Imidazo[1,2- a]pyrimidine as a New Antileishmanial Pharmacophore against Leishmania amazonensis Promastigotes and Amastigotes

Abstract

Leishmania poses a substantial threat to the human population all over the globe because of its visceral and cutaneous spread engendered by all 20 species. Unfortunately, the available drugs against leishmania are already hobbled with toxicity, prolonged treatment, and increasing instances of acquirement of resistance. Under these grave circumstances, the development of new drugs has become imperative to keep these harmful microbes at bay. To this end, a Groebke-Blackburn-Bienaymé multicomponent reaction-based library of different imidazo-fused heterocycles has been synthesized and screened against Leishmania amazonensis promastigotes and amastigotes. Among the library compounds, the imidazo-pyrimidine 24 has been found to be the most effective (inhibitory concentration of 50% (IC₅₀) < 10 μM), with selective antileishmanial activity on amastigote forms, a stage of the parasite related to human disease. The compound 24 has exhibited an IC₅₀ value of 6.63 μM, being ∼two times more active than miltefosine, a reference drug. Furthermore, this compound is >10 times more destructive to the intracellular parasites than host cells. The observed in vitro antileishmanial activity along with suitable in silico physicochemical and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of compound 24 reinforce the imidazo-pyrimidine scaffold as a new antileishmanial pharmacophore and encourage further murine experimental leishmaniasis studies.

Figure 1

Imidazo-pyridine-based molecules having antileishmanial activity.

Scheme 1. General Synthetic Protocol for the Formation of Imidazo-Fused Heterocycles.

Figure 2

Antileishmanial activity and cytotoxicity of imidazo-pyridine analogues (in μM). Pro and ama mean promastigotes and amastigotes, respectively, of L. amazonensis (L.A.). Cytotoxicity is the toxic effect on murine macrophages. These results correspond to the average of three experiments performed in duplicate.

Figure 3

Antileishmanial activity and cytotoxicity of compounds 13 and 14 (in μM). Pro and ama mean promastigotes and amastigotes, respectively, of L. amazonensis (L.A.). Cytotoxicity is the toxic effect on murine macrophages. These results correspond to the average of three experiments performed in duplicate.