The role of natural anti-parasitic guided development of synthetic drugs for leishmaniasis

Abstract

Leishmaniasis is a parasitic disease and categorised as a neglected tropical disease (NTD). Each year, between 70,0000 and 1 million new cases are believed to occur. There are approximately 90 sandfly species which can spread the Leishmania parasites (over 20 species) causing 20,000 to 30,000 death per year. Currently, leishmaniasis has no specific therapeutic treatment available. The prescribed drugs with several drawbacks including high cost, challenging administration, toxicity, and drug resistance led to search for the alternative treatment with less toxicity and selectivity. Introducing the molecular features like that of phytoconstituents for the search of compounds with less toxicity is another promising approach. The current review classifies the synthetic compounds according to the core rings present in the natural phytochemicals for the development of antileishmanial agents (2020-2022). Considering the toxicity and limitations of synthetic analogues, natural compounds are at the higher notch in terms of effectiveness and safety. Synthesized compounds of chalcones (Compound 8; IC₅₀: 0.03 μM, 4.7 folds more potent than Amphotericin B; IC₅₀: 0.14 μM), pyrimidine (compound 56; against L. tropica; 0.04 μM and L. infantum; 0.042 μM as compared to glucantime: L. tropica; 8.17 μM and L. infantum; 8.42 μM), quinazoline and (compound 72; 0.021 μM, 150 times more potent than miltefosine). The targeted delivery against DHFR have been demonstrated by one of the pyrimidine compounds 62 with an IC₅₀ value of 0.10 μM against L. major as compared to the standard trimethoprim (IC₅₀: 20 μM). The review covers the medicinal importance of antileishmanial agents from synthetic and natural sources such as chalcone, pyrazole, coumarins, steroids, and alkaloidal-containing drugs (indole, quinolines, pyridine, pyrimidine, carbolines, pyrrole, aurones, and quinazolines). The efforts of introducing the core rings present in the natural phytoconstituents as antileishmanial in the synthetic compounds are discussed with their structural activity relationship. The perspective will support the medicinal chemists in refining and directing the development of novel molecules phytochemicals-based antileishmanial agents.

Keywords: Antileishmanial agents; Drug resistance; Leishmaniasis; Natural agents; SAR.