Zero Hunger (SDG 2), Good Health & Well-being (SDG 3)
Exploration of N-phenylbenzamides as potential antischistosomal agents Masebe Kanyanta 1 , Chilufya Lengwe 1 , Dickson Mambwe 1 , Karol R. Francisco 2 , Lawrence J. Liu 3 , Yujie Uli Sun 2 , Dilini K. Amarasinghe 2 , Conor R. Caffrey 2 and Peter Mubanga Cheuka 1,* 1 Department of Chemistry, School of Natural Sciences, University of Zambia, P.O Box 32379, Lusaka, Zambia 2 Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA. E-mail: peter.cheuka@unza.zm Schistosomiasis is a neglected tropical disease caused by a parasitic flatworm of the genus Schistosoma. It affects more than 240 million people in the Middle East, South America, Southeast Asia and sub- Saharan Africa thereby causing considerable morbidity. Praziquantel (PZQ), a pyrazino-isoquinolone derivative used as an oral antischistosomal drug for all adult species of the worms, is safe and efficacious. However, it does not prevent reinfection and its repeated use in mass drug administration programs poses a risk of developing drug resistance. For the Schistosoma mansoni flatworm pathogen, we have reported a structure-activity relationship study of 25 derivatives of the N-phenylbenzamide compound, 1 (MMV687807), a Medicines for Malaria Venture compound for which bioactivity was originally identified in 2018. Synthesized compounds were cross screened against the HEK 293 mammalian cells. Compounds 9 and 11 were identified as fast acting schistosomicidal compounds whereby adult worm integrity was severely compromised within 1 h. Against HEK 293 mammalian cells, both compounds exhibited high CC50 values (9.8 ± 1.6 and 11.1 ± 0.2 μM respectively) which could translate to comfortable selectivity. When evaluated in a concentration-response format, compound 9 was active in the nanomolar range (EC50 = 80 nM), translating to a selectivity index of 123 over HEK 293 cells. The data encourage the further investigation of N- phenylbenzamide as antischistosomal agents. Research is on-going to explore further SAR, incorporation of diverse structural functionalities and progression some of these frontrunner compounds for DMPK evaluation. Key words: Schistosomiasis, mansoni, phenylbenzamides, cytotoxicity References 1. Yao, H.; Liu, F.; Chen, J.; Li, Y.; Cui, J.; Qiao, C. Antischistosomal Activity of N,N’-Arylurea Analogs against Schistosoma Japonicum. Bioorg. Med. Chem. Lett. 2016 . 2. Gryseels, B.; Polman, K.; Clerinx, J.; Kestens, L. Human Schistosomiasis. Lancet. 2006 , 368, 1106–1118. 3. Aruleba, R. T.; Adekiya, T. A.; Oyinloye, B. E.; Masamba, P.; Mbatha, L. S.; Pretorius, A.; Kappo, A. P. PZQ Therapy: How Close Are We in the Development of Effective Alternative Anti-Schistosomal Drugs? Infect. Disord. - Drug Targets. 2019 , 19, 337–349. 4. Taman, A.; El-bardicy, S.; Tadros, M.; Ayoub, M.; Mansour, B.; El-shehabi, F.; El-beshbishi, S. N. In Vitro Efficacy of New Synthetic Benzimidazole-Related Compounds against Schistosoma Mansoni Adult Worms. Asian Pac. J. Trop. Med. 2020 , 13, 566–572.
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