Design, Synthesis, and Medicinal Chemistry Profiling of Analogues of Mmv676444 and Mmv1794959, for their Biological Activities

Abstract

The impact of the global disease burden leaves a lasting toll of mortality and disability, par ticularly on the most affected regions, impeding development and economic advancement. A prevalent disease with devastating public health challenges particularly in sub-Saharan Africa is malaria. Despite some positive impact of global efforts on its prevalence, morbidity, and mortality, the emergence and spread of drug-resistant strains of malaria‘s causative agent, raises concerns about the long-term therapeutic efficacy of the most potent drugs for its treatment. In view of this, the discovery of more potent, user-friendly drugs, remains crucial for addressing drug resistance in malaria. Drug discovery employs phenotypic screening to identify new chemical entities for medicinal chemistry explorations, potentially leading to first-in-class medicines. These drugs have the potential to serve as candidates for multiple diseases, often exhibiting novel mechanisms of action, highlighting their critical role in com bating drug resistance. In this project, two scaffolds, MMV676444 and MMV1794959, iden tified in phenotypic screens were explored for their therapeutic potential, primarily against malaria. A total of 36 analogues of the MMV676444 scaffold were synthesised and characterized us ing spectroscopic and spectrometric techniques, including Nuclear Magnetic Resonance (NMR) spectroscopy, Mass spectroscopy (MS) and Fourier-Transform Infrared (FTIR). The prepared analogues were tested in vitro against the sensitive strain NF54 of the malaria para site and H37rv of Mycobacterium tuberculosis (MTB). While poor antitubercular activities (MIC 33.3 µM – > 62.5 µM) were generally observed, some of the analogues showed prom ising antimalarial activity, with the most active analogue, CFA/092, yielding an IC50 value of 12 nM. Further studies conducted on CFA/092 indicated favourable metabolic stability, con firming its suitability for further optimization as a lead scaffold. Furthermore, preliminary investigations on selected analogues also showed encouraging activity (IC50 = 1.16 µM – 3.71 µM) against L. donovani promastigotes. On the other hand, 2 analogues of MMV1794959 were successfully synthesised and charac terised with 1H and 13C NMR, LC-MS, and FTIR. Though the analogues (CFA/P3021 and CFA/P3076) exhibited reduced lipophilicity and improved solubility in comparison to the hit scaffold, they were poorly active against malaria (P. falciparum (3D7)).