Design, synthesis, structure-activity relationship and mechanism of action studies of a series of 4-chloro-1-phthalazinyl hydrazones as a potent agent against Leishmania braziliensis

Abstract

With the aim to identify a potential drug candidate to treat cutaneous leishmaniasis, a series of 1-phthalazinyl hydrazones were synthesized and tested against Leishmania braziliensis parasite, one of the main responsible of this disease in the world. A structure-activity relationship permitted to identify two phthalazines containing nitroheterocyclic moiety 3l and 3m as promising new lead compounds. These compounds showed a significant antileishmanial activity against promastigote form of L. braziliensis, with EC₅₀ values in sub-micromolar and nanomolar ranges. The phthalazine 3l also displayed a selective and excellent activity against the clinically relevant intracellular amastigotes form, with a EC₅₀ value in sub-micromolar range (0.59 μM), without affecting the viability of the host cells. Oxidative stress was identified as the possible mode of action of the most active phthalazine. Considering their significant antileishmanial activity and ease synthesis, the phthalazine containing nitroheterocyclic represents a promising agent against Leishmania braziliensis for the rational design of new leads.

Keywords: Antileishmanial activity; Leishmania braziliensis; Nitroheterocycle; Phthalazine; Promastigotes; Superoxide dismutase.