Design, synthesis, in silico and antiproliferative evaluation of novel pyrazole derivatives as VEGFR-2 inhibitors
As the blockade of the VEGFR-2 signaling pathway is a viable approach in cancer therapy, the present study focuses on a series of pyrazole based VEGFR-2 inhibitors that were designed on the basis of
the hybridization approach, supported by docking and in silico computational studies. The designed compounds were synthesized through facile synthetic methods and the structures were confirmed by 1H
NMR, 13C NMR, MS and elemental analysis. The compounds were screened for in vitro antiproliferative activity against the HT-29 (human colon cancer) and MCF-7 (human breast cancer) cell lines by MTT
assay. The compounds were also studied for in vitro inhibitory activity against VEGFR-2 kinase. Among all the tested compounds, compound 6h emerged as a potent agent in the antiproliferative study
against HT-29 and MCF-7 cells, with IC50 values of 2.36 and 6.59 μM, respectively. Moreover, the same compound exhibited the highest VEGFR-2 inhibitory activity with an IC50 value of 1.89 μM. In
docking studies, the designed compounds showed similar and essential key interactions as those of known VEGFR-2 inhibitors. The present study may lead to new molecules in the development of
anticancer agents targeting VEGFR-2. A novel series of 4-(4-(1,3-dimethyl-1H-pyrazole-5-carboxamido)phenoxy)-N-picolinamides was designed, synthesized and evaluated for their antiproliferative and
VEGFR-2 inhibitory activity in vitro. Compound 6h showed potent antiproliferative activity against the HT-29 and MCF-7 cell lines, with IC50 values of 2.36 and 6.59 µM, respectively. It also
exhibited the highest VEGFR-2 inhibitor activity with an IC50 value of 1.89 µM.
>> Read More
Novel pyridine-2,4,6-tricarbohydrazide thiourea compounds as small key organic molecules for the potential treatment of type-2 diabetes mellitus: In vitro studies against yeast α- and β-glucosidase and in silico molecular modeling
A range of novel pyridine-2,4,6-tricarbohydrazide thiourea compounds (4a–i) were synthesized in good to excellent yields (63–92%). The enzyme inhibitory potentials of these compounds were
investigated against α- and β-glucosidases because these enzymes play a crucial role in treating type-2 diabetes mellitus (T2DM). As compared to the reference compound acarbose (IC50
38.22 ± 0.12 μM), compounds 4i (IC50 25.49 ± 0.67 μM), 4f (IC50 28.91 ± 0.43 μM), 4h (IC50 30.66 ± 0.52 μM), and 4e (IC50 35.01 ± 0.45 μM) delivered better inhibition against α-glucosidase and were
quite inactive/completely inactive against β-glucosidase. The structure–activity relationship of these compounds was developed and elaborated with the help of molecular docking studies. Novel
pyridine-2,4,6-tricarbohydrazide thiourea compounds (4a–i) were synthesized and tested for their inhibitory activities against α- and β-glucosidases. Compounds 4e, 4f, 4h, and 4i showed better
inhibition against α-glucosidase than the reference compound acarbose and were inactive against β-glucosidase. Molecular docking studies revealed the structure–activity relationship of these
>> Read More
Synthesis, antitumor activity evaluation, and DNA-binding study of coumarin-based agents
A novel series of coumarin-thiadiazole heterocycle derivatives was synthesized by the nucleophilic substitution reaction. The synthesized compounds were structurally verified by IR, 1H NMR, 13C NMR,
mass spectra, and elemental analyses. The antitumor activity of the synthesized compounds was evaluated through DNA binding assays and the 60-cell line panel according to the US NCI-DTP protocol or a
selection of human tumor cell lines: breast cancer (MCF-7), liver cancer (HepG-2), and colorectal cancer (HCT-116). Most of the compounds had better DNA/ethidium bromide fluorescence quenching rather
than methyl green displacement, suggesting superior DNA intercalation over DNA groove binding. Compounds 8 and 14b showed the best quenching effect with KSV = 4.27 × 105 M−1. Moreover, the results
for compounds 8, 4c, and 4e revealed a possible dual DNA binding mode with the intercalation to be superior, with KSV 4.27 × 105, 3.96 × 105, and 3.51 × 105 M−1, respectively, compared to 42%, 45%,
and 43% methyl green displacement, respectively. Out of the 60-cell line panel, the leukemia HL-60 cell line was the most susceptible to growth inhibition when treated with 14a, resulting in 61%
growth, followed by the lung carcinoma cell line NCI-H522 showing 67% growth when treated with 9. Moreover, compound 10c had an IC50 value of 24.9 μg/mL against the HepG-2 cell line. Novel
coumarin-thiadiazole heterocycle derivatives were evaluated with regard to their DNA-binding/cleavage and tumor cell line inhibition activities. Compounds 4c and 4e showed dual DNA binding mode.
