New antileishmanial quinoline linked isatin derivatives targeting DHFR-TS and PTR1: Design, synthesis, and molecular modeling studies.

In a search for new drug candidates for one of the neglected tropical diseases, leishmaniasis, twenty quinoline-isatin hybrids were synthesized and tested for their in vitro antileishmanial activity against Leishmania major strain. All the synthesized compounds showed promising in vitro activity against the promastigote form in a low micromolar range (IC 50 = 0.5084–5.9486 μM) superior to the reference miltefosine (IC 50 = 7.8976 μM). All the target compounds were then tested against the intracellular amastigote form and showed promising inhibition effects (IC 50 = 0.60442–8.2948 μM versus 8.08 μM for miltefosine). Compounds 4e , 4b and 4f were shown to possess the highest antileishmanial activity against both promastigote and amastigote forms. The most active compounds were proven to exhibit their significant antileishmanial effects through antifolate mechanism, targeting DHFR-TS and PTR1. To evaluate the safety profile of the most active derivatives 4e , 4b and 4f, the in vitro cytotoxicity test was carried out and displayed higher selectivity indices than the reference miltefosine. Molecular docking within putative target protein PTR1 confirmed the high potentiality of the most active compounds 4e , 4b and 4f to block the catalytic activity of Lm-PTR1. [Display omitted] • New quinoline-isatin hybrids were synthesized as antileishmanial agents. • Compounds 4e , 4b and 4f showed the highest in vitro activity. • The most active derivatives acted as DHFR-TS/PTR1 inhibitors. • The promising compounds displayed low toxicity in VERO cells. • In silico studies of the promising compounds showed high docking scores. [ABSTRACT FROM AUTHOR]