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 (IC50 symbolscript 0.5084-5.9486 mu M) superior to the reference miltefosine (IC50 symbolscript 7.8976 mu M). All the target compounds were then tested against the intracellular amastigote form and showed promising inhibition effects (IC50 symbolscript 0.60442-8.2948 mu M versus 8.08 mu M 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, tar-geting 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. Mo-lecular docking within putative target protein PTR1 confirmed the high potentiality of the most active com-pounds 4e, 4b and 4f to block the catalytic activity of Lm-PTR1.

Automated summary

In this study, new quinoline-isatin hybrids were synthesized and tested for their antileishmanial activity. All compounds showed promising in vitro activity against Leishmania major strain and were found to have higher activity than the reference drug miltefosine. Compounds 4e, 4b, and 4f showed the highest antileishmanial activity against both promastigote and amastigote forms.