Synthesis and biological evaluation of coumarin–1,2,3-triazole–dithiocarbamate hybrids as potent LSD1 inhibitors

Abstract

Two series of coumarin–1,2,3-triazole–dithiocarbamate hybrids were designed, synthesized and evaluated for their inhibitory activity towards lysine specific demethylase 1 (LSD1). Compounds 8a, 8d–8f, 8i–8l presented potent activity against lysine specific demethylase 1. Among them, compound 8k showed potent and reversible inhibition against lysine specific demethylase 1 with an IC₅₀ value of 0.39 μM, which was 74-fold more potent than that of tranylcypromine (2-PCPA). Besides, compound 8k displayed excellent selectivity against lysine specific demethylase 1 without inhibition against monoamine oxidases (MAOs) A and B. Further investigation revealed that compound 8k was active at both recombinant and cell levels by upregulating the expression of H3K4me1, H3K4me2 and H3K9me2.