27) displayed remarkable anti-inflammatory profiles showing distinctive % protection and ED50 values, especially 10 and 27 (ED50 35.7 and 38.7 μmol/kg, respectively) which were nearly equiactive to celecoxib (ED50 32.1 μmol/kg). Compounds 10, 17, and 27 exhibited distinctive COX-2 inhibition with a noticeable COX-2 selectivity (SI values 7.83, 6.87, and 7.16, respectively), close to that of celecoxib (SI 8.68). Additionally, 5, 10, 17, 19, and 27 proved to be gastrointestinal tract safe (0–20% ulceration) and non-toxic, being well tolerated by the experimental animals up to 250 mg/kg orally and 80 mg/kg parenterally. Collectively, the in vivo ED50 values for the most potent five derivatives agree with their in vitro COX-2 selectivity indices, suggesting their usefulness as selective anti-inflammatory COX-2 inhibitors. The bipyrazole 10 and the pyranopyrazole 27 could be considered as the most active members in this study, being nearly equiactive to celecoxib, besides their obvious selective COX-2 inhibition, high safety margin, and predicted pharmacokinetic (ADME-T) suitability for oral use. Novel polysubstituted pyrazoles and pyranopyrazoles were synthesized and evaluated for their in vivo and in vitro anti-inflammatory activities. Five analogs (5, 10, 17, 19, and 27) displayed in vivo ED50 values that correspond to the in vitro COX-2 selectivity indices. Bipyrazole 10 and pyranopyrazole 27 (structurally related to celecoxib) showed the highest anti-inflammatory and COX-2 inhibitory activities with GIT-sparing profiles and high safety margins.
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From Lead to Drug Utilizing a Mannich Reaction: The Topotecan Story ()
Natural products are a rich source of bioactive compounds, and numerous natural compounds have found application in cancer chemotherapy. However, unfavorable physicochemical properties often prevent the use of the original natural product as a drug. A prominent example is camptothecin from the Chinese tree Camptotheca acuminata, which shows extraordinary cytotoxic activity based on a specific molecular mode of action (inhibition of human topoisomerase I). Due to its extremely poor solubility, the original natural product cannot be used as a drug. The marketed drug topotecan was developed from this lead structure by semi-synthesis utilizing a Mannich aminomethylation as the crucial step. In this review, the long-distance run leading to this drug and further perspectives are summarized. The marketed topoisomerase I inhibitor topotecan was developed by semi-synthesis from the alkaloid camptothecin, with a Mannich aminomethylation as the central step. This review summarizes the long-distance run leading to this drug as well as further perspectives.
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Cover Picture: Arch. Pharm. Chem. Life Sci. (3-4/2017) ()

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Editorial Board: Arch. Pharm. Chem. Life Sci. (3-4/2017) ()

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Interaction of Approved Drugs with Synaptic Vesicle Protein 2A ()
Levetiracetam (LEV) and its recently approved derivative brivaracetam are anti-epileptic drugs with a unique mechanism of action. The synaptic vesicle protein 2A (SV2A) was previously identified as their main target. In the current study, we tested a collection of 500 approved drugs for interaction with the human SV2A protein expressed in Chinese hamster ovary cells. Competition binding studies were performed using cell lysates with high SV2A expression and [3H]brivaracetam as a radioligand. A hit rate of 3% was obtained, defined as compounds that inhibited radioligand binding by more than 90% at a screening concentration of 20 μM. Subsequent concentration–inhibition curves revealed the antihistaminic prodrug loratadine (Ki = 1.16 μM) and the antimalarial drug quinine (Ki = 2.03 μM) to be the most potent SV2A protein ligands of the investigated drug library. Both compounds were similarly potent as LEV (Ki = 1.74 μM), providing structurally novel scaffolds for SV2A ligands. A pharmacophore model was established, which indicated steric and electronic conformities of brivaracetam with the new SV2A ligands, and preliminary structure–activity relationships were determined. The anti-convulsive effects of the natural product quinine may – at least in part – be explained by interaction with SV2A. Loratadine and quinine represent new lead structures for anti-epileptic drug development. [3H]Brivaracetam binding to human synaptic vesicle protein 2A (SV2A), the target of the anti-epileptic drug levetiracetam (LEV), was used to screen a library of approved drugs. Loratadine (Ki = 1.16 µM) and quinine (Ki = 2.03 µM) were found to have similar potency as LEV (Ki = 1.74 µM). Pharmacophore modeling revealed common features of the three drugs. Interaction of quinine with SV2A may be responsible for its anti-convulsive effects.
