Journal Article

Unlocking potent anti-tuberculosis natural products through structure–activity relationship analysis

Wibowo, Joko Tri, Rahmawati, Siti Irma, Murniasih, Tutik, Budiyanto, Fitri, Bayu, Asep, Abdjul, Delfly Booby, Putra, Masteria Yunovilsa, Indriani, Dwi Wahyu

2025

Overview

Tuberculosis (TB) remains a world health problem due to the high number of affected individuals, high mortality rates, prolonged treatment durations, and the increasing prevalence of resistance to commercial TB drugs. The emergence of resistance to anti-TB drugs has necessitated urgent research into drug discovery and development, focusing on novel mechanisms of action against Mycobacterium tuberculosis resistant strains. Natural products, with their remarkable structural diversity and bioactivity, are promising sources for the development of new TB drugs or the identification of potential chemical scaffolds exhibiting potent and novel biological activity with minimal or no cytotoxicity to host cells. This review focuses on potent anti-TB natural products with minimum inhibitory concentration (MIC) values below 5 µg mL –1 and examines their structure–activity relationship (SAR). Significant characteristics and relevant biological properties of each compound were analysed using a Random Forest, machine learning algorithm, to explore SAR. Using molecular docking, AutoDock Vina was utilised to assess molecular interactions with protein targets, and predictive accuracy was enhanced using the XGBoost machine learning model. These analyses provide insights into the mode of action of these compounds and help identify key structural features contributing to their anti-TB activity. In addition, this review examines the correlation between the potency of selected anti-TB compounds and their cytotoxicity, offering valuable insights for the identification of promising scaffolds in TB drug discovery. Graphical Abstract

• Publisher: Springer Nature Singapore,Springer Nature B.V,North Sulawesi Research and Development Agency,Jalan 17 Agustus,Manado,North Sulawesi 95116,Indonesia%Research Center for Vaccine and Drugs,Research Organization for Health,National Research and Innovation Agency(BRIN),Jalan Raya Jakarta Bogor KM.46,Cibinong,Bogor,West Java 16911,Indonesia,Research Center for Vaccine and Drugs,Research Organization for Health,National Research and Innovation Agency(BRIN),Jalan Raya Jakarta Bogor KM.46,Cibinong,Bogor,West Java 16911,Indonesia,SpringerOpen
• Subject: algorithms / Anti-TB scaffold / Biocompatibility / Biological activity / Biological properties / Biomedical and Life Sciences / Bioorganic Chemistry / Candidates / Cytotoxicity / Data collection / Drug development / Drug discovery / Drug resistance / Drugs / Enzymes / FDA approval / Food Science / Infectious diseases / Learning algorithms / Life Sciences / Machine learning / mechanism of action / Medicinal Chemistry / Metabolites / Minimum inhibitory concentration / Molecular docking / Molecular interactions / mortality / Mycobacterium tuberculosis / Natural Products / Optimization / Pharmacokinetics / Pharmacology/Toxicology / Plant Biochemistry / Plant Sciences / R&D / Research & development / Review / Scaffolds / structure-activity relationships / Structure–activity relationship / Toxicity / Tuberculosis