Synthesis and Anticancer Activity of N-Aryl-5-substituted-1,3,4-oxadiazol-2-amine Analogues

In continuance of our search for anticancer agents, we report herein the synthesis and anticancer activity of some novel oxadiazole analogues. The compounds were screened for anticancer activity as per National Cancer Institute (NCI US) protocol on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers cell lines. N-(2,4-Dimethylphenyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-amine (4s) showed maximum activity with mean growth percent (GP) of 62.61 and was found to be the most sensitive on MDA-MB-435 (melanoma), K-562 (leukemia), T-47D (breast cancer), and HCT-15 (colon cancer) cell lines with GP of 15.43, 18.22, 34.27, and 39.77, respectively. Maximum GP was observed on MDA-MB-435 (melanoma) cell line (GP = 6.82) by compound N- (2,4-dimethylphenyl)-5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-amine (4u)

Structure-based discovery of small molecule APC-Asef interaction inhibitors: In silico approaches and molecular dynamics simulations

Colorectal cancer, which is considered one of the leading causes of mortality worldwide, develops through the formation of benign polyps on the inner colon or rectum wall. Truncations in adenomatous polyposis coli (APC) gene lead to the spread of the disease in the entire colon region when combined with the guanine nucleotide exchange factor (GEF) Asef. A series of peptidomimetic agents were previously discovered as protein-protein interaction inhibitors that can target the APC-Asef interface. Structure-based virtual screening (SBVS), using a set of docking methods combined with molecular dynamics simulations, was carried out to identify new small drug-like agents. After the initial screening process, compounds with diverse chemical scaffolds and direct interaction with Arg549 and other active site residues were chosen and subjected to induce fit. The amide functional group found in the ligand hit structures showed strong interactions with Arg549, leading to observable conformational changes that allow suitable positioning within the peptide binding site. Furthermore, the pH-specific MD simulations of the top hit 838 within the APC-Asef binding site depicted significant interactions required for biochemical recognition in changing microenvironment. Predicted inhibitory constant (Ki) values and binding free energies of hits further described the significance of the amide group over the other chemical scaffolds. This combination of in silico approaches provides key insights for colorectal drug discovery programs targeting the APC-Asef interaction. [Figure not available: see fulltext.] © 2020, Springer-Verlag GmbH Germany, part of Springer Nature

Synthesis and Anticancer Activity of N-Aryl-5-substituted-1,3,4-oxadiazol-2-amine Analogues

In continuance of our search for anticancer agents, we report herein the synthesis and anticancer activity of some novel oxadiazole analogues. The compounds were screened for anticancer activity as per National Cancer Institute (NCI US) protocol on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers cell lines. N-(2,4-Dimethylphenyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-amine (4s) showed maximum activity with mean growth percent (GP) of 62.61 and was found to be the most sensitive on MDA-MB-435 (melanoma), K-562 (leukemia), T-47D (breast cancer), and HCT-15 (colon cancer) cell lines with GP of 15.43, 18.22, 34.27, and 39.77, respectively. Maximum GP was observed on MDA-MB-435 (melanoma) cell line (GP=6.82) by compound N-(2,4-dimethylphenyl)-5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-amine (4u)

Scaffold identification and drug repurposing for finding potential Dengue envelope inhibitors through ligand-based pharmacophore model

Most of the existing DENV entry inhibitors were discovered through structure-based, high-throughput screening techniques and optimization approaches by aiming β-OG pocket. However, the class of precise chemical scaffolds with superior antiviral activity targeting the early stages of virus infection that is considered to be beneficial in therapeutics and is still in process. In this study, ligand-based pharmacophore modeling using existing DENV entry inhibitors provided two best models, AADRR-2 and AAADR-2 (A- accepter, D- donor, R-ring) to screen public and DrugBank datasets. Further, approximately 36000 molecules were filtered using Zinc13 by employing the ideal validated models. Additionally, using β-OG binding pocket as target site, molecular docking experiments including induced-fit studies were conducted that provided further structurally divergent ligands. Moreover, the refined list of preferential hits were filtered out based on the best fitness score, binding energy and interaction paradigm, among them fused pyrimidine, hydrazone and biphenyl core comprising scaffolds were identified possessing profound interaction profile with key amino acid residues, ALA-50, GLN-200, PHE-193 and PHE-279 in 100 ns MD simulations. Additionally, the search for similar chemical fingerprints from DrugBank library was also carried out and Eltrombopag (Promacta/Revolade® prescribed in thrombocytopenia) was identified as a preferential β-OG pocket binder. The identified pyrazole-based hydrazone class of drug, Eltrombopag is in phase II clinical trials employed to treat dengue-mediated thrombocytopenia. Communicated by Ramaswamy H. Sarma</p

