Identification of new modulator of DNA repairing pathways based on natural product (±)-peharmaline A.

The complex heterogenic environment of tumour mass often leads to drug resistance and facilitate chemo insensitivity triggering more malignant phenotypes among cancer patients. Major DNA-damaging cancer drugs have been consistently proven unsuccessful in terms of elevating chemo-resistance. (±)-peharmaline A, a hybrid natural product isolated from seeds of Peganum harmala L. possesses significant cytotoxic activities. Herein, we have described the design, and synthesis of a novel library of close and simplified analogues around the anticancer natural product (±)-peharmaline A and investigated their cytotoxic activities, which led to the identification of three structurally simplified lead compounds exhibiting better potency than parent natural product. Among them, demethoxy analogue of peharmaline A was further investigated for its anticancer potential eliciting demethoxy analogue as potent DNA-damage inducing agent attenuating the expression of the proteins responsible for the DNA damage repair. Therefore, this demethoxy analogue warrants detailed investigations for the confirmations of the molecular mechanism-based studies responsible for its anticancer activity. ______________________________________________________________________________.

Postmodification of voxelotor (GBT 440) via [Rh]-catalyzed cross dehydrogenative coupling with olefins.

The directed Rh(III)-catalyzed cross dehydrogenative coupling of the pyrazole unit of the GBT-440 scaffold has been explored with simple as well as conjugated olefins to synthesize post-functionalized GBT-440 analogues. The screening of these synthesized compounds for improving the oxygen binding efficiency of the hemoglobin isolated from the sickled red blood cells revealed that some of these compounds are as good as GBT-440.

Experimental and statistical analysis of As(III) adsorption from contaminated water using activated red mud doped calcium-alginate beads.

Arsenic present in water bodies causes devastating effects on aquatic organisms and indirectly poses a hazardous threat to human existence. There is an urgent need to develop potential and convincing technologies to troubleshoot this problem. In the present study, an adsorbent has been prepared using the waste red mud from hazardous aluminium industry and doping it with calcium-alginate beads (ARMCB) for the effective removal of As(III) from wastewater. The concentration of As(III) was reduced from 0.101 mg/L to 0.008 mg/L after adsorption which effectively met the economic and environmental conditions imposed by WHO (>0.01 mg/L). Further, the statistical Response Surface Methodology (RSM) is adopted to analyze the combined effects of four operational parameters namely: pH, sorbent dosage, contact time and initial concentration on the adsorption of As(III) from the synthetic contaminated water samples. A high correlation coefficient (R2) value of 0.9672 projected by ANOVA confirmed the satisfactory regression of the developed model. The maximum adsorption capacity is found to be 1.807 mg/g at optimum operating conditions. The surface characterization of the adsorbent before and after adsorption by SEM, EDX, XRD, and FTIR confirms the potentiality of the adsorbent towards As(III) ions. Thermodynamic, adsorption isotherms and kinetic analysis respectively projected the endothermic Langmuir model adsorption of As(III) and the pseudo-second-order rate kinetics of the sorption mechanism. The current study aids the implementation of the developed robust technique for the successful removal of As(III) from industrial and domestic polluted water samples.

Repurposing of a drug scaffold: Identification of novel sila analogues of rimonabant as potent antitubercular agents.

The structural similarity between an MmpL3 inhibitor BM212, and a cannabinoid receptor modulator rimonabant, prompted us to investigate the anti-tubercular activity of rimonabant and its analogues. Further optimization, particularly through incorporation of silicon into the scaffold, resulted in new compounds with significant improvement in anti-tubercular activity against Mycobacterium tuberculosis (H37Rv). The sila analogue 18a was found to be the most potent antimycobacterial compound (MIC, 31 ng/mL) from this series with an excellent selectivity index.

Structure-activity relationship studies of novel pyrazole and imidazole carboxamides as cannabinoid-1 (CB1) antagonists.

The synthesis and biological evaluation of novel pyrazole and imidazole carboxamides as CB1 antagonists are described. As a part of eastern amide SAR, various chemically diverse motifs were introduced on rimonabant template. The central pyrazole core was also replaced with its conformationally constrained motif and imidazole moieties. In general, a range of modifications were well tolerated. Several molecules with low- and sub-nanomolar potencies were identified as potent CB1 receptor antagonists. The in vivo proof of principle for weight loss is demonstrated with a lead compound in DIO mice model.