Compound 14a was the most active regarding DNA cleavage as well as in leukemia cell line inhibition, resulting in 61% growth.
>> Read More
Cover Picture: Arch. Pharm. Chem. Life Sci. (12/2017)
2-Alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles: An Overview on Synthetic Strategies and Biological Activity
2-Alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles represent an important class of ATP-competitive protein kinase inhibitors, offering the possibility of multiple interactions with different regions
of the target enzyme. The necessity of exploring the effects of diverse chemical decorations around the imidazole core prompted the design of several synthetic routes aimed at achieving both
efficiency and flexibility. Additionally, the optimization of established protocols and the extensive use of transition metal-catalyzed cross-coupling reactions have been broadening the spectrum of
preparative methodologies within the last decade. This review summarizes the progress in the development of synthetic strategies leading to 2-alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles and
1-alkyl-2-alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles and offers a glance at the biological activities of this class of compounds. Many examples of
2-alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles and 1-alkyl-2-alkylsulfanyl-4(5)-aryl-5(4)-heteroarylimidazoles have been reported as ATP-competitive inhibitors of different protein kinases. This
review focuses on how diverse synthetic strategies offer high flexibility in varying the substitution pattern of this class of molecules, providing the optimal moieties for potent and selective
inhibition of the desired target enzyme.
>> Read More
Synthesis, Biological Evaluation, and Molecular Modeling Study of Substituted Benzyl Benzamides as CETP Inhibitors
Cardiovascular disease is the most common cause for mortality and morbidity in the developed world; its risk is inversely related to the high-density lipoprotein (HDL) cholesterol levels. Therefore,
there is a great interest in developing new cholesteryl ester transfer protein (CETP) inhibitors capable of raising HDL as a novel approach for the prevention of cardiovascular disease. Herein, the
synthesis and characterization of ten benzyl benzamides 8a–j that aim at CETP inhibition was performed. The in vitro CETP inhibition bioassay revealed that benzamide 8j had the best activity, with a
percent inhibition of 82.2% at 10 μM concentration and an IC50 value of 1.3 μM. The docking study shows that the verified compounds accommodate the binding cleft of CETP and are enclosed by a
hydrophobic lining. Furthermore, the scaffold of 8a–j matches the pharmacophoric points of CETP inhibitors, particularly in its hydrophobic and aromatic functionalities. New cholesteryl ester
transfer protein (CETP) inhibitors capable of raising the high-density lipoprotein levels may be a novel approach for the prevention of cardiovascular disease. Ten new benzyl benzamides (8a–j) were
characterized for their CETP inhibitory activities. The scaffold of 8a–j matches the pharmacophoric points of CETP inhibitors, particularly in its hydrophobic and aromatic functionalities.
