Microwave-Assisted Ru(II)-Catalyzed Regioselective Methyl Acylation of 2-Arylbenzoazoles: Synthesis of Benzofuran Conjugates via C-H Activation/Annulation.

An efficient Ru(II)-catalyzed C-H functionalization protocol for 2-arylbenzoazoles as the directing group and sulfoxonium ylide has been developed. Gratifyingly, concomitant annulation was observed when 3-(benzo[d]azol-2-yl) phenol was used, enabling the construction of benzofuran conjugates. Notably, the utilization of water as the solvent and an energy efficient approach makes the reaction greener, contributing to overall sustainability. This protocol exhibits excellent scalability up to the gram scale with a diverse array of substitutions. Furthermore, the mechanism was examined by ESI-MS, and photophysical studies were also performed.

Exploration of cytotoxic potential and tubulin polymerization inhibition activity of cis-stilbene-1,2,3-triazole congeners.

To scrutinize cis-stilbene based molecules with potential anticancer and tubulin polymerization inhibition activity, a new series of cis-stilbene-1,2,3-triazole congeners was designed and synthesized via a click chemistry protocol. The cytotoxicity of these compounds 9a-j and 10a-j was screened against lung, breast, skin and colorectal cancer cell lines. Based on the results of MTT assay, we further evaluated the selectivity index of the most active compound 9j (IC50 3.25 ± 1.04 µM on HCT-116) by comparing its IC50 value (72.24 ± 1.20 µM) to that of the normal human cell line. Further, to confirm apoptotic cell death, cell morphology and staining studies (AO/EB, DAPI and Annexin V/PI) were carried out. The outcomes of studies showed apoptotic features like change in cell shape, cornering of nuclei, micronuclei formation, fragmented, bright, horseshoe-shaped nuclei, etc. Moreover, active compound 9j displayed G2/M phase cell cycle arrest with significant tubulin polymerization inhibition activity with an IC50 value of 4.51 µM. Additionally, in silico ADMET, molecular docking and molecular dynamic studies of 9j with 3E22 protein proved the binding of the compound at the colchicine binding site of tubulin.

Ru(II)-Catalyzed regioselective carbene insertion into ß-carbolines and isoquinolines.

A protocol for carbene insertion into the inert C(sp2)-H bond has been established wherein ß-carbolines and isoquinolines are explored as intrinsic directing groups. The Ru(II)-catalyzed strategy employing sulfoxonium ylides as the carbene precursor offers an effective and atom-economical functionalization of substrates of biological interest with only DMSO as the sole by-product. The strategy is scalable to gram scale, and it also showcases a wide range of functional group tolerance. ESI-MS studies assisted in the identification of intermediates and consolidation of a probable mechanistic pathway. Furthermore, investigations revealed that the functionalized molecules not only displayed selective inhibition against cancer cell lines, but also demonstrated promising photophysical properties.

Ru(II)-Catalyzed Regioselective C-N Bond Formation on Benzothiazoles Employing Acyl Azide as an Amidating Agent.

A Ru(II)-catalyzed regioselective direct ortho-amidation of 2-aryl benzo[d]thiazoles employing acyl azides as a nitrogen source has been accomplished. This approach utilizes the efficiency of benzothiazole as a directing group and the role of acyl azide as an effective amidating agent toward C-N bond formation, thereby evading the general Curtius rearrangement. The protocol highlights significant functional group tolerance, single-step, and external oxidant-free conditions, with the release of only innocuous molecular nitrogen as the byproduct. The reaction mechanism and the intermediates associated with this selective Ru-catalyzed reaction have been investigated using ESI-MS. The protocol also aided in the construction of ortho-amidated ß-carbolines, unveiling another class of fluorescent molecules.

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects.

Microwave-assisted (MWA) multicomponent reactions (MCRs) have successfully emerged as one of the useful tools in the synthesis of biologically relevant heterocycles. These reactions are strategically employed for the generation of a variety of heterocycles along with multiple point diversifications. Over the last few decades classical MCRs such as Ugi, Biginelli, etc. have witnessed enhanced yield and efficiency with microwave assistance. The highlights of MWA-MCRs are high yields, reduced reaction time, selectivity, atom economy and simpler purification techniques, such an approach can accelerate the drug discovery process. The present review focuses on the recent advances in MWA-MCRs and their mechanistic insights over the past decade and shed light on its advantage over the conventional approach.

Development of ß-carboline-benzothiazole hybrids via carboxamide formation as cytotoxic agents: DNA intercalative topoisomerase IIα inhibition and apoptosis induction.

In quest of promising anticancer agents, the pharmacophores of natural (ß-carboline) and synthetic origin (benzothiazole) were adjoined by a carboxamide bridge and three-point diversification was accomplished. The in vitro cytotoxic ability of the compounds was established on adherent and suspension human cancer cell lines and compounds 8u and 8f advanced as pre-eminent molecules with IC50 values of 1.46 and 1.81 µM respectively in A549 cell line. The cytospecificity was entrenched for potent compounds 8u and 8f by evaluating against normal human lung epithelial cells and selectivity index was calculated. Furthermore, EtBr displacement, relative viscosity and gel-based topoisomerase II target assays unveiled the intercalative topo-II inhibitory capability and DNA binding studies (absorbance) revealed the dissociation constant (Kd) for compounds 8u and 8f as 98 and 103 µM respectively. Additionally, cell-based flow cytometric assays like Annexin-V/PI dual staining aids in the quantification of apoptosis induced and JC-1 staining disclosed the depolarization of mitochondrial membrane potential by compound 8u in A549 cells in a dose-dependent manner. Moreover, wound healing assay established the inhibition of in vitro cell migration by compound 8u on A549 cells. In addition, molecular docking studies proved the binding of compounds 8u and 8f in the active site of DNA complexed with topo IIα and stabilized by interactions with DNA base pairs and amino acid residues. Remarkably, the compounds 8u and 8f follow Lipinski's rule of five and are in the recommended range for Jorgensen's rule of three with a minimal violation and other pharmacokinetic parameters revealing druggability of the synthesized hybrids.

ß-Carboline directed regioselective hydroxylation by employing Cu(OAc)2 and mechanistic investigation by ESI-MS.

A ß-carboline directed regioselective C-H activation protocol for hydroxylation has been developed by employing Cu(OAc)2, a cost-effective 3d metal. This fastidious reaction proceeds under microwave irradiation and furnishes exclusively ortho-hydroxylated products with moderate to good yields under greener reaction conditions. Gratifyingly, this approach retains considerable functional group tolerance and is feasible on both electron-rich and electron-deficient substrates. This protocol signifies monohydroxylation on ß-carboline via C-H functionalization which leads into development of biologically relevant molecules. The reaction mechanism was confirmed by intercepting and characterizing all the proposed intermediates by ESI-QTOF-MS.