Design,molecular docking and synthesis of novel 5,6-dichloro-2-methyl-1H-benzimidazole derivatives as potential urease enzyme inhibitors

A novel series of 5,6-dichloro-2-methyl-1H-benzimidazole derivatives was synthesized and then screened for their urease inhibitory activity. All compounds showed more potent inhibitory activity in the range of IC₅₀ = 0.0294 ± 0.0015–0.1494 ± 0.0041 µM than thiourea (IC₅₀ = 0.5117 ± 0.0159 µM), as a reference inhibitor. Among all the tested compounds, the compound 15 (IC₅₀ = 0.0294 ± 0.0015 µM) having strong electron-withdrawing nitro group on the phenyl ring was recorded as the most potent inhibitor of urease. All compounds were docked at the active sites of the Jack bean urease enzyme to investigate the reason of the inhibitory activity and the possible binding interactions of enzyme-ligand complexes.     

Design,synthesis, docking studies and biological evaluation of novel chalcone derivatives as potential histone deacetylase inhibitors

A group of novel chalcone derivatives comprising hydroxamic acid or 2-aminobenzamide group as zinc binding groups (ZBG) were synthesized. The structure of the prepared compounds was fully characterized by IR, NMR and elemental microanalyses. Most of the tested compounds displayed strong to moderate HDAC inhibitory activity. Some of these compounds showed potent anti-proliferative activity against human HepG2, MCF-7 and HCT-116 cell lines. In particular, compounds 4a and 4b exhibited significant anti-proliferative activity against the three cell lines compared to SAHA as reference drug and displayed promising profile as anti-tumor candidates. The results indicated that these chalcone derivatives could serve as a promising lead compounds for further optimization as antitumor agents.     

Unexpected small molecules as novel SIRT2 suicide inhibitors

A series of sirtuin inhibitor candidates were assembled based on an intermediate ester (1a) our accidently discovered. After screening and evaluation, several SIRT2 selective inhibitors were identified, which can inhibit all the deacetylation, defatty-acylation and debenzoylation of SIRT2. Among these inhibitors, compound 1e was the best SIRT2 selective inhibitors. The primary study on the inhibitory mechanism indicated that compound 1e may be a suicide inhibitor acting as an irreversible way. Given almost all reported sirtuin inhibitors are non-covalent, sirtuin covalent inhibitors are still need to be developed. These findings will facilitate for further development of SIRT2 selective and suicide inhibitors.     

Design,synthesis and molecular docking of novel pyrazolo[1,5-a][1,3,5]triazine derivatives as CDK2 inhibitors

Cyclin Dependent Kinases CDKs unpredictable activity has been accounted for a wide assortment of human malignancies, so it might be conceivable to design pharmacologically relevant ligands that go about as specific and potent inhibitors of CDK2 action. In this respect, a series of novel pyrazolo[1,5-a][1,3,5]triazine derivatives were designed, synthesized and evaluated for CDK2 enzyme inhibitory and anticancer activity. Compounds 9f and 10c showed best CDK2 inhibition among the newly synthesized compounds, with percent inhibition at 82.38%, and 81.96% against CDK2 and IC₅₀ of 1.85 and 2.09 µM, respectively. Additionally, the newly synthesized compounds were tested for their antiproliferative activity against 60 NCI cell lines. Molecular docking revealed the binding mode of these new compounds into the roscovitine binding site of CDK2 enzyme (PDB code: 3ddq). Conclusively, pyrazolotriazine derivatives represent a talented starting point for further study as anticancer drug.     

Design,synthesis and evaluation of novel indole derivatives as AKT inhibitors

Herein, we describe the discovery and synthesis of a new series of 1,2,4,7-tetra-substituted indole derivatives as novel AKT inhibitors by optimization of a weak hit methyl 4-(2-aminoethoxy)-1H-indole-2-carboxylate (1). Both representative compounds 6a and 6o exhibited the most potent inhibitory activities against AKT1, with inhibition rates of 72.5% and 78.6%, respectively, at concentrations of 10 nM. In addition, compounds 6a and 6o also potently inhibited the phosphorylation of the downstream GSK3 protein and displayed slightly better anti-proliferative activities in a prostate cancer cell line.     

