Zero Hunger (SDG 2), Good Health & Well-being (SDG 3)
A promising class of antiprotozoal agents, design and synthesis of novel Pyrimidine–Cinnamoyl hybrids Francis Kayamba 1,2 , Rajshekhar Karpoormath 1* 1 Department of Pharmaceutical Chemistry, Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4000, South Africa 2 Department of Chemistry and Biology, School of Natural and Applied Sciences, Mulungushi University, PO Box, 80415, Kabwe, ZambiaAffiliation.1, Affiliation 2 E-mail: karpoormath@ukzn.ac.za Malaria continues major global health crisis, especially in Africa, The emergence of antimalarial drug resistance necessitates an urgent need for alternative and cost-effective antimalarials. Using a molecular hybridization approach, we report an efficacious novel class of antiprotozoal agents; (E)- 1-(4-(4,6-diphenylpyrimidin-2-yl)piperazin-1-yl)-3-phenyl prop-2-en-1-one derivatives (8a-r). In vitro, antiprotozoal evaluation against the NF54 chloroquine-sensitive strain of Plasmodium falciparum identified compounds 8o and 8l as the most potent candidates with IC50 values of 0.18 ± 0.02 μM and 0.21 ± 0.001 μM with a good safety index of 18.59 and 16.75 to human kidney epithelial (HEK293) cells, respectively. Further investigation of the binding affinities against recombinant forms of two P. falciparum heat shock protein 70 homologues; PfHsp70-1 and PfHsp70-z, essential and promising druggable candidates revealed compound 8l exhibited the highest binding affinity for PfHsp70-1 and PfHsp70-z. Furthermore, molecular docking of PfHsp70-1 revealed compounds 8l and 8o had the highest binding affinity of −10.5 kcal/mol and −10.1 kcal/mol, respectively. Therefore, it was speculated that PfHsp70–1 may be a possible target of some compounds under study. Taken together, this paper demonstrates the importance of using the molecular hybridization approach in the development of newer cinnamoyl clubbed with 4,6-diphenyl pyrimidine hybrids as potential antiprotozoal agents.T Key words: Malaria, resistance, falciparum, hybridization, protein References 1. F.H. Nosten et al. “New malaria maps”Lancet (2019) 2. F. Kayamba et al.” Lactate dehydrogenase and malate dehydrogenase: potential antiparasitic targets for drug development studies” Bioorg. Med. Chem. (2021) 3. L.E. Buyon et al. The molecular basis of antimalarial drug resistance in Plasmodium vivaxInt J Parasitol Drugs Drug Resist (2021) 4. A.M. Ganai et al. “Development of pyrimidine-cinnamamide hybrids as potential anticancer agents: a rational design approach”J. Mol. Struct. (2022) 5. F. Kayamba et al. “Design and synthesis of quinoline-pyrimidine inspired hybrids as potential plasmodial inhibitors” Eur. J. Med. Chem. (2021) 6. A. Amalraj et al. “Biological activities of curcuminoids, other biomolecules from turmeric and their derivatives - a review”J Tradit Complement Med (2017)
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