Design and synthesis of quinoline-pyrimidine inspired hybrids as potential plasmodial inhibitors

Presently, artemisinin-based combination therapy (ACT) is the first-line therapy of Plasmodium falciparum malaria. With the emergence of malaria parasites that are resistant to ACT, alternative antimalarial therapies are urgently needed. In line with this, we designed and synthesised a series of novel N-(7-chloroquinolin-4-yl)-N’-(4,6-diphenylpyrimidin-2-yl)alkanediamine hybrids (6a-7c) and evaluated their inhibitory activity against the NF54 chloroquine-susceptible strain as a promising class of antimalarial compounds. The antiplasmodial screening revealed that seven analogues showed promising to good activity with half-maximal inhibitory concentration (IC50) = 0.32 μM–4.30 μM. Compound 7a with 1,4-diamine butyl linker and 4-hydroxyl phenyl on fourth and sixth position of pyrimidine core showed the most prominent activity with an IC50 value of 0.32 ± 0.06 μM, with a favourable safety profile of 9.79 to human kidney epithelial (HEK293) cells. The remaining six analogues showed moderate activity with IC50 values ranging from 7.50 μM to 83.01 μM. We further investigated the binding affinities of the molecules to two essential cytosolic P. falciparum heat shock protein 70 homologues; PfHsp70-1 and PfHsp70-z. Compound 7a exhibited the highest binding affinity for both PfHsp70s with KD in a lower nanomolar range (4.4–11.4 nM). Furthermore, molecular docking revealed that compounds 6, 6k, 7b and 7a exhibited better fitness in PfHsp70-1 with compound 7a showing the highest and lowest binding scores of −9.8 kcal/mol. Therefore, we speculate that PfHsp70-1 is one of the targets of these inhibitors. The bioisoteric replacement of the groups at phenyl ring at the fourth and sixth position of the pyrimidine core had a constructive association with antiplasmodial activity. The promising antiplasmodial activity of the synthesised analogues illustrates how crucial molecular hybridisation is as a strategy in the development of quinoline-pyrimidine hybrids as prospective antiprotozoal agents.

Publication year: 2021
Authors: Kayamba F. a. Malimabe T. b,c, Ademola I.K. d, Pooe O.J. e, Kushwaha N.D. a, Mahlalela M. a, van Zyl R.L. b,c, Gordon M. d, Mudau P.T. f, Zininga T. f,g, Shonhai A. g, Nyamori V.O. h, Karpoormath R. a

a – Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa
b – Pharmacology Division, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, 2193, South Africa
c – WITS Research Institute for Malaria (WRIM), Faculty of Health Sciences, University of Witwatersrand, Johannesburg, 2193, South Africa
d – School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, Durban, 4000, South Africa
e – Discipline of Biochemistry, School of Life Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa
f – Department of Biochemistry University of Venda, School of Mathematical and Natural Sciences, Thohoyandou, 0950, South Africa
g – Department of Biochemistry, Stellenbosch University, Stellenbosch, 7600, South Africa
h – School of Chemistry and Physics, University of KwaZulu-Natal, Westville Campus, Durban, 4000, South Africa

Published in: European Journal of Medicinal Chemistry, 2021, Vol. 217, p. 113330
DOI: 10.1016/j.ejmech.2021.113330


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