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An Efficient Synthesis of bi-Aryl Pyrimidine Heterocycles: Potential New Drug Candidates to Treat Alzheimer's Disease ()
A series of 13 novel pyrimidine-based sulfonamides 6a–m were synthesized in short periods of time under microwave conditions in good to excellent yield (54–86%). The chemical structures of these heterocycles consist of a central pyrimidine ring having a phenyl group and pyrimidine groups with sulfonamide motifs. The enzyme inhibitory potential of these compounds was investigated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) because these enzymes play a crucial role in the treatment of Alzheimer's disease. As compared to the reference compound eserine (IC50 = 0.04 ± 0.0001 μM for AChE and IC50 = 0.85 ± 0.0001 μM for BChE), the IC50 values of the synthesized compounds ranged from 3.73 ± 0.61 μM to 57.36 ± 0.22 μM for AChE and 4.81 ± 0.16 μM to 111.61 ± 0.53 μM for BChE. Among these tested compounds, 6j having a −CH3 group was found to be the most potent one against both enzymes (AChE, IC50 = 3.73 ± 0.61 μM; BChE, IC50 = 4.81 ± 0.16 μM). Quantitative structure–activity relationship (QSAR) and molecular docking studies of the synthesized compounds were also performed. A series of 13 novel pyrimidine-based sulfonamides were synthesized under microwave conditions in good to excellent yield (54–86%). The acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential of these compounds was investigated. Compound 6j having a –CH3 group was found to be the most potent one against both enzymes (AChE, IC50 = 3.73 ± 0.61 µM; BChE, IC50 = 4.81 ± 0.16 µM).
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Synthesis, Characterization, and Evaluation of Difluoropyrido[4,3-b]indoles as Potential Agents for Acetylcholinesterase and Antiamnesic Activity ()
Acetylcholinesterase (AChE) inhibitors are currently the most widely prescribed drugs for Alzheimer's disease. The high potential of indole compounds in medicinal chemistry led us to discover a novel series of fluoroindole compounds. The synthesis and pharmacological analysis of the difluoropyrido[4,3-b]indoles 11–34 are described. Compounds 11–34 were tested for AChE inhibition activity using a rat brain homogenate. Compounds 25–29 display a promising in vitro profile with an IC50 value range of 46–51.6 nM and show significant protective effect on scopolamine-induced amnesia. The present data indicate that compounds 25–29 may represent attractive potent molecules for the treatment of Alzheimer's disease. A new series of difluoropyrido[4,3-b]indoles were synthesized and assayed for their activities as acetylcholinesterase (AChE) inhibitors in rat brain homogenates. Compounds 25–29 show an IC50 value range of 46–51.6 nM and have significant protective effects on scopolamine-induced amnesia. Thus, compounds 25–29 may represent attractive molecules for the treatment of Alzheimer's disease.
