Surender Singh Jadav

Monoamine oxidase inhibitory activity of 3,5-biaryl-4,5-dihydro-1H-pyrazole-1-carboxylate derivatives.

Ethyl and phenyl carbamate derivatives of pyrazoline (3a-3h) were synthesized and tested for their MAO inhibitory activity. All the compounds were found to be selective towards MAO-A. Phenyl carbamates (3e-3h) were better than ethyl carbamates (3a-3d) and displayed the best selectivity index. Compound 3f (KiMAO-A; 4.96 ± 0.21 nM) was found to be equally potent as that of standard drug, Moclobemide (KiMAO-A; 5.01 ± 0.13 nM) but with best selectivity index (8.86 × 10(-5)). Molecular docking studies with R &S conformer of 3f revealed S-enantiomer is better than R-enantiomer as reported earlier by other groups. It is proposed that VdWs radii of the substitution (bulkiness) in ring B determine the potency of phenyl carbamates.

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.

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).

Synthesis, cytotoxic activity and docking studies of new 4-aza-podophyllotoxin derivatives

Abstract The synthesized nine aza-podophyllotoxin derivatives (8a–f, 10, 12and14) have been evaluated for their cytotoxicity in a panel of tumor cancer cell lines (Zr-75-1, MCF7, KB, Gurav, DWD, Colo-205, A-549 and Hop62). Among them, 8a and 8b compounds show stronger growth inhibition activity than the standard drug etoposide. Further, molecular docking simulations were carried out against human topoisomerase II, a putative target for these classes of molecules.

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).

In vivo anti-inflammatory activity and docking study of newly synthesized benzimidazole derivatives bearing oxadiazole and morpholine rings

In search of potential therapeutics for inflammatory disease, we report herein the synthesis, characterization and anti-inflammatory activities of a new series of 1-{(5-substituted-1,3,4-oxadiazol-2-yl)methyl}-2-(morpholinomethyl)-1H-benzimidazoles (5a-r). The anti-inflammatory activity of the compounds was evaluated using carrageenan induced rat paw edema test. Some compounds showed excellent anti-inflammatory activity in carrageenan induced rat paw edema test. 1-{(5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl)methyl}-2-(morpholinomethyl)-1H-benzimidazole (5g) showed maximum anti-inflammatory (74.17±1.28% inhibition) with reduced ulcerogenic and lipid peroxidation profile and also showed significant COX-2 inhibition with IC50 values of 8.00μM. Compounds 5o and 5q were also found to exhibit good COX-2 inhibition with IC50 values of 11.4 and 13.7μM concentrations. Molecular docking study showed that morpholine and oxadiazole rings linked to the benzimidazole nucleus play an important role in binding with the COX-2.

Molecular hybrid design, synthesis and biological evaluation of N-phenyl sulfonamide linked N-acyl hydrazone derivatives functioning as COX-2 inhibitors: new anti-inflammatory, anti-oxidant and anti-bacterial agents

Herein, we report the design, synthesis and biological evaluation of the anti-inflammatory activities of N-phenyl sulfonamide linked N-acylhydrazones (NPS–NAH), using the molecular hybridization approach. Hybrid compounds were further validated by theoretical studies. Compound 1f from series-1 and compound 2a from series-2 exhibited strong selective COX-2 enzyme inhibition at IC50 = 8.9 μM and 8.4 μM respectively. Effective in vivo anti-inflammatory profiling of potent and selective COX-2 inhibitors, including compound 1f and 2a was carried out and compared with known COX-2 inhibitors. Subsequently, these compounds were tested for antioxidant activity, and 1h (IC50 = 28.62 μM) from series-1 and compound 2d (IC50 = 25.34 μM) from series-2 were found to be potent anti-oxidants. Additionally, these compounds were screened for antibacterial activity, and compound 1l and 2b exhibited better Gram +ve and −ve anti-bacterial activity than the reference standards, Ciprofloxacin and Norfloxacin. These results validated the idea of exploiting the hybridization strategy for the identification of new N-phenyl sulfonamide–NAH derivatives for optimizing anti-inflammatory, antioxidant and anti-bacterial activities.

Mechanism of immunoprotective effects of curcumin in DLM-induced thymic apoptosis and altered immune function: an in silico and in vitro study

Abstract Curcumin, a main component of Curcuma Longa Linn, is a plant polyphenol used as an immune-enhancer in the Indian system of traditional medicine. However, its underlying mechanism of immune-protection remains unknown. The present study is designed to delineate the role of curcumin in deltamethrin (DLM)-induced thymocyte apoptosis and altered immune functions. In silico studies revealed that curcumin has a strong binding affinity toward CD4 and CD8 receptors. DLM (25 µM) induces thymocytes apoptosis through oxidative stress and caspase-dependent pathways. Various concentrations of curcumin (1, 10 and 50 µg/ml), when added along with DLM, caused a concentration- and time-related amelioration in apoptogenic signaling pathways induced by DLM. Inhibition of DLM-induced reactive oxygen species production, replenishment of glutathione and suppression of caspase activities by curcumin may thus be responsible for the suppression of downstream cascade of events, i.e. apoptosis, phenotypic changes and altered cytokine release. Thus, this study clearly demonstrates that the mechanism of immunoprotection of curcumin in DLM-induced thymic apoptosis includes inhibition of oxidative stress and caspase-dependent pathways underlying apoptosis.

Synthesis, Anticancer and Molecular Docking Studies of2-(4-chlorophenyl)-5-aryl-1,3,4-Oxadiazole Analogues

Among a series of ten, 2-(4-chlorophrnyl)-5-aryl-1,3,4-oxadiazole analogs, 4c showed maximum activity on various cancer cell lines, with average growth percent of 95.37%. The molecular docking studies for the compounds 4a & 4c showed that the residue Cys797 is present near to the para substitution of phenyl group while the five member oxadiazole ring of ligandswas lying near to Leu792 and Met 793 of EGFR tyrosine kinase active

Synthesis, in vitro antiproliferative activity, antioxidant activity and molecular modeling studies of new carbazole Mannich bases

A new class of carbazole Mannich bases were synthesized from 4-hydroxycarbazole by reacting with aromatic aldehydes and cyclic amines under mild reaction conditions in good yields. The method does not require column chromatographic purification for isolation of the products. The synthetic potential of these carbazole Mannich bases is exemplified by the ortho-quinone methide formation and subsequent in situ trapping with active methylene compounds bearing a cyano group to construct biologically active pyrano[3,2-c]carbazoles. Further, all the synthesized Mannich bases were tested for their in vitro antiproliferative activity against three cancer cell lines (Hela, MDA-MB-231, and HepG2). The results indicated that these compounds showed selective cytotoxicity against Hela cells. In addition, the synthesized carbazole Mannich bases were also screened for their scavenging activity of the 2,2-diphenyl-1-picrylhydrazyl radical and most of the compounds showed very good antioxidant activity. In silico molecular docking study of synthesized carbazole Mannich bases against colchicine binding site of the tubulin polymer was investigated.