Synthesis, molecular docking, and antimalarial activity of hybrid 4-aminoquinoline-pyrano[2,3-c]pyrazole derivatives
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 synthesiz...
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my.utm.948362022-04-29T22:27:59Z http://eprints.utm.my/id/eprint/94836/ Synthesis, molecular docking, and antimalarial activity of hybrid 4-aminoquinoline-pyrano[2,3-c]pyrazole derivatives Shamsuddin, Mohd. Asyraf Ali, Amatul Hamizah Zakaria, Nur Hanis Mohammat, Mohd. Fazli Hamzah, Ahmad Sazali Shaameri, Zurina Lam, Kok Wai Lee, Mark Wun Fui Agustar, Hani Kartini Mohd. Abd. Razak, Mohd. Ridzuan Latip, Jalifah Hassan, Nurul Izzaty QD Chemistry 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. MDPI 2021-11 Article PeerReviewed application/pdf en http://eprints.utm.my/id/eprint/94836/1/LeeWunFui2021_SynthesisMolecularDockingandAntimalarial.pdf Shamsuddin, Mohd. Asyraf and Ali, Amatul Hamizah and Zakaria, Nur Hanis and Mohammat, Mohd. Fazli and Hamzah, Ahmad Sazali and Shaameri, Zurina and Lam, Kok Wai and Lee, Mark Wun Fui and Agustar, Hani Kartini and Mohd. Abd. Razak, Mohd. Ridzuan and Latip, Jalifah and Hassan, Nurul Izzaty (2021) Synthesis, molecular docking, and antimalarial activity of hybrid 4-aminoquinoline-pyrano[2,3-c]pyrazole derivatives. Pharmaceuticals, 14 (11). pp. 1-17. ISSN 1424-8247 http://dx.doi.org/10.3390/ph14111174 DOI:10.3390/ph14111174 |
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QD Chemistry Shamsuddin, Mohd. Asyraf Ali, Amatul Hamizah Zakaria, Nur Hanis Mohammat, Mohd. Fazli Hamzah, Ahmad Sazali Shaameri, Zurina Lam, Kok Wai Lee, Mark Wun Fui Agustar, Hani Kartini Mohd. Abd. Razak, Mohd. Ridzuan Latip, Jalifah Hassan, Nurul Izzaty Synthesis, molecular docking, and antimalarial activity of hybrid 4-aminoquinoline-pyrano[2,3-c]pyrazole derivatives |
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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. |
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Shamsuddin, Mohd. Asyraf Ali, Amatul Hamizah Zakaria, Nur Hanis Mohammat, Mohd. Fazli Hamzah, Ahmad Sazali Shaameri, Zurina Lam, Kok Wai Lee, Mark Wun Fui Agustar, Hani Kartini Mohd. Abd. Razak, Mohd. Ridzuan Latip, Jalifah Hassan, Nurul Izzaty |
author_facet |
Shamsuddin, Mohd. Asyraf Ali, Amatul Hamizah Zakaria, Nur Hanis Mohammat, Mohd. Fazli Hamzah, Ahmad Sazali Shaameri, Zurina Lam, Kok Wai Lee, Mark Wun Fui Agustar, Hani Kartini Mohd. Abd. Razak, Mohd. Ridzuan Latip, Jalifah Hassan, Nurul Izzaty |
author_sort |
Shamsuddin, Mohd. Asyraf |
title |
Synthesis, molecular docking, and antimalarial activity of hybrid 4-aminoquinoline-pyrano[2,3-c]pyrazole derivatives |
title_short |
Synthesis, molecular docking, and antimalarial activity of hybrid 4-aminoquinoline-pyrano[2,3-c]pyrazole derivatives |
title_full |
Synthesis, molecular docking, and antimalarial activity of hybrid 4-aminoquinoline-pyrano[2,3-c]pyrazole derivatives |
title_fullStr |
Synthesis, molecular docking, and antimalarial activity of hybrid 4-aminoquinoline-pyrano[2,3-c]pyrazole derivatives |
title_full_unstemmed |
Synthesis, molecular docking, and antimalarial activity of hybrid 4-aminoquinoline-pyrano[2,3-c]pyrazole derivatives |
title_sort |
synthesis, molecular docking, and antimalarial activity of hybrid 4-aminoquinoline-pyrano[2,3-c]pyrazole derivatives |
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MDPI |
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2021 |
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http://eprints.utm.my/id/eprint/94836/1/LeeWunFui2021_SynthesisMolecularDockingandAntimalarial.pdf http://eprints.utm.my/id/eprint/94836/ http://dx.doi.org/10.3390/ph14111174 |
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