α-Amylase and mycobacterium-TB H37Rv antagonistic efficacy of novel pyrazole-coumarin hybrids: an in vitro and in silico investigation.

The present investigation of minutiae to acquire structural information of the novel pyrazole-coumarin hybrids (PC1-PC10) synthesized using ultrasound methods and characterized using different spectroscopic techniques: mass, 1H-NMR, 13 C-NMR and IR spectroscopy, and theoretically explored using the DFT approach with a B3LYP/6-311G (d, p) basis set, and there in vitro, antagonistic efficacy against α-amylase and mycobacterium-TB H37Rv are described in this article. Pyrazole-coumarin hybrids (PC1-PC10) showed α-amylase inhibition ranging from IC50 (0.32-0.58 mM) when compared with acarbose (IC50 = 0.34 mM). Similarly, Mycobacterium-TB H37Rv strain inhibition screening showed MIC values ranging from 62.5 to 1000 µg/mL when compared with rifampicin and isoniazid MIC = 0.25 and 0.20 µg/mL, respectively. Molecular docking and MD simulation studies were performed to determine the active sites and rationalize the activities of the active compounds. To investigate the binding conformation and dynamics responsible for their activity, the three most active compounds (PC1, PC3 and PC6) were docked into the porcine pancreatic α-amylase active site (PDB ID:1OSE), and mycobacterium-TB H37Rv active site (PDB ID: 4TZK). The binding interactions between PC1, PC3, and PC6 with α-amylase were like those responsible for inhibiting α-amylase by acarbose. Also, the mycobacterium-TB H37Rv inhibiting responsible residues were compared with standard isoniazid and rifampicin.Communicated by Ramaswamy H. Sarma.

Water mediated construction of trisubstituted pyrazoles/isoxazoles library using ketene dithioacetals.

A small molecule library of alkyl, sulfone, and carboxamide functionalized pyrazoles and isoxazoles has been developed via a rapid sequential condensation of various alpha-acylketene dithioacetals (1a-o) with hydrazine hydrate or hydroxylamine hydrochloride, followed by oxidation of sulfide to sulfone using water as the reaction medium. An efficient and safe oxidation of sulfides (4/5a-o) to the corresponding sulfones (6/7a-o) using sodium per borate system in aqueous medium is reported. The concise and two step synthesis of trisubstituted pyrazoles and isoxazoles was investigated under variety of reaction condition. The newly developed methodology has the advantage of excellent yield and chemical purity with short reaction time using water as a solvent.

Novel DNA-directed alkylating agents: design, synthesis and potent antitumor effect of phenyl N-mustard-9-anilinoacridine conjugates via a carbamate or carbonate linker.

A series of phenyl N-mustard-9-anilinoacridine conjugates via a carbamate or carbonate linker was synthesized for antitumor evaluation. The carbamate or carbonate linker is able to lower the reactivity of the phenyl N-mustard pharmacophore and thus, these conjugates are rather chemically stable. The in vitro studies revealed that these derivatives possessed significant cytotoxicity with IC(50) in sub-micromolar range in inhibiting human lymphoblastic leukemia (CCRF-CEM), breast carcinoma (MX-1), colon carcinoma (HCT-116) and human non-small cell lung cancer (H1299) cell growth in vitro. Compounds 10a, 10b, 10e, 10i, and 15a were selected for evaluating their antitumor activity in nude mice bearing MX-1 and HCT-116 xenografts. Remarkably, total tumor remission was achieved by these agents with only one cycle of treatment. Interestingly, no tumor relapse was found in mice treated with 10a over 129 days. This agent is capable of inducing DNA interstrand cross-linking in human non-small lung cancer H1299 cells in a dose dependent manner by modified comet assay and has a long half-life in rat plasma.

Synthesis and biological activity of stable and potent antitumor agents, aniline nitrogen mustards linked to 9-anilinoacridines via a urea linkage.

To improve the chemical stability and therapeutic efficacy of N-mustard, a series of phenyl N-mustard linked to DNA-affinic 9-anilinoacridines and acridine via a urea linker were synthesized and evaluated for antitumor studies. The new N-mustard derivatives were prepared by the reaction of 4-bis(2-chloroethyl)aminophenyl isocyanate with a variety of 9-anilinoacridines or 9-aminoacridine. The antitumor studies revealed that these agents exhibited potent cytotoxicity in vitro without cross-resistance to taxol or vinblastine and showed potent antitumor therapeutic efficacy in nude mice against human tumor xenografts. It also showed that 24d was capable of inducing marked dose-dependent levels of DNA cross-linking by comet assay and has long half-life in rat plasma.

Three-dimensional quantitative structure-activity relationship of 1,4-dihydropyridines as antitubercular agents.

Three-dimensional quantitative structure-activity relationship (3D QSAR) methods, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), were applied on a series of 1,4-dihydropyridines possessing antitubercular activity. The study was performed using 33 compounds, in which 22 molecules were used for the derivation of the 3D QSAR models (training set) and 11 molecules were used to evaluate the predictive ability of the derived models (test set). Superimpositions were performed using three alignment rules: atom-based fitting, SYBYL QSAR rigid body field fit of the steric and electrostatic fields of the molecules, and flexible fitting (multifit). Both methods were analyzed in terms of their predictive abilities and produced comparable results with high internal as well as external predictivities. Steric and electrostatic fields of the inhibitors were found to be relevant descriptors for SAR. Use of lowest unoccupied molecular orbital energies or ClogP as additional descriptors in the QSAR table did not improve the significance of the 3D QSAR models. Both CoMFA and CoMSIA models based on multifit alignment showed better correlative and predictive properties than other models. A QSAR study using genetic function approximation was also performed for the same set of molecules using different types of physicochemical descriptors to deal with cell-based activity data. The QSAR models revealed the importance of spatial properties and conformational flexibility of side chains for antitubercular activity. Inclusion of fractional polar solvent accessible surface area as a descriptor in the model generation resulted in models with significant internal and external predictivities for the same test set molecules, which may support the possible mode of action of these compounds.