Design and synthesis of pyrano2,3-c]pyrazole-4-aminoquinoline hybrids as effective antimalarial compounds
Document Type
Article
Publication Date
12-1-2024
Abstract
In this work, a series of nineteen novel pyrano2,3-c]pyrazole-4-aminoquinoline hybrids were synthesized as potent antimalarial agents by covalently linking the scaffolds of 4-aminoquinoline and pyrano2,3-c]pyrazoles via an ethyl linker and characterized using Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (NMR). Molecular docking was used to test each hybrid's and standard chloroquine's ability to bind to Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH), an important enzyme in the parasite's glycolytic pathway. The hybrid compounds had a stronger binding affinity than the standard chloroquine (CQ). The schizontical antimalarial test of pyrano2,3-c]pyrazole-4-aminoquinoline hybrid compound shows that all nineteen hybrid compounds were potent with the IC50 values ranging from 0.0151 to 0.301 mu M against the CQ-sensitive 3D7 P. falciparum strain, and were active against the CQ-resistant K1 P. falciparum strain with the IC50 values ranging from 0.01895 to 2.746 mu M. All the tested hybrid compounds were less potent than the standard drug chloroquine dipaspate (CQDP) against the CQ-sensitive 3D7 strain. In contrast, nine of the nineteen hybrids (16d, 16g, 16h, 16i, 16l, 16n, 16o, 16r, and 16s) displayed superior antimalarial activity than the CQDP against the CQ-resistant K1 P. falciparum strain. Among all the tested hybrids, 16c against the 3D7 strain and 16h against the K1 strain were the most promising antimalarial agents with 0.0151 and 0.01895 mu M of IC50 values, respectively. In addition, the compounds were selective, showing moderate to low cytotoxic activity against a human normal liver WRL68 cell line. The synthesis of pyrano2,3-c]pyrazole-4-aminoquinoline hybrids introduces new chemical entities that have the potential to exhibit potent antimalarial activity. It could address the ongoing challenge of drug resistance in malaria treatment.
Keywords
Pyrano2, 3-c]pyrazile-4-aminoquinolines, Malaria, CQ-Resistant K1, P. falciparum, Pf LDH
Divisions
Parasit
Funders
Universiti Kebangsaan Malaysia,Ministry of Higher Education, Malaysia [Grant no. FRGS/1/2019/STG01/UKM/02/3]
Publication Title
European Journal of Medicinal Chemistry
Volume
279
Publisher
Elsevier
Publisher Location
65 RUE CAMILLE DESMOULINS, CS50083, 92442 ISSY-LES-MOULINEAUX, FRANCE