Screening of traditional medicinal plant extracts and compounds identifies a potent anti-leishmanial diarylheptanoid from Siphonochilus aethiopicus

Abstract

Available anti-leishmanial drugs are associated with toxic side effects, necessitating the search for safe and effective alternatives. This study is focused on identifying traditional medicinal plant natural products for anti-leishmanial potential and possible mechanism of action. Compounds S and T. cordifolia residual fraction (TC-5) presented the best anti-leishmanial activity (IC₅₀: 0.446 and 1.028 mg/ml) against promastigotes at 48 h and less cytotoxicity to THP-1 macrophages. These test agents elicited increased expression of pro-inflammatory cytokines; TNFα and IL-12. In infected untreated macrophages, NO release was suppressed but was significantly (p < 0.05) increased in infected cells treated with compound S. Importantly, Compound S was found to interact with LdTopoII_dimer in silico, resulting in a likely reduced ability of nucleic acid (dsDNA)-remodelling and, as a result, parasite proliferation in vitro. Thereby, Compound S possesses anti-leishmanial activity and this effect occurs via a Th1-mediated pro-inflammatory response. An increase in NO release and its inhibitory effect on LdTopoII may also contribute to the anti-leishmanial effect of compound S. These results show the potential of this compound as a potential starting point for the discovery of novel anti-leishmanial leads.

Communicated by Ramaswamy H. Sarma

Keywords:

• Anti
• diarylheptanoid
• L. donovani
• Siphonochilus aethiopicus
• topoisomerase II

Authors’ contributions

S Singh and IE conceptualized the work, designed the experiments, wrote and edited the manuscript. EM designed and executed the experiments, performed the data interpretation and wrote the manuscript. EM, JS and RJ performed experiments. EM performed the Real Time, MTT, Infectivity and Parasitemia assays. JS performed the experiments related to cytokine analysis and nitric oxide production. RJ performed in silico interaction of Compound S with LdTopoII_dimer. AC and GDG helped in writing the manuscript. IE, EM, JS and RJ revised the manuscript. S Singh, JI, NI and RPP evaluated the work progress. All authors contributed to the article and approved the submitted version.

Data availability

The contributions presented in the study are included in the research article and further inquiries can be directed to the corresponding authors.

Disclosure statement

The authors have no competing interest to declare.

Additional information

Funding

This study was partly funded by the Africa-India Mobility Fund (AIMF-18-004) awarded by the African Academy of Sciences to Ezenyi I.C., and a CSIR Scientist Pool Officer (SRA) funding agency research grant (13(9160-A)2021-Pool) provided to Dr. Evanka Madan. JS is a recipient of the BioCare Women Scientist Fellowship from DBT. The work in Shailja Singh’s lab at Special Centre for Molecular Medicine (SCMM), JNU, is supported by IRHPA IPA/2020/000007, Department of Science and Technology and Drug and Pharmaceuticals Research Program (DPRP) (Project No. P/569/2016-1/TDT, SS). The work in Ramendra Pati Pandey’s lab is supported by Indian Council of Medical Research (ICMR) (Project No. 6/9-7(275) KA/2021/ECD-II). RJ acknowledges Research Associate I fellowship from Indo-DBT (Department of Biotechnology, Government of India) and Swiss National Science Foundation (SNSF). The funders had no role in the study design; collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit this article for publication.