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Design and Synthesis of Novel Anti-Plasmodial Histone Deacetylase Inhibitors Containing an Alkoxyamide Connecting Unit ()
Despite recent declines in mortality, malaria remains an important global health problem. New therapies are needed, including new drugs with novel modes of action compared to existing agents. Among new potential therapeutic targets for malaria, inhibition of parasitic histone deacetylases (HDACs) is a promising approach. Homology modeling of PfHDAC1, a known target of some anti-plasmodial HDAC inhibitors, revealed a unique threonine residue at the rim of the active site in close proximity to the location of the cap group of vorinostat-type HDAC inhibitors. Aiming to obtain HDAC inhibitors with potent and preferential anti-plasmodial activity, we synthesized a mini-library of alkoxyamide-based HDAC inhibitors containing hydrogen bond acceptors in the cap group. Using a 5-step synthetic route, 12 new inhibitors were synthesized and assayed against Plasmodium falciparum asexual blood stage parasites (clones 3D7 and Dd2) and human cells (HepG2). The most active compound 6h (Pf3D7 IC50: 0.07 µM; PfDd2 IC50: 0.07 µM) was 25-fold more toxic against the parasite versus human HepG2 cells. Selected compounds were shown to cause hyperacetylation of P. falciparum histone H4, indicating inhibition of one or more PfHDACs. A homology model of PfHDAC1, a known target of anti-plasmodial HDAC inhibitors, revealed a threonine residue at the rim of the active site not present in the human orthologs. Aiming to explore this difference, a mini-library of 12 alkoxyamide-based HDAC inhibitors containing hydrogen bond acceptors in the cap group was synthesized. The inhibitors were shown to cause hyperacetylation of P. falciparum histone H4, indicating inhibition of one or more PfHDACs.
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Design, Synthesis, and Biological Evaluation of Novel 1,2,4-Trioxanes as Potential Antimalarial Agents ()
A series of substituted 1,2,4-trioxanes were synthesized and evaluated for their antimalarial potential, in silico ADME properties and cytotoxicity on neuronal cell lines. Among the 15 synthesized substituted 1,2,4-trioxanes, two compounds (compound 15, IC50 = 25.71 nM; compound 21, IC50 = 19.6 nM) exhibited promising in vitro antimalarial potential comparable to those of the existing drugs chloroquine and artemisinin. Both of these compounds were found to be nontoxic up to 20 µM concentration in neuronal PC-12 cells. Compound 21 may serve as an optimized lead compound because of its less in vitro toxicity and lower probability to cross the blood brain barrier. A series of substituted 1,2,4-trioxanes were synthesized and evaluated for their antimalarial potential, ADME properties, and neuronal cell cytotoxicity. Two compounds (15, IC50 = 25.71 nM; 21, IC50 = 19.6 nM) showed in vitro antimalarial potential comparable to those of chloroquine and artemisinin. Due to its less toxicity and low probability to cross the blood brain barrier, compound 21 can be considered an optimized lead.
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Design, Synthesis, and Evaluation of the Kinase Inhibition Potential of Pyridylpyrimidinylaminophenyl Derivatives ()
In view of potent kinase inhibitors for the treatment of myriad human disorders, we synthesized some structurally variant amide/cyclic amide derivatives based on pyridylpyrimidinylaminophenyl amine, the key pharmacophore of the kinase inhibitor drug molecule, imatinib, and evaluated their kinase inhibition potency. Among the various synthesized amides, compound 20, a cyclic amide/pyridin-2(1H)-one derivative, exhibited an IC50 value comparable to that of the drug imatinib against c-Src kinase, and another compound (14) containing a 2-((4-methyl-2-oxo-2H-chromen-6-yl)oxy)acetamide demonstrated an IC50 value of 8.39 μM. Furthermore, the constitution of the cyclic amide derivative was confirmed by the single-crystal X-ray diffraction technique. These results may serve as a gateway for developing novel next-generation kinase inhibitors. Building on the pyridylpyrimidinylaminophenyl scaffold, the active pharmacophore of imatinib, various heterocyclic acids were conjugated and a small library of amides was synthesized. The kinase inhibitory potential of the synthesized amides was evaluated against Abl1 and c-Src. Two compounds, 14 and 20, showed IC50 values of 2.67 and 8.39 µM against the kinase Abl1.
