Synthesis and heme detoxification of pyrano[2,3-c]pyrazole- aminoquinoline hybrids as antimalarial agents Lekkala Ravindar 1 , Siti Aishah Hasbullah 1 , Ahmad Fadhlurrahman bin Ahmad Hidayat 2 , Ng Yan Hong 3 , Khairul Azreena Bakar 3 , Shevin Rizal Feroz 3 , Nurul Izzaty Hassan 1 1 Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), 2 Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Malaysia, 3 Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia Malaria is a life-threatening disease transmitted through mosquito bites (Anopheles). Due to plasmodium protozoa, this disease is dangerous and can cause death. Consequently, developing cost-effective and effective antimalarials is essential. The hybridization of 4-aminoquinoline and pyrano[2,3-c]pyrazoles enhances the antimalarial activity of pyrano[2,3-c]pyrazole-aminoquinolines, as both 4-aminoquinoline and pyranopyrazoles have diverse therapeutic applications. Our lab has recently reported a successful cascade process for conjugating 4-aminoquinolines and pyrano[2,3c]pyrazoles as antimalarial hybrids 1 . Functionalizing a heterocyclic component at the -NH of the ethyl linkage may enhance the lipophilicity of the resulting compound. In this project, the design and synthesis of four novel pyrano[2,3c]pyrazole-aminoquinolines containing various substituted aromatic/ heterocyclic rings on the pyrano[2,3c]pyrazole moiety have been expanded. The synthesis proceeds via multi component reactions involving diethyloxalacetate, hydrazine, aldehyde, and malononitrile using ethanol as a solvent in the presence of acetic acid as a catalyst 2 . Followed by the synthesis of 4-(bromoethylamino)- 7-chloroquine through a bromination reaction 3 and finally fusing between four pyranopyrazoles and 4-aminoquinoline via nucleophilic substitution, which yields about 30 - 40%. The higher yield was obtained in the case of hybrid 4 (40%) containing a strong electron-withdrawing -NO 2 group at the para position of the phenyl ring attached to the pyranopyrazole moiety. A nano ITC microcalorimeter was used to study the possible interaction between four hybrids and hemin at 37°C. Determination of the dissociation constant (K d ) values from ITC experiments revealed varying affinities of the hybrids to hemin, reflecting the difference in their structures. Hybrid 1 and 2 exhibited strong affinity to hemin with K d values of 4.301×10 -7 M and 9.925×10 -7 M, respectively. On the other hand, hybrids 3 and 4 interacted with hemin with markedly lower affinities, with K d values of 1.013×10 -5 M and 1.137×10 -5 M, respectively. One mechanism of action of antimalarial drugs is binding to heme, which prevents the formation of heme crystals, thus leading to the accumulation of the toxic hemein the digestive vacuole, killing the Plasmodium parasite . Hence, the ability of compounds to bind favourably to heme can be used to evaluate their potential as antimalarial agents. Based on these results, hybrids 1 and 2 formed more stable interactions with hemin and thus are better antimalarial candidates. References 1. M.A. Shamsuddin et al . Synthesis, Molecular Docking, and Antimalarial Activity of Hybrid 4-Aminoquinoline- pyrano[2,3-c]pyrazole Derivatives . Pharmaceuticals , 2021, 14 (11) 1174. 2. M.F. Mohammat et al . Practical synthesis and electronic study of non-spiro and spiropyrano [2, 3-c] pyrazole-3- carboxylate derivatives via uncatalyzed domino one-pot, four-component reactions. Organic Communications , 2018, 11 (3), 149. 3. S. Eswaran et al . New Quinoline Derivatives: Synthesis and Investigation of Antibacterial and Antituberculosis Properties . European Journal of Medicinal Chemistry, 2010, 45 (8) 3374.
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