Design, Synthesis, Characterization, Antimalarial and Adme Evaluation of Analogues of MMV902507(SFK78) and MMV1900279

Abstract

Malaria which is predominant in Sub-Saharan Africa has long existed among individuals globally. According to the WHO malaria report 2024, 263 million cases and 597,000 deaths were recorded globally in 2023, and Africa carried the highest burden. Over the years, efforts by the scientific community to eradicate the disease yielded some results, however, the emergence of resistance to antimalarial drugs has threatened these positive gains as the mortality and morbidity is on the rise in recent times. Therefore, there is the need to find new chemical matter with novel mechanism of action against the parasite. Phenotypic screening is an approach that has been used in drug discovery to find new chemical entities. MMV902507 (SFK78) and MMV1900279 are chemical entities that were identified through phenotypic screening of various chemical libraries. I here in report the chemical modifications of these phenotypic hits and the antimalarial properties, as well as their ADME properties. The hits (MMV902507 (SFK78) and MMV1900279) possessed antimalarial activity against the blood and liver stages of the Plasmodium parasite. It displayed no cross resistance against the drug resistant Dd2 strain of the parasite. Overall, 19 compounds based on the MMV902507 (SKF78) scaffold were synthesized and characterized using spectroscopic and spectrometric techniques. The synthesized analogues were tested in vitro against the sensitive 3D7 strain of the parasite coupled with their solubilities. The compound ADA090 showed similar activity (IC50 value of 0.15 µM) with the hit compound (0.17 µM) while ADA097 gave a better solubility of 161.94 µM compared to the hit compound MMV902507 (27 µM). On the other hand, 13 compounds based on MMV1900279 were prepared. Compound ADA129 showed superior activity of 0.1 µM against the sensitive strain of the parasite compared to the hit compound (0.3 µM) when tested in vitro while ADA138 showed better solubility at 998 µM. ADME evaluation of some selected derivatives of MMV902507 revealed several compounds with superior stability in Human microsomes and rat hepatocytes. Compounds ADA095, ADA096 and ADA097 were metabolically more stable than the hit MMV902507 with ADA096 as the most stable. Compound ADA096 returned clearance of (Clint Mics 3.5 µL/min/mg) in human microsomes and (Clint Heps 2.7 µL/min/10-6 cells) in rat hepatocytes with half-life of 394 min and 361 min respectively. The hit compound on the other hand had (Clint Mics 578 µL/min/mg) in human microsomes and (Clint Heps 85 µL/min/10-6 cells) in rat hepatocytes, with half-lives of 3 min and 16 min respectively.