Natural Sciences

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Browsing Natural Sciences by Author "Banda, Harrison"

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    Synthesis and antischistosomal structure-activity relationship profiling of n-pyridazin-3-ylbenzamides.
    (2025) Banda, Harrison
    Schistosomiasis is a neglected tropical disease and the second most fatal tropical disease. The 2024 World Health Organization (WHO) report indicates global mortality rates of 130,000 and 150,000 schistosomiasis deaths attributed to the causative agents Schistosoma mansoni and S. haematobium, respectively, both of which species are endemic to Zambia. Although praziquantel (PZQ) remains the almost exclusive standard of care drug, it has some shortcomings including ineffectiveness against immature parasites, challenges in paediatric dosing, a high adult dose and has shown drug resistance. Therefore, there remains an unmet medical need to develop other treatment options with different modes of action to circumvent the now well-known mechanism of resistance. This study was based on Medicines for Malaria Venture’s compound MMV687807, which was preliminarily shown to possess promising in vitro antischistosomal activity but whose extensive structure-activity exploration was not undertaken yet. The study was also inspired by the desire to design analogues with better physicochemical properties such as logarithms of partition coefficient or distribution (LogP or LogD) and solubility. Accordingly, the study introduced an N-pyridazin-3-yl heterocyclic ring in lieu of the N-phenyl carbocyclic ring thereby editing the N-phenylbenzamide (N-PhBA) scaffold of MMV687807, MK1-11, etc., to the N-pyridazin-3-ylbenzamides (N-PdzBAs) seeing that N-PhBAs had high hydrophobicity (e.g. MMV687807: LogD = 5.14; MK1-11: LogD = 4.36) and hence possessed low aqueous solubility (e.g. MK1-11: Saq = 13.3 µM). Six target compounds were successfully synthesized by EDCI-mediated amide coupling to the required purity i.e. ≥ 95 %. Liquid chromatography – mass spectrometry (LC-MS) was used as the ultimate criterion of purity and to profile retention time (tR) while ultraviolet-visible (UVVis), infrared (IR), proton (1H) and carbon-13 (13C) nuclear magnetic resonance (NMR) spectroscopic methods were used for characterization. Compared to the first-generation NPhBAs (e.g. MK1-11), N-PdzBAs showed much lower in vitro activity (severity score ≤ 1) on S. mansoni adult worms but favourably lower in vitro cytotoxicity (CC50 > 20 µM) on the HEK293 cell line (an experimental result which also agreed with in silico predictions), favourably higher estimated aqueous solubility (Saq > 100 µM) and lower hydrophobicity (cLogP ≤ 4). Therefore, although inferior activity-wise, the new pyridazinic analogues possess favourable physicochemical properties and could still find utility against other diseases. KEY WORDS: EDCI-mediated amide coupling, N-pyridazin-3-ylbenzamide, S. mansoni antischistosomal activity, HEK293 cytotoxicity, hydrophobicity, aqueous solubility