Fokou, J. B. H. | bioRxiv Science

bioRxiv2025

Discovery and structure-activity relationship analysis of 2-Pyridyl Thienopyrimidine derivatives as promising therapeutic candidates for the treatment of Buruli ulcer

Mycobacterium ulcerans, the bacterium causing Buruli ulcer (BU), can potentially develop resistance to existing antibiotics (rifampicin - clarithromycin/ moxifloxacin), underscoring the need for new antimycobacterial treatments. This study screened the Pathogen Box from Medicines for Malaria Venture (MMV) to identify M. ulcerans inhibitors. Four hit compounds were found, including the 2-(6-methylpyridin-2-yl)-N-(pyrimidin-4-yl)thieno[3,2-d]pyrimidin-4-amine MMV688122 as a novel anti-M. ulcerans chemotype. Synthesis of structural analogues of MMV688122 allowed the identification of 2-(4-methylpyridin-2-yl)-N-(pyrimidin-4-yl)thieno[3,2-d]pyrimidin-4-amine MMV1578877 as the most potent, with submicromolar activity. Importantly, this analogue was non-cytotoxic up to 100 {micro}M in human fibroblasts. Structure-activity relationship (SAR) studies indicated the crucial role of the methylpyridin-2-yl group in inhibiting M. ulcerans and the possibility to replace the thienopyrimidine core by a quinazoline. While MMV1578877 showed better metabolic stability than MMV688122, further improvement and testing in real-world M. ulcerans clinical isolates are still required. Further metabolite identification and SAR data should guide the optimization of this novel chemotype to enable in vivo testing. Author SummaryBuruli ulcer is a neglected tropical disease that causes severe skin ulcers and long-term disability, mostly affecting people in remote African communities. Current treatments rely on antibiotics that are not always effective and may lead to resistance. In this study, we searched for new drug candidates by testing a library of compounds provided by the Medicines for Malaria Venture (MMV). We discovered a promising new chemical family that can kill the bacteria responsible for Buruli ulcer in the lab. One compound, in particular, showed strong activity without harming human cells. This compound also showed better stability and effectiveness. These findings bring us closer to developing a new, safer, and more effective treatment for Buruli ulcer.

pharmacology and toxicology↗

bioRxiv2024

Chitosan nanocapsules with Alstonia boonei extract modulate the immune system in Wistar rats

The development of biosynthetic methods for nanoparticles using plants presents an exciting opportunity to better utilize our rich and diverse medicinal flora. We are particularly interested in creating nanocapsules using Alstonia boonei, a Cameroonian plant known for its immunomodulatory properties. Chitosan nanocapsules were synthesized from the methanol/dichloromethane extract of the powdered stem bark of A. boonei after harvest and drying. The encapsulation of the secondary metabolites was achieved using the ionic gelation method, which involved the agitation of a chitosan solution, extract, and tripolyphosphate. Subsequently, the encapsulation efficiency was calculated. Infrared spectroscopy identified the various functional groups present in the nanocapsules. The acute toxicological profile of these chitosan nanocapsules at a limit dose of 2000 mg/kg, along with their immunomodulatory activities, was evaluated in Wistar rats. The immunomodulatory potential was assessed in dexamethasone-induced immunosuppressed rats by measuring total blood count, delayed-type hypersensitivity response, and hemagglutinating antibody titre between groups of animals after 14 days of treatment. The data collected on the synthesis and characterization confirmed the formation of nanocapsules. This was evidenced by infrared spectroscopy and an entrapment efficiency of 69%. Powder X-ray diffraction confirmed the presence of chitosan in the polymer material. SEM imaging further confirmed the formation of nanocapsules. The toxicological profile of these nanocapsules was found to be satisfactory. Administration of chitosan nanocapsules containing Al. boonei methanol/dichloromethane extracts at doses of 100 mg/kg, 200 mg/kg, and 500 mg/kg body weight significantly prevented dexamethasone-induced immunosuppression in rats. This was achieved by increasing the parameters of total blood count (hematocrit, mean corpuscular volume, platelets, lymphocytes, and granulocyte counts), hemagglutinating antibody titre values, and delayed type hypersensitivity response induced by chicken red blood cells. However, doses of 500 mg/kg of crude A. boonei extract and 500 mg/kg body weight of empty chitosan nanocapsules did not show this effect. The nanocapsules generated from the extracts of chitosan and A. boonei are responsible for immunostimulatory activity and possess therapeutic potentials for the prevention of depressed immune depressed conditions with satisfactory safety at acute dose.

pharmacology and toxicology↗