Synthesis, in vitro biological evaluation and in silico studies of certain arylnicotinic acids conjugated with aryl (thio)semicarbazides as a novel class of anti-leishmanial agents

Abstract Herein we introduce new compounds as conjugates of arylnicotinic acids with aryl (thio)semicarbazides derivatives. Based on a structure-guided approach, they were designed to possess antileishmanial activity through antifolate mechanism, via targeting Leishmania major pteridine reductase 1 ( Lm -PTR1). The in vitro antipromastigote and antiamastigote activity were promising for many thiosemicarbazide derivatives and superior to the reference miltefosine. The most active compounds 8i and 8j exhibited their antiamastigote activity with IC 50 values of 4.2 and 3.3 μM, respectively, compared to reference miltefosine (IC 50 value of 7.3). Their antifolate mechanism was confirmed via the ability of folic and folinic acids to reverse the anti-leishmanial activity of these compounds, comparably to Lm -PTR1 inhibitor trimethoprim. Interestingly, the in vitro cytotoxicity test of the most active compounds displayed higher selectivity indices than that of miltefosine emphasizing their safety on mammalian cells. Furthermore, the docking experiments on Lm -PTR1 as a putative target rationalized the in vitro antileishmanial activity. The in silico predictions exhibited promising pharmacokinetics and drug-likeness profiles of the most active compounds. Generally, this work introduces a fruitful matrix for new antileishmanial chemotype which would extend the chemical space for the antileishmanial activity.