Synthesis, biological evaluation and docking studies of methylene bearing cyanopyrimidine derivatives possessing a hydrazone moiety as potent Lysine specific demethylase-1 (LSD1) inhibitors: A promising anticancer agents

• A series of potent Cyanopyrimidine-hydrazone derivatives were synthesized and evaluated for their in-vitro anticancer screening on NCI 60 cell lines along with LSD1 inhibition target assay. • In five-dose screening, compound 5a showed potent anti-cancer activity with GI 50 value of 0.414 µM and 0.417 µM against HOP-62 and OVCAR-4 cell lines respectively. • It inhibited LSD1 with IC 50 value of 0.956 µM which was the proposed mechanism behind anticancer activity. • Compound 5a was found to be the most potent compound of the series with best anticancer activity. A series of novel cyanopyrimidine-hydrazone hybrids were synthesized and characterized with various spectroscopic techniques. The synthesized compounds were tested at NCI, USA, on a 60-cell line panel and most of the compounds showed remarkable cytotoxic activity against different cancer cell lines. Compound 5a was found to be the most potent compound of the series and it was further selected for five dose assays wherein it exhibited GI 50 value of 0.414 µM and 0.417 µM against HOP-62 and OVCAR-4 cell lines respectively. The in-silico mechanistic studies indicated that these compounds are acting through inhibition of lysine specific demethylase 1 (LSD1) as evident from in-vitro LSD1 inhibition activity of compounds. Among various synthesized derivatives, compound 5a was found to have IC50-value of 0.956 µM. In addition, absorption, distribution, metabolism, excretion and toxicity profile (ADMET) was assessed for these novel derivatives to get an insight on their pharmacokinetic/dynamic attributes which revealed that synthesized compounds showed acceptable metabolic stability in human liver microsomes with minimal inhibition of cytochrome P450s (CYPs). The results indicated that compound 5a could be a promising lead compound for further development as a therapeutic agent for anticancer activity.