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Antiviral and Cytostatic Evaluation of 5-(1-Halo-2-sulfonylvinyl)- and 5-(2-Furyl)uracil Nucleosides ()
Transition metal-catalyzed halosulfonylation of 5-ethynyl uracil nucleosides provided (E)-5-(1-chloro-2-tosylvinyl)uridines. Tetrabutylammonium fluoride-mediated direct CH arylation of 5-iodouracil nucleosides with furan or 2-heptylfuran gave 5-furyl-substituted nucleosides without the necessity of using the organometallic substrates. These two classes of 5-substituted uracil nucleosides as well their corresponding ester derivatives were tested against a broad range of DNA and RNA viruses and the human immunodeficiency virus (HIV). The 3′,5′-di-O-acetyl-5-(E)-(1-chloro-2-tosylvinyl)-2′-deoxyuridine (24) inhibited the growth of L1210, CEM and HeLa cancer cells in the lower micromolar range. The (β-chloro)vinyl sulfone 24 and 5-(5-heptylfur-2-yl)-2′-deoxyuridine (10) displayed micromolar activity against varicella zoster virus (VZV). The 5-(5-heptylfur-2-yl) analog 10 and its 3′,5′-di-O-acetyl-protected derivative showed similar activity against the cytomegalovirus (CMV). The 5-(fur-2-yl) derivatives of 2′-deoxyuridine and arabino-uridine inhibited the replication of herpes simplex virus (HSV) TK+ strains while the 5-(5-heptylfur-2-yl) derivative 10 displayed antiviral activity against the parainfluenza virus. Uracil nucleosides substituted at C5 with 2-sulfonylvinyl or heteroaren-2-yl scaffolds were synthesized and evaluated for their antiviral and cytostatic activities. The 3′,5′-di-O-acetyl-5-(E)-(1-chloro-2-tosylvinyl)-2′-deoxyuridine 24 inhibited the growth of L1210 cells in the lower micromolar range (IC50 = 5.6 ± 4.7  μM) and displayed micromolar activity against varicella zoster virus (EC50 = 4 µM).
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Synthesis and Anticonvulsant Properties of New 3,3-Diphenyl-2,5-dioxo-pyrrolidin-1-yl-acetamides and 3,3-Diphenyl-propionamides ()
The focused library of new amides derived from 3,3-diphenyl-2,5-dioxo-pyrrolidin-1-yl-acetic acid (2a–t) and 3,3-diphenyl-propionic acid (3a–t) as potential anticonvulsant agents was synthesized. The final products were obtained in the amidation reaction of the given carboxylic acid (2, 3) with appropriate secondary amines in the presence of carbonyldiimidazole (CDI) as a coupling reagent. The initial anticonvulsant screening was performed in mice intraperitoneally (i.p.) using the “classical” maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models, whereas the acute neurological toxicity was determined applying the rotarod test. Additionally, several compounds were studied also in the 6-Hz seizures recognized as the animal model of human pharmacoresistant epilepsy. In this series, compound 3q displayed a broad spectrum of activity across the preclinical seizure models (ED50 MES = 31.64 mg/kg; ED50 scPTZ = 75.41 mg/kg, ED50 6-Hz (32 mA) = 38.15 mg/kg). Consequently, compound 3q revealed a wider spectrum of protection, higher activity or/and a better safety profile than the commonly used antiepileptic drugs such as phenytoin, ethosuximide, valproic acid, or/and levetiracetam. Notably, the in vitro studies showed that the most possible mechanism of action of 3q may be connected to the interaction with neuronal voltage-sensitive sodium channels (site 2). Other substances were active predominantly in the chemically induced seizures. The results of the current studies indicate that the presence of the pyrrolidine-2,5-dione ring is important but not indispensable for anticonvulsant activity. New amides derived from 3,3-diphenyl-2,5-dioxo-pyrrolidin-1-yl-acetic acid (2a–t) and 3,3-diphenyl-propionic acid (3a–t) were synthesized as potential anticonvulsant agents. The most potent compound 3q displayed a broad spectrum of activity across the three preclinical seizure models, MES, scPTZ, and 6-Hz (32-mA), with a wider spectrum of protection, higher activity and/or a better safety profile than the commonly used antiepileptic drugs.
