A novel library of hybrids as potential antimalarial agents: design, synthesis, characterization and in vitro biological evaluation.
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Date
2021
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Abstract
Malaria continues to be a fundamental health threat worldwide due to the rise of resistance in frontline medications, including artemisinin-based combination therapy (ACT). The condition requires new, innovative drug candidates to overcome existing challenges in the current treatment. The synthetic alteration involving existing pharmacophoric antimalarial drugs and natural products were utilized to construct an antimalarial candidate that could serve as a potent and effective lead compound for potential optimization. In continuing our ongoing research and the need to discover newer antimalarials, we endeavored to synthesize a novel library of antimalarial hybrids analogues comprising 4,6-diphenylpyrimidine core, a pharmacophoric moiety inspired by pyrimethamine and chalcone. Pyrimidine is a versatile heterocyclic building block of many drugs with vast medicinal properties such as antimicrobial, anti-inflammatory, analgesic, anticonvulsant, anticancer, and antioxidant. Fifty-three hybrids consisting of pyrimidine core fused with other significant antimalarial moieties, namely quinoline, cinnamoyl and 1,2,3-triazole through an alkane diamine linker, particularly piperazine, were synthesized. All the newly synthesised compounds were identified based on physicochemical and spectral data (IR, 1H NMR, 13C NMR and HRMS) per their predicted structures and preliminarily screened for antimalarial (in vitro) activities. Also, the binding affinities of two essential cytosolic Plasmodium (P) falciparum heat shock protein 70 homologues (PfHsp70-1 and PfHsp70-z) were examined.
Pyrimidine-quinoline hybrids (Chapter 3) demonstrated antimalarial ranging from 0.32 to 83 μM. Of this series, compounds 7a and 7b were the most potent with IC50 value of 0.32 ± 0.06 μM and IC50 1.62 ± 1.14 μM, respectively with a safety profile of 9.79 to human kidney epithelial (HEK293) cells for 7a. Equally, compounds 7a and 7b presented the highest binding affinity of two essential cytosolic P. falciparum heat shock protein 70 homologues; PfHsp70-1 and PfHsp70-z, with KD in a lower nanomolar range (4.4-11.4 nM)
Pyrimidine-cinnamoyl hybrids (Chapter 4) exhibited antimalarial activity from 0.18 to 50 μM. Compounds 8a and 8l were the most active with IC50 value of 0.18 ± 0.02 μM and IC50 0.21 ± 0.00 μM with the safety profile of 18.59 and 16.75 to human kidney epithelial (HEK293) cells, correspondingly. Compounds 8a and 8l showed the highest binding affinity of two essential cytosolic P. falciparum heat shock protein 70 homologues; PfHsp70-1 and PfHsp70-z, with KD in a lower nanomolar range (9.69-10.8 nM).
Pyrimidine-1,2,3-triazole hybrids (Chapter 5) showed antimalarial activity from 0.04 to 2.41 μM. Compounds 8c, 8e and 8t were the most promising with IC50 values ranging from 0.18 to 0.29 μM with a safety profile tenfold compared to human kidney epithelial (HEK293) cells. Similarly, compounds 8c, 8e and 8t displayed the highest binding affinity of two essential cytosolic P. falciparum heat shock protein 70 homologues; PfHsp70-1 and PfHsp70-z, with KD in a lower nanomolar range (11.3-90.0 nM).
The pyrimidine-1,2,3-triazole hybrid library demonstrated the most promising family as it had eight more potent compounds with IC50 values less than 0.50 μM, followed by the pyrimidine-cinnamoyl and lastly, pyrimidine-quinoline. All families exhibited PfHsp70-1 and PfHsp70-z enzyme activity in nanomolar concentration with a safety of 10-fold against human kidney epithelial (HEK293) mammalian cells.
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Doctoral Degree. University of KwaZulu-Natal, Durban.