Synthesis and biological evaluation of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamides as antimitotic agents.

A library of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamides (7a-al) have been designed, synthesized and screened for their anti-proliferative activity against some selected human cancer cell lines namely DU-145, A-549, MCF-7 and HeLa. Most of them have shown promising cytotoxicity against lung cancer cell line (A549), amongst them 7f was found to be the most potent anti-proliferative congener. Furthermore, 7f exhibited comparable tubulin polymerization inhibition (IC50 value 2.04 µM) to the standard E7010 (IC50 value 2.15 µM). Moreover, flow cytometric analysis revealed that this compound induced apoptosis via cell cycle arrest at G2/M phase in A549 cells. Induction of apoptosis was further observed by examining the mitochondrial membrane potential and was also confirmed by Hoechst staining as well as Annexin V-FITC assays. Furthermore, molecular docking studies indicated that compound 7f binds to the colchicine binding site of the ß-tubulin. Thus, 7f exhibits anti-proliferative properties by inhibiting the tubulin polymerization through the binding at the colchicine active site and by induction of apoptosis.

Synthesis and biological evaluation of imidazo[2,1-b]thiazole-benzimidazole conjugates as microtubule-targeting agents.

A series of imidazo[2,1-b]thiazole-benzimidazole conjugates were synthesized and evaluated for their antiproliferative activity against four human cancer cell lines i.e.; HeLa (cervical), A549 (lung), MCF-7 (breast) and DU-145 (prostate) along with normal HEK-293 cell line. Amongst them, conjugate 6d displayed significant cytotoxicity against human lung cancer cell line, A549 with IC50 value 1.08 µM. Further, cell cycle analysis revealed that this compound arrested the cell cycle at G2/M phase in A549 cells. Furthermore, the tubulin polymerization assay results suggest that this conjugate (6d) exhibits significant inhibitory effect on the tubulin assembly with an IC50 value of 1.68 µM. Moreover, the apoptotic inducing properties of compound 6d was confirmed by Hoechst staining, measurement of mitochondrial membrane potential (ΔΨm) and annexin V-FITC assay. Further, molecular docking studies revealed that compound 6d occupied the colchicine binding site.

Iodine mediated oxidative cross-coupling of unprotected anilines and heteroarylation of benzothiazoles with 2-methylquinoline.

Iodine-promoted oxidative C-H/C-H cross-coupling of unprotected anilines and 2-methylquinoline to furnish C4-carbonylated aniline (4-aminophenyl)(quinoline-2-yl) methanones in moderate to good yields has been demonstrated. This work provides the first site-selective approach for the synthesis of free amino groups containing methanones including unprecedented C-H functionalization rather than the N-H functionalization of unprotected anilines via the Kornblum oxidation of 2-methylquinoline. Furthermore, we noticed that the incorporation of KOH under standard conditions provides 2-heteroarylbenzothiazoles from benzothiazoles and 2-methylquinoline in good to excellent yields. These transformations do not require any transition metals or peroxides and tolerate various functional groups such as methoxy, hydroxy, bromo, chloro and nitro groups. Moreover, a plausible mechanistic pathway is proposed.

Iodine-catalyzed Csp3-H functionalization of methylhetarenes: One-pot synthesis and cytotoxic evaluation of heteroarenyl-benzimidazoles and benzothiazole.

An efficient one-pot synthetic procedure has been developed for the preparation of heteroarenyl-benzimidazoles via oxidative Csp3-H functionalization with o-phenylenediamine using I2-DMSO in open air from easily available starting materials. Based on a logical plan a spectrum of multi fundamental reactions like iodination, Kornblum oxidation and amination were brought into one-pot. By using this simple method a library of heteroarenyl-benzimidazoles derivatives (3a-t and 5a-g) and heteroarenyl-benzothiazole (3u) have been synthesized in good to excellent yield and screened for their cytotoxicity against a group of four human cancer cell lines. Among them 3h, 3q and 5b showed significant cytotoxic activities with an IC50 of 1.69, 1.62 and 2.81µM respectively against lung cancer (A549) cell line.

Design, synthesis of phenstatin/isocombretastatin-oxindole conjugates as antimitotic agents.

A series of phenstatin/isocombretastatin-oxindole conjugates was synthesized and tested for their cytotoxic activity against five human cancer cells such as prostate (DU-145), lung (A549), colon (HT-29), breast (MCF-7), liver (HepG2) cancer cells with IC50 values ranging from 0.049 to 38.90 µM. Amongst them, two conjugates (5c and 5d) showed broad spectrum of antiproliferative efficacy on lung cancer cells with an IC50 value of 79 nM and 93 nM, respectively, whereas on colon cancer cells with an IC50 values 45 nM and 49 nM, respectively. In addition, cell cycle assay revealed that these conjugates (5c and 5d) arrest at the G2/M phase and leads to apoptotic cell death which was confirmed by Annexin V-FITC and mitochondrial membrane depolarization. Further, the tubulin polymerization assay analysis results suggest that these conjugates particularly 5c and 5d exhibit significant inhibitory effect on the tubulin assembly with an IC50 value of 1.23 µM and 1.01 µM, respectively. Molecular docking studies indicated that these compounds (5c and 5d) occupy the colchicine binding site of the tubulin.