An efficient protocol for synthesis of 3,3′-diindolyl methanes using recyclable Fe – pillared interlayered clay (Fe-PILC) catalyst under aqueous medium have been developed. All synthesized 3,3′-diindolylmethanes showed promising antileishmanial activity against Leishmania donovani promastigotes as well as axenic amastigotes. Structure-activity relationship analysis revealed that nitroaryl substituted diindolylmethanes showed potent antileishmanial activity. The 4-nitrophenyl linked 3,3′-diindolylmethane 8g was found to be the most potent antileishmanial analog showing IC50 values of 7.88 and 8.37 μM against both L. donovani promastigotes and amastigotes, respectively. Further, a pharmacophore based QSAR model was established to understand the crucial molecular features of 3,3′-diindolylmethanes essential for potent antileishmanial activity. These compounds also exhibited promising antifungal activity against Cryptococcus neoformans, wherein fluorophenyl substituted 3,3′-diindolylmethanes were found to be most potent antifungal agents. Developed synthetic protocol will be useful for economical and eco-friendly synthesis of potent antileishmanial and antifungal 3,3′-diindolylmethane class of compounds.
An expedient and metal-free synthetic protocol for construction of substituted quinolines has been developed from anilines and phenylacetaldehydes using imidazolium cation-based ionic liquids as the reaction medium. Mechanistic analysis indicated that the reaction occurs through C-C and C-N bond formation to produce isolable 2,3-disubstituted quinoline intermediates, which undergo C-C bond cleavage to produce 3-substituted quinolines. The reaction proceeds smoothly with a range of functionalities in good to excellent yields. Advantages of this protocol include metal-free, environmentally friendly, recyclable reaction media, higher yields and shorter reaction times, and thus is promising for the efficient combinatorial synthesis of structurally diverse 2,3-disubstituted and 3-substituted quinolines.
An efficient one-pot multi-component synthesis of flavans using perchloric acid supported on silica as a recyclable heterogeneous catalyst has been described. This is the first report of direct one-step construction of a flavan skeleton from a phenolic precursor. The method involves a Knoevenagel-type condensation leading to in situ formation of transient O-quinone methide which further undergoes [4 + 2]-Diels-Alder cycloaddition with styrene to yield a flavan skeleton. The method provides easy access to a wide range of bio-active natural products viz. flavonoids, anthocyanins and catechins.
An efficient formic acid catalyzed one-pot synthesis of 4-arylquinoline 2-carboxylates in water via three-component coupling of arylamines, glyoxylates and phenylacetylenes has been described. 4-Arylquinoline 2-carboxylates 1o and 1q displayed significant antioxidant activity as indicated by their Fe-reducing power in the ferric reducing ability of plasma (FRAP) assay. The compounds were found to react directly with hydrogen peroxide, which might be one of the mechanisms of their antioxidant effect. Compounds 1o and 1q effectively quenched H2O2 and amyloid-β-generated reactive oxygen species (ROS) and also displayed significant protection against H2O2-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Additionally, all compounds exhibited promising P-glycoprotein induction activity in human adenocarcinoma LS-180 cells, indicating their potential to enhance amyloid-β clearance from Alzheimer's brains. Furthermore, all compounds were relatively non-toxic to SH-SY5Y and LS-180 cells (IC50 > 50 μM). The promising antioxidant, ROS quenching, neuroprotective and Pgp-induction activity of these compounds strongly indicate their potential as anti-Alzheimer's agents.
A cobalt acetylacetonate catalyzed oxidative diketonation of alkynes via C(sp)-H bond functionalization has been described. The reaction involves a free-radical mechanism, wherein the phenyl radical formed from phenyl hydrazine couples with Co(II) activated alkyne to produce 1,2-diketones. The reaction proceeds at room temperature in DMF with the use of Ag2O/air as the oxidizing system. The utility of the protocol for the synthesis of a series of imidazoles including a potent platelet aggregation inhibitor trifenagrel has been demonstrated.
Polysubstituted pyrrole natural products, lamellarins, are known to overcome multi-drug resistance in cancer via the inhibition of p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux pumps. Herein, a series of simplified polysubstituted pyrroles, prepared via a one-pot domino protocol, were screened for P-gp inhibition in P-gp overexpressing human adenocarcinoma LS-180 cells using a rhodamine 123 efflux assay. Several compounds showed the significant inhibition of P-gp at 50 μM, as indicated by increase in the intracellular accumulation of Rh123 in LS-180 cells. Furthermore, pyrrole 5i decreased the efflux of digoxin, a FDA approved P-gp substrate in MDCK-MDR1 cells with an IC50 of 11.2 μM. In in vivo studies, following the oral administration of a P-gp substrate drug, rifampicin, along with compound , the Cmax and AUC0-∞ of rifampicin was enhanced by 31% and 46%, respectively. All the compounds were then screened for their ability to potentiate ciprofloxacin activity via the inhibition of Staphylococcus aureus Nor A efflux pump. Pyrrole showed the significant inhibition of S. aureus Nor A efflux pump with 8- and 4-fold reductions in the MIC of ciprofloxacin at 50 and 6.25 μM, respectively. The molecular docking studies of compound with the human P-gp and S. aureus Nor A efflux pump identified its plausible binding site and key interactions. Thus, the results presented herein strongly indicate the potential of this scaffold for its use as multi-drug resistance reversal agent or bioavailability enhancer.
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