Targeting Leishmaniasis with Nitrovinyl Derivatives: Synthesis, In Vitro Assessment, and Computational Exploration

Leishmaniasis is an affliction caused by the protozoan parasites of the Leishmania genus. This disease impacts a substantial global populace, exceeding one million individuals, leading to disability-adjusted life years and fatalities, particularly within tropical regions. At present, the existing drug therapies have not attained a degree of efficacy that can be unequivocally classified as genuinely triumphant. In this context, the conception of novel compounds possessing the capacity to impede the parasite's life cycle at various stages holds considerable significance.

In this research endeavor, an exploration was undertaken involving the design and synthesis of nineteen derivatives incorporating the nitrovinyl pharmacophore. The subsequent evaluation of their impacts on L. major was conducted through a combination of in vitro (amastigote and promastigote inhibition) and in silico (molecular docking) investigations.

All of the compounds were synthesized and purified with good yields. In the amastigote inhibition assay, compounds 10, 15, and 18 showed better inhibitory effects than the standard drug meglumine antimonate (MA). Regarding the synergistic impact of synthesized compounds and MA together, all outcomes were significantly better than those of monotherapy of each in amastigote and macrophage forms. In the promastigote assay, compounds 2, 8, 12, 15, 16, 17, and 19 demonstrated superior inhibitory effects compared to MA. Moreover, compounds 4, 12, and 15 showed the best synergies with MA in inhibiting amastigotes. According to docking scores, 1XTP (a SAM-dependent methyltransferase) and 4G5D (Prostaglandin F synthase) receptors were found to be the most probable targets in their mechanism of action.

In vitro evaluations and computational analyses strongly suggest that these compounds could be effective against both L. major amastigotes and promastigotes. Additionally, they exhibited notable synergistic interactions with MA against both living forms of the parasite.