2. Academic Validation
  3. Design and synthesis of pyrano[2,3-c]pyrazole-4-aminoquinoline hybrids as effective antimalarial compounds

Design and synthesis of pyrano[2,3-c]pyrazole-4-aminoquinoline hybrids as effective antimalarial compounds

  • Eur J Med Chem. 2024 Sep 5:279:116828. doi: 10.1016/j.ejmech.2024.116828.
Ravindar Lekkala 1,  Yan Hong Ng 2,  Shevin Rizal Feroz 2,  Nur Aqilah Zahirah Binti Norazmi 1,  Amatul Hamizah Ali 1,  Siti Aishah Hasbullah 1,  Norzila Ismail 3,  Hani Kartini Agustar 4,  Yee Ling Lau 5,  Nurul Izzaty Hassan 6
Affiliations

Affiliations

  • 1 Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), Bangi, 43600, Selangor, Malaysia.
  • 2 Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600, Bangi, Selangor, Malaysia.
  • 3 Department of Pharmacology, School of Medical Sciences, Universiti Sains Malaysia, 16150, KubangKerian, Kelantan, Malaysia.
  • 4 Department of Earth Sciences and Environment, Universiti Kebangsaan Malaysia, Bangi, 43600, Selangor, Malaysia.
  • 5 Department of Parasitology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
  • 6 Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), Bangi, 43600, Selangor, Malaysia. Electronic address: drizz@ukm.edu.my.
PMID: 39244861 DOI: 10.1016/j.ejmech.2024.116828
Abstract

In this work, a series of nineteen novel pyrano[2,3-c]pyrazole-4-aminoquinoline hybrids were synthesized as potent antimalarial agents by covalently linking the scaffolds of 4-aminoquinoline and pyrano[2,3-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 pyrano[2,3-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 μM 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 μM. 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 μM 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 pyrano[2,3-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

CQ-Resistant K1; CQ-Sensitive 3D7; Malaria; P. falciparum; PfLDH; Pyrano[2,3-c]pyrazile-4-aminoquinolines.

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