Synthesis, Characterisation, and In Vitro Anticancer Activity of Curcumin Analogues Bearing Pyrazole/Pyrimidine Ring Targeting EGFR Tyrosine Kinase

In search of potential therapeutics for cancer, we described herein the synthesis, characterization, and in vitro anticancer activity of a novel series of curcumin analogues. The anticancer effects were evaluated on a panel of 60 cell lines, according to the National Cancer Institute (NCI) screening protocol. There were 10 tested compounds among 14 synthesized compounds, which showed potent anticancer activity in both one-dose and 5-dose assays. The most active compound of the series was 3,5-bis(4-hydroxy-3-methylstyryl)-1H-pyrazole-1-yl(phenyl)methanone (10) which showed mean growth percent of −28.71 in one-dose assay and GI50 values between 0.0079 and 1.86 µM in 5-dose assay

Stereoselective total synthesis of stagonolide E

The first total synthesis of a 10-membered macrolide, stagonolide E is described from readily available 4-penten-1-ol. The synthetic strategy involves Jacobsen's kinetic resolution, Sharpless epoxidation, Stille-Gennari, and Yamaguchi lactonization as key reactions

In vitro studies of the antileishmanial activity of the newer 2-(substitutedphenoxy)-N-[(aryl)methylidene]acetohydrazide analogues

A series of new 2-(substitutedphenoxy)-N-[(aryl)methylidene]acetohydrazide analogues (8a-n) were synthesized in search of potential therapeutics for leishmaniasis. All the compounds were characterized by infrared (IR), nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry. The compounds were further evaluated for in vitro antileishmanial activity against promastigotes of Leishmania donovani as per the standard protocol reported elsewhere. 2-(2,4-Dichlorophenoxy)-N′-{[4-(morpholin-4-yl)phenyl]methylidene}acetohydrazide (8k) showed the most promising antileishmanial activity with IC50 of 48.10 µM, free from cytotoxicity (>153.08 µM)

Design, synthesis, optimization and antiviral activity of a class of hybrid dengue virus E protein inhibitors

The β-OG pocket is a cavity in the flavivirus envelope (E) protein that was identified by Proc. Natl. Acad. Sci. U.S.A.2003, 100, 6986 as a promising site for the design of antiviral agents that interfere with virus entry into the host cell. The availability of the X-ray crystal structure of the dengue virus (DENV) E protein provided an opportunity for in silico drug design efforts to identify candidate inhibitors. The present study was set up to explore whether it is possible to generate a novel class of molecules that are hybrids between two hit compounds that have been reported previously by ACS. Chem. Biol.2008, 3, 765 following an in silico screening effort against the DENV E protein. First, a library of twenty hybrid molecules were designed and synthesized to explore the feasibility of this strategy. Antiviral evaluation in a virus-cell-based assay for DENV proved this approach to be successful, after which another twenty-four molecules were produced to further explore and optimize the potency of this novel class of hybrid inhibitors. In the end, a molecule was obtained with an EC50 against dengue virus serotype 2 in the low micromolar range (23, 1.32±0.41μM).publisher: Elsevier articletitle: Design, synthesis, optimization and antiviral activity of a class of hybrid dengue virus E protein inhibitors journaltitle: Bioorganic & Medicinal Chemistry Letters articlelink: http://dx.doi.org/10.1016/j.bmcl.2015.02.059 content_type: article copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.status: publishe