Antischistosomal structure-activity relationships of nitrated n-phenyl benzamide derivatives.

Thumbnail Image
Sichinga, John
Journal Title
Journal ISSN
Volume Title
The University of Zambia
Schistosomiasis is a chronic parasitic disease caused by blood-dwelling trematodes of the genus Schistosoma. It ranks second on a list of neglected tropical parasitic diseases. Globally, about 280,000 deaths are recorded annually while more than 240 million people get infected and more than 700 million people risk being infected. The disease is associated with approximately 3.3 million disability-adjusted life years. It also causes a total estimated annual global economic loss amounting to US$641,790,130. Africa alone accounts for more than 90% of schistosomiasis cases with Schistosoma mansoni and Schistosoma haematobium species being the most prevalent. For over 40 years, praziquantel has stood out as the principal drug of choice in the treatment and control of schistosomiasis. It is efficacious and safe. It has also been very instrumental in preventive chemotherapy. However, it faces emerging drug resistance, lacks antischistosomal activity against juvenile worms, does not provide a 100% cure, and does not prevent re-infection. N-phenylbenzamides have shown potential as antischistosomal agents although they have not been extensively studied. This study was inspired by one compound, MMV687807, which was active against Schistosoma mansoniworms and was 100% lethal at 10 µM against Schistosoma haematobium adult worms whose further medicinal chemistry exploration, identified MK1-11, from the recent study that reported its exhibited potency against Schistosoma mansoni adult worms attributed to trifluoromethyl group (CF3), an electron-withdrawing group. This study, therefore, sought to further enhance activity by nitrating the core-scaffold of the front-runner compound, MK1-11.The analogs of this compound were thus synthesized and tested in vitro on Schistosoma mansoni juvenile worms. The successfully synthesized analogs were confirmed by HPLC-MS, 1H-NMR, and 13C-NMR spectroscopic techniques. The 1H-NMR and 13C-NMR results were analyzed using a spectral data analyzing software called MestReNova. The %-death-of-worms effect produced by the tested compounds were 62%, 28%, 56%, and 42% at 50 µM with reduced effects of 41.67%, 25%, 54.17%, and 25% at 10 µM respectively. Structure-activity relationships (SARs) appeared to confirm earlier findings being electron-withdrawing groups are essential for potency. Generally, analogs containing nitro and trifluoromethyl groups on the phenyl rings as depicted in JS-03 and JS-05 exhibited enhanced activity. However, regioisomerism (ortho or meta substitution) in these two analogs did not seem to affect activity. Due to low activity on juvenile worms, the analogs could not be tested on adult worms. Consequently, enhancement or decrease in activity with respect to the front-runner compound,MK1-11 which was only tested on adult worms and also using a different in vitro biological assay method could not be deduced. There is need, therefore, to consider resynthesizing the front-runner compound by further research, test it on both juvenile and adult worms using the same in vitro assay method as the newly synthesized analogs in order to assess to what extent activity is improved upon or compromised.