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Background: Neglected tropical diseases (NTDs) afflict nearly 2 billion people worldwide and are caused by various pathogens, such as bacteria, protozoa, and trypanosoma, prevalent in tropical and subtropical regions. Among the 17 NTDs recognized by the World Health Organization (WHO), protozoal infections caused by Plasmodium, Entamoeba, Leishmania, and Trypanosoma are particularly prominent and pose significant public health. Indonesia, endowed with a rich biodiversity owing to its tropical climate, harbors numerous plant species with potent biological activities that hold promise for therapeutic interventions. Hence, efforts have been directed towards exploring Indonesian plant extracts and isolated compounds for their potential in combating protozoal diseases., Methods: This study evaluated the antiprotozoal properties of 48 plant extracts sourced from the Cratoxylum, Diospyros, and Artocarpus genera. These extracts were screened using cell-based assays against Plasmodium falciparum (Pf), Entamoeba histolytica (Eh), Leishmania donovani (Ld), Trypanosoma brucei rhodesiense (Tbr), and Trypanosoma cruzi (Tc)., Results: Extracts derived from the roots of Cratoxylum arborescens, obtained through dichloromethane extraction, exhibited significant activity against protozoa, with an IC 50 value ranging from 0.1 to 8.2 µg/mL. Furthermore, cochinchinone C was identified as an active compound capable of inhibiting the growth of Pf, Eh, Ld, and Tbr, Tc trypomastigote, and Tc epimastigote with IC 50 values of 5.8 µM, 6.1 µM, 0.2 µM, 0.1 µM, 0.7 µM, and 0.07 µM, respectively. Cochinchinone C is the first compound reported to exhibit activity against protozoal neglected tropical diseases, showing low cytotoxicity with a selectivity index greater than 10 when tested against carcinoma and normal cell lines. This suggests indicating its potential as a candidate for further drug development. This is the first report of cochinchinone C's activity against these protozoans., Conclusion: These findings establish cochinchinone C as a strong candidate for antiprotozoal drug development, highlighting the untapped therapeutic potential of Indonesia's rich plant biodiversity., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Microorganisms in nature are highly diverse biological resources, which can be explored for drug discovery. Some countries including Brazil, Columbia, Indonesia, China, and Mexico, which are blessed with geographical uniqueness with diverse climates and display remarkable megabiodiversity, potentially provide microorganismal resources for such exploitation. In this review, as an example of drug discovery campaigns against tropical parasitic diseases utilizing microorganisms from such a megabiodiversity country, we summarize our past and on-going activities toward discovery of new antimalarials. The program was held in a bilateral collaboration between multiple Indonesian and Japanese research groups. In order to develop a new platform of drug discovery utilizing Indonesian bioresources under an international collaborative scheme, we aimed at: 1) establishment of an Indonesian microbial depository, 2) development of robust enzyme-based and cell-based screening systems, and 3) technology transfer necessary for screening, purification, and identification of antimalarial compounds from microbial culture broths. We collected, characterized, and deposited Indonesian microbes. We morphologically and genetically characterized fungi and actinomycetes strains isolated from 5 different locations representing 3 Indonesian geographical areas, and validated genetic diversity of microbes. Enzyme-based screening was developed against two validated mitochondrial enzymes from Plasmodium falciparum, dihydroorotate dehydrogenase and malate:quinone oxidoreductase, while cell-based proliferation assay was developed using the erythrocytic stage parasite of 3D7 strain. More than 17 thousands microbial culture extracts were subjected to the enzyme- and cell-based screening. Representative anti-malarial compounds discovered in this campaign are discussed, including a few isolated compounds that have been identified for the first time as anti-malarial compounds. Our antimalarial discovery campaign validated the Indonesian microbial library as a powerful resource for drug discovery. We also discuss critical needs for selection criteria for hits at each stage of screening and hit deconvolution such as preliminary extraction test for the initial profiling of the active compounds and dereplication techniques to minimize repetitive discovery of known compounds., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)