Design,synthesis and biological evaluation of indole derivatives as Vif inhibitors

The crystal structure of viral infectivity factor (Vif) was reported recently, which makes it possible to design new inhibitors against Vif by structure-based drug design. Through analysis of the protein surface of Vif, the C2 pocket located in the N-terminal was found, which is suit for developing small molecular inhibitors. Then, in our article, fragment-based virtual screening (FBVS) was conducted and a series of fragments was obtained, among which, Zif-1 bearing indole scaffold and pyridine ring can form H-bonds with Tyr148 and Ile155. Subsequently, 19 derivatives of Zif-1 were synthesized. Through the immune-fluorescence staining and Western blot assays, Zif-15 shows potent activity in inhibiting Vif-mediated A3G degradation. Further docking experiment shows that Zif-15 form H-bond interactions with residues His139, Tyr148 and Ile155. Therefore, Zif-15 is a promising lead compound against Vif that can be used to treat AIDS.     

Design,synthesis and in vitro evaluation studies of sulfonyl-amino-acetamides as small molecule BACE-1 inhibitors

The identification of a series of sulfonyl-amino-acetamides as BACE-1 (β-secretase) inhibitors for the treatment of Alzheimer’s disease is reported. The derivatives were designed based on the docking simulation study, synthesized and assessed for BACE-1 inhibition in vitro. The designed ligands revealed desired binding interactions with the catalytic aspartate dyad and occupance of S1 and S2′ active site regions. These in silico results correlated well with in vitro activity. Out of 33 compounds synthesized, 12 compounds showed significant inhibition at 10 μM concentration. The most active compound 2.17S had IC₅₀ of 7.90 μM against BACE-1, which was concomitant with results of in silico docking study.     

Design,synthesis, and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors

Four series of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (12a–e, 13a–f, 14a–f and 15a–i) were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, PC-3 and MCF-7) and c-Met kinase. Five selected compounds (13b, 15b, 15d, 15e and 15f) were further evaluated for the activity against HepG2 and Hela cell lines. Eighteen of the compounds showed excellent cytotoxicity activity and selectivity with the IC₅₀ valuables in single-digit μM to nanomole range. Seven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15f showed superior activity to Foretinib, with the IC₅₀ values of 1.04 ± 0.11 μM, 0.02 ± 0.01 μM and 9.11 ± 0.55 μM against A549, PC-3 and MCF-7 cell lines, which were 0.62 to 19.5 times more active than Foretinib (IC₅₀ values: 0.64 ± 0.26 μM, 0.39 ± 0.11 μM, 9.47 ± 0.22 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that replacement of quinoline nucleus of the previous active compounds with 1H-pyrrolo[2,3-b]pyridine moiety maintained even improved the potent cytotoxic activity. The results suggested that the introduction of fluoro atoms to the aminophenoxy part of target compounds or the phenyl group of pyrimidine substituted on C-4 position was benefit for the activity.     

Synthesis,molecular docking and cholinesterase inhibitory activity of hydroxylated 2-phenylbenzofuran derivatives

We have designed, synthesized and evaluated a series of hydroxylated 2-phenylbenzofuran derivatives as potential cholinesterase inhibitors. Starting from a series of 2-phenylbenzofurans previously published, in this paper we present a complete synthesis and the influence on the activity of one or two hydroxyl groups located in meta or in meta and para positions respectively of the 2-phenyl ring and highlight the importance of position of hydroxyl groups. Moreover, simultaneous introduction of halogen at position 7 of the benzofuran scaffold resulted in an improved inhibitory activity against the enzyme. To further provide molecular insight and to identify the most probable ligand-binding site of the protein, docking studies were performed for the top-ranked compounds. Docking results revealed conserved ligand-binding residues and supported the role of catalytic site residues in enzyme inhibition.     

