Targeting Leishmaniasis with Nitrovinyl Derivatives: Their Synthesis, In Vitro Assessment, and Computational Exploration
Authors: Asadipour Ali , Khani Fatemeh Ghelich , Langarizadeh Mohammad Amin , Salarkia Ehsan , Tavakoli Marziye Ranjbar , Sharifi Fatemeh , Amirheidari Bagher , Ranjbar Mehdi , Faghih-Mirzaei Ehsan , Pourshojaei Yaghoub 
Published: October 2024

Introduction:
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.

Methods:
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.

Results:
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.

Conclusion:
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.

conclusion:
In summary, our results suggest that combination therapies are generally more effective than single-drug therapy. Notably, the novel compounds synthesized in the course of this research (compounds 16-19) proved to be among the most efficacious agents. Consequently, the focus of computational analyses was primarily directed towards these compounds. As an extension of this study, it is recommended that compounds bearing the nitrovinyl pharmacophore in conjunction with the benzyloxy functional group be synthesized. This proposition stems from the anticipation that such compounds could be subjected to more comprehensive investigation, shedding light on both their inhibitory capabilities and their potential for synergistic interactions. Moreover, owing to the versatility and expandability of these compounds within the binding pockets associated with the examined receptors, notably the 1XTP receptor, it becomes feasible to delineate potential routes for derivatization for better fitting properties. Furthermore, it is advisable to explore the impact of these compounds on various Leishmania species to discern their potential broad-spectrum efficacy in curbing this global jeopardy.