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- Title
Synthesis, Molecular Docking, and Antimalarial Activity of Hybrid 4-Aminoquinoline-pyrano[2,3-c]pyrazole Derivatives.
- Authors
Shamsuddin, Mohd Asyraf; Ali, Amatul Hamizah; Zakaria, Nur Hanis; Mohammat, Mohd Fazli; Hamzah, Ahmad Sazali; Shaameri, Zurina; Lam, Kok Wai; Mark-Lee, Wun Fui; Agustar, Hani Kartini; Mohd Abd Razak, Mohd Ridzuan; Latip, Jalifah; Hassan, Nurul Izzaty
- Abstract
Widespread resistance of Plasmodium falciparum to current artemisinin-based combination therapies necessitate the discovery of new medicines. Pharmacophoric hybridization has become an alternative for drug resistance that lowers the risk of drug–drug adverse interactions. In this study, we synthesized a new series of hybrids by covalently linking the scaffolds of pyrano[2,3-c]pyrazole with 4-aminoquinoline via an ethyl linker. All synthesized hybrid molecules were evaluated through in vitro screenings against chloroquine-resistant (K1) and -sensitive (3D7) P. falciparum strains, respectively. Data from in vitro assessments showed that hybrid 4b displayed significant antiplasmodial activities against the 3D7 strain (EC50 = 0.0130 ± 0.0002 μM) and the K1 strain (EC50 = 0.02 ± 0.01 μM), with low cytotoxic effect against Vero mammalian cells. The high selectivity index value on the 3D7 strain (SI > 1000) and the K1 strain (SI > 800) and the low resistance index value from compound 4b suggested that the pharmacological effects of this compound were due to selective inhibition on the 3D7 and K1 strains. Molecular docking analysis also showed that 4b recorded the highest binding energy on P. falciparum lactate dehydrogenase. Thus, P. falciparum lactate dehydrogenase is considered a potential molecular target for the synthesized compound.
- Subjects
MOLECULAR docking; PYRAZOLE derivatives; LACTATE dehydrogenase; DRUG interactions; DRUG target
- Publication
Pharmaceuticals (14248247), 2021, Vol 14, Issue 11, p1174
- ISSN
1424-8247
- Publication type
Article
- DOI
10.3390/ph14111174