. 2018 Nov 5;23(11):2878.

doi: 10.3390/molecules23112878.

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

Yongxian Fan¹, Yuele Lu², Xiaolong Chen³, Babu Tekwani⁴, Xing-Cong Li⁵, Yinchu Shen⁶

Affiliations

¹ Institute of Fermentation Engineering, College of Biotechnology and Bioengineering, Zhejiang University of Technology, 18# Chaowang Road, Hangzhou 310032, China. lilyfan@zjut.edu.cn.
² Institute of Fermentation Engineering, College of Biotechnology and Bioengineering, Zhejiang University of Technology, 18# Chaowang Road, Hangzhou 310032, China. luyuele@zjut.edu.cn.
³ Institute of Fermentation Engineering, College of Biotechnology and Bioengineering, Zhejiang University of Technology, 18# Chaowang Road, Hangzhou 310032, China. richard_chen@zjut.edu.cn.
⁴ National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences and Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, USA. btekwani@olemiss.edu.
⁵ National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences and Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, USA. xcli7@olemiss.edu.
⁶ Institute of Fermentation Engineering, College of Biotechnology and Bioengineering, Zhejiang University of Technology, 18# Chaowang Road, Hangzhou 310032, China. syc@zjut.edu.cn.

PMID: 30400596
PMCID: PMC6278306
DOI: 10.3390/molecules23112878

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

Yongxian Fan et al. Molecules. 2018.

. 2018 Nov 5;23(11):2878.

doi: 10.3390/molecules23112878.

Authors

Yongxian Fan¹, Yuele Lu², Xiaolong Chen³, Babu Tekwani⁴, Xing-Cong Li⁵, Yinchu Shen⁶

Affiliations

¹ Institute of Fermentation Engineering, College of Biotechnology and Bioengineering, Zhejiang University of Technology, 18# Chaowang Road, Hangzhou 310032, China. lilyfan@zjut.edu.cn.
² Institute of Fermentation Engineering, College of Biotechnology and Bioengineering, Zhejiang University of Technology, 18# Chaowang Road, Hangzhou 310032, China. luyuele@zjut.edu.cn.
³ Institute of Fermentation Engineering, College of Biotechnology and Bioengineering, Zhejiang University of Technology, 18# Chaowang Road, Hangzhou 310032, China. richard_chen@zjut.edu.cn.
⁴ National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences and Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, USA. btekwani@olemiss.edu.
⁵ National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences and Department of BioMolecular Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, USA. xcli7@olemiss.edu.
⁶ Institute of Fermentation Engineering, College of Biotechnology and Bioengineering, Zhejiang University of Technology, 18# Chaowang Road, Hangzhou 310032, China. syc@zjut.edu.cn.

PMID: 30400596
PMCID: PMC6278306
DOI: 10.3390/molecules23112878

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**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.

See this image and copyright information in PMC

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

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

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Conflict of interest statement

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