Design and Synthesis of S-Acetophenylhydrazones of 5-Methyl-1,3,4-Thiadiazole-2-Thiol as SHP2 Inhibitory Agents.

We report herein the rational design, synthesis and evaluation of a library of 21 S-acetophenylhydrazones of 5-methyl-1,3,4-thiadiazole-2-thiol bearing a substituted benzylidene moiety (compounds 5a-5u). Compound 5f ((E)-N'-(2,6-dichlorobenzylidene)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)acetohydrazide) emerged as the most potent SHP2 inhibitor (IC50 = 0.120 ± 0.006 µM). Further, cell-based studies revealed its moderate yet best-in-library cytotoxicity against MCF-7 cells (IC50 = 86.46 ± 2.32 µM) in a dose-dependent manner. Compound 5f also exhibited in vitro anti-survival (33% colony formation) and anti-migratory effect (45% wound closure) on MCF-7 cells upon treatment with sub-IC50 dose. In vivo toxicological evaluation of compound 5f revealed excellent safety profile in mice at an oral dose of 2000 mg/kg BW. Our current study yielded a novel heterocyclic scaffold designed through systematic lead-guided optimization displaying submicromolar SHP2 inhibitory activity. The lead molecule identified from in vitro studies was effective against the proliferation, survival and migration of human breast cancer cells with an excellent in vivo safety profile.