Design,synthesis, anticancer evaluation and docking studies of new pyrimidine derivatives as potent thymidylate synthase inhibitors

Cancer is a perplexing and challenging problem for researchers. In this study, a series of 6-aryl-5-cyano-pyrimidine derivatives were designed, synthesized and evaluated for their anticancer activity against HePG-2, MCF-7 and HCT-116 cell lines. Compounds 2, 3d, 4a-c, 5, 8 and 12 displayed high anticancer activity, comparable to that of 5-fluorouracil. Additionally, those compounds with effective anticancer activity were further assessed for their ability to inhibit thymidylate synthase (TS) enzyme. All the tested compounds demonstrated a marked TS inhibitory activity (33.66–74.98%), with IC₅₀ ranging from 3.89 to 15.74 nM. Moreover, apoptosis studies were conducted on the most potent compound 8, to evaluate its proapoptotic potential. Interestingly, compound 8 induced the level of active caspase 3, and elevated the Bax/Bcl2 ratio 44 folds in comparison to the control. Finally, a molecular docking study was conducted to detect the probable interaction between the active compounds and the thymidylate synthase active site.     

Discovery of novel 3,5-disubstituted indole derivatives as potent inhibitors of Pim-1, Pim-2, and Pim-3 protein kinases

A series of novel 3,5-disubstituted indole derivatives as potent and selective inhibitors of all three members of the Pim kinase family is described. High throughput screen identified a pan-Pim kinase inhibitor with a promiscuous scaffold. Guided by structure-based drug design, SAR of the series afforded a highly selective indole chemotype that was further developed into a potent set of compounds against Pim-1, 2, and 3 (Pim-1 and Pim-3: IC(50)≤2nM and Pim-2: IC(50)≤100nM).     

Identification of novel acetylcholinesterase inhibitors: Indolopyrazoline derivatives and molecular docking studies

The synthesis of novel indolopyrazoline derivatives (P1-P4 and Q1-Q4) has been characterized and evaluated as potential anti-Alzheimer agents through in vitro Acetylcholinesterase (AChE) inhibition and radical scavenging activity (antioxidant) studies. Specifically, Q3 shows AChE inhibition (IC₅₀: 0.68 ± 0.13 μM) with strong DPPH and ABTS radical scavenging activity (IC₅₀: 13.77 ± 0.25 μM and IC₅₀: 12.59 ± 0.21 μM), respectively. While P3 exhibited as the second most potent compound with AChE inhibition (IC₅₀: 0.74 ± 0.09 μM) and with DPPH and ABTS radical scavenging activity (IC₅₀: 13.52 ± 0.62 μM and IC₅₀: 13.13 ± 0.85 μM), respectively. Finally, molecular docking studies provided prospective evidence to identify key interactions between the active inhibitors and the AChE that furthermore led us to the identification of plausible binding mode of novel indolopyrazoline derivatives. Additionally, in-silico ADME prediction using QikProp shows that these derivatives fulfilled all the properties of CNS acting drugs. This study confirms the first time reporting of indolopyrazoline derivatives as potential anti-Alzheimer agents.     

Design,synthesis and biological evaluation of lapachol derivatives possessing indole scaffolds as topoisomerase I inhibitors

A series of novel lapachol derivatives possessing indole scaffolds was designed and synthesized. The in vitro anti-proliferative activity of these novel compounds was evaluated in Eca109 and Hela cell lines. Almost all the tested compounds showed manifested potent inhibitory activity against the two tested cancer cell lines. Topo I-mediated DNA relaxation activity indicated that these novel compounds have potent Topoisomerase I inhibition activity. The most potent compounds 4n and 4k demonstrated more cytotoxicity than camptothecin and was comparable to camptothecin in inhibitory activities on Topoisomerase I in our biological assay. In addition, the Hoechst 33342 staining method also showed that the complex can induce Hela cell apoptosis.     