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Design, Synthesis, and Cytotoxic Evaluation of Certain 7-Chloro-4-(piperazin-1-yl)quinoline Derivatives as VEGFR-II Inhibitors ()
Signaling pathway inhibition of VEGFR-II is visualized as valuable tool in cancer management. In the current study, the synthesis of novel 1-4-(7-chloroquinolin-4-yl)piperazin-1-yl)-2-(N-substituted-amino)-ethanone derivatives (4a–t) was achieved through the amination of 2-chloro-1-(4-(7-chloroquinolin-4-yl)piperazin-1-yl)ethanone (3) with different secondary amines. The structures of the target compounds were confirmed by IR, 1H-NMR, 13C-NMR, HRMS, and microanalysis. Compounds 4a–t were subjected to in vitro anticancer screening against human breast cancer (MCF-7) and prostate cancer (PC3) cell lines. The highest cytotoxicty against both cell lines was displayed by 2-(4-(4-bromobenzyl)piperazin-1-yl)-1-(4-(7-chloroquinolin-4-yl)piperazin-1-yl)ethanone (4q), with IC50 values of 6.502 and 11.751 μM against MCF-7 and PC3 cells, respectively, compared with the standard drug doxorubicin (MCF-7: 6.774 μM, PC3: 7.7316 μM). Due to its notable activity toward MCF-7 cells, 4q was further evaluated as VEGFR-II inhibitor, showing an IC50 of 1.38 μM compared to sorafenib (0.33 μM). The docking study proved that 4q has a binding mode akin to that of VEGFR-II inhibitors. Novel 1-4-(7-chloroquinolin-4-yl)piperazin-1-yl)-2-(N-substituted-amino)ethanone derivatives (4a–t) were synthesized and evaluated against the human breast cancer cell line MCF-7. Due to its notable activity toward the MCF-7 cells, 4q was further evaluated as VEGFR-II inhibitor, showing an IC50 of 1.38 µM compared to sorafenib (0.33 µM).
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Synthesis and Pharmacological Evaluation of Acrylate-Based Gastrosparing NSAID Prodrugs ()
Dexibuprofen and aceclofenac are well-known NSAID molecules, their oral use leads to gastrointestinal (GI) toxicity. To circumvent that GI toxicity, the prodrug approach is a better alternative. Hence, this research was undertaken to synthesize prodrugs of dexibuprofen and aceclofenac using acrylic polymers with degradable ester bonds. Dexibuprofen was linked to 2-hydroxypropyl methacrylate by an activated ester technique. The resulting material was copolymerized with 2-hydroxyethyl methacrylate and methyl methacrylate (in 1:3 mole ratios) by the free radical polymerization method, utilizing azoisobutyronitrile at 65–70°C. Similarly aceclofenac was also processed. The resulting prodrugs were characterized by IR, NMR, and elemental analysis. The synthesized prodrugs possess optimal physicochemical characteristics such as the intended molecular weight, lipophilicity, partition coefficient, and protein binding. The drug release on hydrolysis was studied in various fluids such as SGF (pH 1.2), SIF (pH 7.4), and SCF (pH 6.8), to establish the drug release kinetics. Pharmacological evaluation exhibited anti-inflammatory activity with remarkable reduction in ulcerogenicity compared to the parent drug. Under the conditions used, the prodrugs showed no antigenicity in Wistar rats. Thus, it was concluded that acrylic-based prodrugs were efficient in drug localization in the stomach, without gastric problems. Dexibuprofen and aceclofenac are well-known NSAID molecules with gastrointestinal toxicity. To circumvent this toxicity, prodrugs of dexibuprofen and aceclofenac were synthesized using acrylic polymers with degradable ester bonds. Pharmacological evaluation showed anti-inflammatory activity with remarkable reduction in ulcerogenicity compared to the parent drugs, indicating efficient drug localization in the stomach, without gastric problems.
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