Anti-Leishmanial and Cytotoxic Activities of a Series of Maleimides: Synthesis, Biological Evaluation and Structure-Activity Relationship

Abstract

In the present study, 45 maleimides have been synthesized and evaluated for anti-leishmanial activities against L. donovani in vitro and cytotoxicity toward THP1 cells. All compounds exhibited obvious anti-leishmanial activities. Among the tested compounds, there were 10 maleimides with superior anti-leishmanial activities to standard drug amphotericin B, and 32 maleimides with superior anti-leishmanial activities to standard drug pentamidine, especially compounds 16 (IC₅₀ < 0.0128 μg/mL) and 42 (IC₅₀ < 0.0128 μg/mL), which showed extraordinary efficacy in an in vitro test and low cytotoxicities (CC₅₀ > 10 μg/mL). The anti-leishmanial activities of 16 and 42 were 10 times better than that of amphotericin B. The structure and activity relationship (SAR) studies revealed that 3,4-non-substituted maleimides displayed the strongest anti-leishmanial activities compared to those for 3-methyl-maleimides and 3,4-dichloro-maleimides. 3,4-dichloro-maleimides were the least cytotoxic compared to 3-methyl-maleimides and 3,4-non-substituted maleimides. The results show that several of the reported compounds are promising leads for potential anti-leishmanial drug development.

Keywords: Leishmania donovani; SAR; anti-leishmanial activity; cytotoxicity; maleimides.

Scheme 1

Synthesis of N-substituted maleimide derivatives. Path A: a. CH₃COOH. Path B: b. toluene, 25–65 °C, 2–8 h; c. CH₃COONa, (Et)₃N, 101 °C, 10–24 h.

Figure 1

Chemical structures of the studied N-substituted maleimides.

Figure 2

The chemical structure of pentamidine.

Figure 3

The chemical structure of amphotericin B.