English Abstract
Abstract :
Leishmaniasis is a parasitic disease caused by Leishmania species, transmitted
through the bites of infected sandflies. It poses a significant public health
challenge in many tropical and subtropical regions, leading to severe morbidity
and mortality. Current treatments, such as miltefosine, are limited by toxicity,
resistance, and accessibility issues. Therefore, developing new compounds with
improved efficacy and safety profiles is essential to combat this disease
effectively and provide better treatment options for affected populations.
This research focuses on synthesizing and characterizing dipicolinic acid
derivatives, evaluating their anti-leishmanial activities, and elucidating their
mechanisms of action. Molecular docking studies were conducted to predict the
binding interactions of these compounds with key targets in the Leishmania
metabolic pathways. Additionally, cytotoxicity assessments and predictions
regarding the absorption, distribution, metabolism, excretion, and toxicity
(ADMET) profiles of the most active compounds were performed. The findings
aim to provide better treatment options for affected populations and contribute
to the ongoing efforts to combat leishmaniasis.
The current study successfully synthesized dipicolinic acid derivatives,
achieving percentage yields between 33.1% and 85.46%, with relatively easy
synthetic method making these compounds attractive candidates for further
study. The structures of the synthesized compounds were confirmed through
spectroscopic and elemental analyses. In vitro screening against two forms
of L.major demonstrated that all compounds exhibited activity, with compound
IV showing the highest efficacy with IC50 of 2.86±0.14 µM against
promastigotes and 3.84±0.16 µM against amastigotes, outperforming the
reference drug miltefosine by nearly three times. Mechanistic studies indicated
that compound 4 inhibits the folic acid pathway, as evidenced by anti-folate
tests and molecular docking, which revealed a docking score of -13.73 kcal/mol
for Lm-PTR1, surpassing that of trimethoprim (-11.91 kcal/mol).
Additionally, in vitro cytotoxicity assays indicated a superior safety profile for
compound IV, with an IS value of 108.2, significantly better than miltefosine.
In silico analyses further suggested favourable bioavailability and the potential
for enhanced toxicity profiles, reinforcing the viability of these compounds as
promising candidates for anti-leishmanial therapies.