>> Read More
Design, Synthesis, Molecular Docking, and Anticancer Activity of Phthalazine Derivatives as VEGFR-2 Inhibitors
Novel series of phthalazine derivatives 6–11 were designed, synthesized, and evaluated for their anticancer activity against two human tumor cell lines, HCT-116 human colon adenocarcinoma and MCF-7
breast cancer cells, targeting the VEGFR-2 enzyme. Compounds 7a,b and 8b,c showed the highest anticancer activities against both HCT116 human colon adenocarcinoma cells with IC50 of 6.04 ± 0.30,
13.22 ± 0.22, 18 ± 0.20, and 35 ± 0.45 μM, respectively, and MCF-7 breast cancer cells with IC50 of 8.8 ± 0.45, 17.9 ± 0.50, 25.2 ± 0.55, and 44.3 ± 0.49 μM, respectively, in comparison to sorafenib
as reference drug with IC50 of 5.47 ± 0.3 and 7.26 ± 0.3 μM, respectively. Eleven compounds in this series were further evaluated for their inhibitory activity against VEGFR-2, where compounds 7a,
7b, 8c, and 8b also showed the highest VEGFR-2 inhibition with IC50 of 0.11 ± 0.01, 0.31 ± 0.03, 0.72 ± 0.08, and 0.91 ± 0.08 μM, respectively, in comparison to sorafenib as reference ligand with
IC50 of 0.1 ± 0.02. Furthermore, molecular docking studies were performed for all synthesized compounds to predict their binding pattern and affinity towards the VEGFR-2 active site, in order to
rationalize their anticancer activity in a qualitative way. Novel series of phthalazine derivatives were designed, synthesized, and evaluated for their anticancer activity against HCT-116 human colon
adenocarcinoma and MCF-7 breast cancer cells, targeting the VEGFR-2 enzyme. Compounds 7a,b and 8b,c showed the most promising activities (IC50 (HCT-116) = 6.04 ± 0.30, 13.22 ± 0.22, 18 ± 0.20, and
35 ± 0.45 µM, respectively) compared to sorafenib as reference drug.
>> Read More
Rational Optimization of Tumor Suppressor-Derived Peptide Inhibitor Selectivity between Oncogene Tyrosine Kinases ErbB1 and ErbB2
The tumor-suppressor protein Mig-6 has been found to directly target and inhibit the human ErbB receptor tyrosine kinases ErbB1 and ErbB2. Despite their highly homologous nature, these two kinases
are separately involved in the development of different types of human cancer. Here, we utilized a rational strategy to iteratively optimize the interaction specificity of the two kinases with a
Mig-6 derived peptide by exploiting structural diversity space. Instead of traditionally improving the peptide binding potency, the optimization attempts to maximize the affinity difference between
peptides binding to ErbB1 and ErbB2. The computational design was also substantiated by using fluorescence-based assays. Consequently, we successfully designed three peptides, HSLTPTQSF, THLMNLLRI,
and NSGCPMHK, with high or moderate selectivity for ErbB1 over ErbB2 (3.1-, 6.3-, and 3.0-fold, respectively) and two peptides, PCMTDFLFT and WVIFPSQTN, with moderate or modest selectivity for ErbB2
over ErbB1 (3.5- and 1.6-fold, respectively). The method is expected to be used for the rational molecular design of selective peptide entities for other protein systems. The tumor suppressor
Mig-6-derived peptide selectivity between the human receptor tyrosine kinases ErbB1 and ErbB2 was improved by using an iteration optimization algorithm. The optimization attempts to maximize the
affinity difference between peptide binding to ErbB1 and ErbB2. A number of peptides were successfully designed to have high selectivity for the two kinases.
