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

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-Bienaym & eacute; 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 mu M), 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 mu M, being similar to 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.

Automated summary

Leishmania poses a substantial threat to the human population and the current drugs against it have limitations. Developing new drugs is crucial, and a library of imidazo-fused heterocycles was synthesized and screened. Compound 24 showed the strongest antileishmanial activity, with selectivity for a stage related to human disease. It was also more destructive to the parasites than host cells. These findings support the potential of imidazo-pyrimidine as a new antileishmanial pharmacophore and encourage further animal studies.