Design,synthesis, and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors

Two series of afatinib derivatives bearing cinnamamide moiety (10a–n and 11a–h) were designed, synthesized and evaluated for the IC₅₀ values against four cancer cell lines (A549, PC-3, MCF-7 and Hela). Two selected compounds (10e, 10k) were further evaluated for the inhibitory activity against EGFR and VEGFR2/KDR kinases. Seven of the compounds showed excellent cytotoxicity activity and selectivity with the IC₅₀ values in single-digit μM to nanomole range. Three of them are equal to more active than positive control afatinib against one or more cell lines. The most promising compound 10k showed the best activity against A549, PC-3, MCF-7 and Hela cancer cell lines and EGFR kinase, with the IC₅₀ values of 0.07 ± 0.02 μM, 7.67 ± 0.97 μM, 4.65 ± 0.90 μM and 4.83 ± 1.28 μM, which were equal to more active than afatinib (0.05 ± 0.01 μM, 4.1 ± 2.47 μM, 5.83 ± 1.89 μM and 6.81 ± 1.77 μM), respectively. Activity of compounds 10e (IC₅₀ 9.1 nM) and 10k (IC₅₀ 3.6 nM) against EGFR kinase were equal to the reference compound afatinib (IC₅₀ 1.6 nM). Structure–activity relationships (SARs) and docking studies indicated that replacement of the aqueous solubility 4-(dimethylamino)but-2-enamide group by cinnamamide moiety didn’t decrease the antitumor activity. The results suggested that methoxy substitution had a significant impact on the activity and methoxy substituted on C-4 or C-2,3,4 position was benefit for the activity.     

Rational design,synthesis, pharmacophore modeling,and docking studies for identification of novel potent DNA-PK inhibitors

Drugs of cancer based upon ionizing radiation or chemotherapeutic treatment may affect breaking of DNA double strand in cell. DNA-PK enzyme has emerged as an attractive target for drug discovery efforts toward DNA repair pathways. Hence, the search for potent and selective DNA-PK inhibitors has particularly considered state-of-the art and several series of inhibitors have been designed. In this article, a novel benchmark DNA-PK database of 43 compounds was built and described. Ligand-based approaches including pharmacophore and QSAR modeling were applied and novel models were introduced and analyzed for predicting activity test for DNA-PK drug candidates. Based upon the modeling results, we gave a report of synthesis of fifteen novel 2-((8-methyl-2-morpholino-4-oxo-4H-benzo[e][1,3]oxazin-7-yl)oxy)acetamide derivatives and in vitro evaluation for DNA-PK inhibitory and antiproliferative activities. These fifteen compounds overall are satisfied with Lipinski's rule of five. The biological testing of target compounds showed five promising active compounds 7c, 7d, 7f, 9e and 9f with micromolar DNA-PK activity range from 0.25 to 5 µM. In addition, SAR of the compounds activity was investigated and confirmed that the terminal aryl moiety was found to be quite crucial for DNA-PK activity. Moreover flexible docking simulation was done for the potent compounds into the putative binding site of the 3D homology model of DNA-PK enzyme and the probable interaction model between DNA-PK and the ligands was investigated and interpreted.     

Synthesis,biological evaluation and molecular docking studies of benzyloxyacetohydroxamic acids as LpxC inhibitors

The inhibition of the UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) represents a promising strategy to combat infections caused by multidrug-resistant Gram-negative bacteria. In order to elucidate the functional groups being important for the inhibition of LpxC, the structure of our previously reported hydroxamic acid 4 should be systematically varied. Therefore, a series of benzyloxyacetohydroxamic acids was prepared, of which the diphenylacetylene derivatives 28 (K_i = 95 nM) and 21 (K_i = 66 nM) were the most potent inhibitors of Escherichia coli LpxC. These compounds could be synthesized in a stereoselective manner employing a Sharpless asymmetric dihydroxylation and a Sonogashira coupling in the key steps. The obtained structure–activity relationships could be rationalized by molecular docking studies.     