>> Read More
Practical Synthesis of α-Amyrin, β-Amyrin, and Lupeol: The Potential Natural Inhibitors of Human Oxidosqualene Cyclase
A practical synthesis of α-amyrin (1), β-amyrin (2), and lupeol (3) was accomplished in total yields of 32, 42, and 40% starting from easily available ursolic acid (4), oleanolic acid (5), and
betulin (6), respectively. Remarkably, these three natural pentacyclic triterpenes exhibited potential inhibitory activity against human oxidosqualene cyclase. A practical synthesis of α-amyrin (1),
β-amyrin (2), and lupeol (3) was accomplished in total yields of 32, 42, and 40% starting from easily available ursolic acid, oleanolic acid, and botulin, respectively. These three natural
pentacyclic triterpenes exhibited potential inhibitory activity against human oxidosqualene cyclase.
>> Read More
6-Nitroazolo[1,5-a]pyrimidin-7(4H)-ones as Antidiabetic Agents
Prevention of the formation of advanced glycation end-products (AGEs) is a reliable approach to achieve control over hyperglycemia and the associated pathogenesis of diabetic vascular complications.
In these terms, new synthetic approaches to 6-nitroazolo[1,5-a]pyrimidines have been developed on the basis of the promising antiglycation activity of their structural analogues, such as
azolo[5,1-c][1,2,4]triazine-4(1H)-ones. A number of nitroazolopyrimidines were obtained by using nitration, chlorodeoxygenation, and amination reactions, and their antidiabetic properties were
elucidated in vitro. It was shown that triazolo[1,5-a]pyrimidine-7(4H)-ones exhibit a higher antiglycation activity than the corresponding 7-alkylamino analogs and aminoguanidine, as the reference
compound. It is suggested that this kind of activity can be associated with the chelating properties possessed by the synthesized 6-nitro-7-oxoderivatives. Furthermore, the compounds obtained were
tested for their inhibitory activity against dipeptidyl peptidase 4 (DPP4), glycogen phosphorylase, and α-glucosidase in vitro, but their activities proved to be significantly inferior to those of
the reference compounds. The compounds of the new 6-nitroazolo[1,5-a]pyrimidine series show promising antiglycation activity. In particular, 2-(α-furyl)-6-nitro-1,2,4-triazolo[1,5-a]pyrimidin-7-one
demonstrated inhibition of the formation of advanced glycation end-products (IC50 = 50.35 μM) at one order of magnitude higher than that of the reference compound, aminoguanidine (IC50 = 765.00 μM).
>> Read More
Synthesis and Carbonic Anhydrase Inhibition of Tetrabromo Chalcone Derivatives
In the present study, human carbonic anhydrase (hCA) enzyme was purified and characterized from fresh blood human red cells by Sepharose-4B-l-tyrosine-sulfanilamide affinity gel chromatography.
Secondly, a series of new tetrabromo chalcone derivatives containing 4,7-methanoisoindol-1,3-dione (2a–i) were synthesized from the addition of Br2 to related chalcone derivatives (1a–i). The
structures of the new molecules (2a–i) were confirmed by means of 1H NMR, 13C NMR and elemental analysis. Finally, the inhibitory effects of 2a–i on CA activities were investigated using the esterase
method under in vitro conditions. The compounds 2a–i exhibited excellent inhibitory effects, in the low nanomolar range, with Ki values in the range of 11.30–21.22 nM against hCA I and in the range
of 8.21–12.86 nM against hCA II. Our findings suggest that the new compounds 2a–i have superior inhibitory effect over acetazolamide (AZA), which is used as clinical CA inhibitor, with obtained Ki
values of 34.50 and 28.93 nM against the hCA I and II isozymes, respectively. In addition to the inhibition assays, molecular modeling approaches were implemented for prediction of the binding
affinities of compounds 2a and 2c, which had the highest inhibition effects, against the hCA I and II isozymes. New tetrabromo chalcone derivatives containing 4,7-methanoisoindol-1,3-dione (2a–i)
were synthesized from the addition of Br2 to related chalcone derivatives and tested for their inhibitory activity on human carbonic anhydrase (hCA) purified from red blood cells. The new compounds
2a–i show higher inhibitory activity than the clinical CA inhibitor acetazolamide (AZA).
>> Read More