Exploration of antiproliferative potential of modified triazole–benzohydrazone scaffold: Multitarget approach

Abstract

A novel series of triazole–benzohydrazone hybrids was efficiently designed and synthesized as antiproliferative agents, targeting different kinases. All compounds were screened via the National Cancer Institute (NCI) against 60 cancer cell lines, where compounds 16, 17, and 18 exhibited growth inhibition percent (GI%) of various leukemia subpanels with values of 70.33%, 64.13%, and 76.03%, respectively. Compound 18 showed broad‐spectrum antiproliferative efficacy toward most cancer cells, with outstanding potency regarding melanoma (MALME‐3M GI% = 101.82%) and breast cancer cell lines (MCF7 GI% = 85.87%), while proving safe toward the WI‐38 normal cell line, compared to doxorubicin. Multikinase investigation including vascular endothelial growth factor receptor 2 (VEGFR‐2), mesenchymal epithelial transition factor (c‐Met), proto‐oncogene B‐Raf, mitogen‐activated protein kinase kinase, extracellular signal‐regulated kinase, and phosphoinositide 3‐kinase was accomplished to reveal its plausible mechanism of action, giving the ultimate potency against both VEGFR‐2 and c‐Met with IC50 values of 0.055 and 0.042 μM, respectively, while displaying moderate to good inhibition concerning the remaining kinases. DNA binding capability was excluded using the methyl green colorimetric assay. Further, it exhibited both early and late apoptotic induction by about 16‐ and 9.4‐fold over the control, respectively, triggering cell cycle arrest in the G2/M phase. Physicochemical properties and bioavailability radar plot inferred drug‐likeness characteristics for compound 18. The molecular docking study assessed the binding pattern with the active sites of c‐Met and VEGFR‐2.

Novel N‐pyrocatechoyl and N‐pyrogalloyl hydrazone antioxidants endowed with cytotoxic and antibacterial activity

“…[ 11 ] Among many, hydrazone scaffold, including N ‐acylhydrazones, was identified as a privileged substrate in medicinal chemistry. [ 12–15 ] Fruitful explorations of hydrazone‐type derivatives exposed their various biological traits, [ 16 ] such as antitumor, [ 17 ] antiproliferative, [ 18 ] antioxidant, [ 19 ] antimicrobial, [ 20 ] antitubercular, [ 21 ] antileishmanial, [ 22 ] anti‐Alzheimer, [ 23 ] antidiabetic, [ 24 ] anti‐inflammatory, [ 25 ] anticonvulsant, [ 26 ] and so on. Also, the frequent employment of hydrazones in medicinal chemistry is welcomed due to simple synthetic methods feasible even without catalysts, as well as to straightforward chemical transformations and tunability.…”