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.
Highlights
Leishmaniasis, which is caused by several species of Leishmania, is one of the major tropical diseases defined by the World Health Organization (WHO), affecting about 12 million people [1,2]
The results suggest that some of the synthesized maleimides might be developed as the anti-leishmanial drugs in the future
All maleimides were synthesized employing two methods according to an improved procedure based on the reported methods [22,32,33], using amines and maleic anhydrides as starting materials (Scheme 1)
Summary
Leishmaniasis, which is caused by several species of Leishmania, is one of the major tropical diseases defined by the World Health Organization (WHO), affecting about 12 million people [1,2]. Pentostam is the most widely used drug, which contains the heavy metal antimony Other medicines, such as amphotericin B and its derivatives [5], liposomal amphotericin B [5], paromomycin [6], and miltefosine [7], have their individual problems, such as toxicity, poor efficacy, or high cost. For most of them, the IC50 s of anti-leishmanial activities still remained to be in micromolar ranges except thiosemicarbazones In addition to great antimicrobial activities, maleimides had been widely researched in medicine as antianxiety [35], anti-inflammatory [36], anticancer [37,38] and neuroprotective agents. No anti-leishmanial activity of maleimides has been reported before this. The results suggest that some of the synthesized maleimides might be developed as the anti-leishmanial drugs in the future
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