Design,synthesis and molecular docking of amide and urea derivatives as Escherichia coli PDHc-E1 inhibitors

By targeting the ThDP binding site of Escherichia coli PDHc-E1, two new ‘open-chain’ classes of E. coli PDHc-E1 inhibitors, amide and urea derivatives, were designed, synthesized, and evaluated. The amide derivatives of compound 6d, with 4-NO₂ in the benzene ring, showed the most potent inhibition of E. coli PDHc-E1. The urea derivatives displayed more potent inhibitory activity than the corresponding amide derivatives with the same substituent. Molecular docking studies confirmed that the urea derivatives have more potency due to the two hydrogen bonds formed by two NH of urea with Glu522. The docking results also indicate it might help us to design more efficient PDHc-E1 inhibitors that could interact with Glu522.     

Synthesis,modification and docking studies of 5-sulfonyl isatin derivatives as SARS-CoV 3C-like protease inhibitors

The Severe Acute Respiratory Syndrome (SARS) is a serious life-threatening and strikingly mortal respiratory illness caused by SARS-CoV. SARS-CoV which contains a chymotrypsin-like main protease analogous to that of the main picornavirus protease, 3CL^pro. 3CL^pro plays a pivotal role in the viral replication cycle and is a potential target for SARS inhibitor development. A series of isatin derivatives as possible SARS-CoV 3CL^pro inhibitors was designed, synthesized, and evaluated by in vitro protease assay using fluorogenic substrate peptide, in which several showed potent inhibition against the 3CL^pro. Structure–activity relationship was analyzed, and possible binding interaction modes were proposed by molecular docking studies. Among all compounds, 8k₁ showed most potent inhibitory activity against 3CL^pro (IC₅₀ = 1.04 μM). These results indicated that these inhibitors could be potentially developed into anti-SARS drugs.     

Synthesis,biological evaluation and molecular modelling studies of 4-anilinoquinazoline derivatives as protein kinase inhibitors

A series of novel 4-anilinoquinazoline derivatives (3a–3j) has been synthesized and evaluated as potential inhibitors for protein kinases implicated in Alzheimer’s disease. Among all the synthesized compounds, compound 3e (N-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazolin-4-amine) exhibited the most potent inhibitory activity against CLK1 and GSK-3α/β kinase with IC₅₀ values of 1.5 μM and 3 μM, respectively. Docking studies were performed to elucidate the binding mode of the compounds to the active site of CLK1 and GSK-3β. The results of our study suggest that compound 3e may serve as a valuable template for the design and development of dual inhibitors of CLK1 and GSK-3α/β enzymes with potential therapeutic application in Alzheimer’s disease.     

Design,synthesis, biological evaluation and molecular modelling studies of indole glyoxylamides as a new class of potential pancreatic lipase inhibitors

A series of eighteen indole glyoxylamide analogues were synthesized, characterized and evaluated for their pancreatic lipase inhibitory activity. Porcine pancreatic lipase (Type II) was used with 4-nitrophenyl butyrate (as substrate) for the in vitro assay. Compound 8f exhibited competitive inhibition against pancreatic lipase with IC₅₀ value of 4.92 µM, comparable to that of the standard drug, orlistat (IC₅₀ = 0.99 µM). Compounds 7a-i and 8a-i were subjected to molecular docking into the active site of human PL (PDB ID: 1LPB) wherein compound 8f possessed a potential MolDock score of −153.037 kcal/mol. Molecular dynamics simulation of 8f complexed with pancreatic lipase, confirmed the role of aromatic substitution in stabilizing the ligand through hydrophobic interactions (maximum observed RMSD = 3.5 Å).