Identification, in-vitro anti-plasmodial assessment and docking studies of series of tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide molecular hybrids as potential antimalarial agents
Copyright © 2022. Published by Elsevier Masson SAS..
Malaria is the most lethal parasitic infections in the world. To address the emergence of drug resistance to current antimalarials, here we report the design and synthesis of new series of tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide hybrids by using multicomponent Petasis reaction as the key step and evaluated in vitro for their antimalarial effectiveness. The structure of all the compounds were confirmed by NMR Spectroscopy and mass spectrometry. Most of the compounds showed potent antimalarial activity against both CQ-sensitive (3D7) and CQ-resistant (W2) strains. A8, A5, and A4 are the most potent compounds that showed excellent anti-plasmodial activity against CQ-resistant strain in the nanomolar range with IC50 values 55.7 nM, 60.8 nM, and 68.0 nM respectively. To assess the parasite selectivity, the in vitro cytotoxicity of selected compounds (A3-A6, A8) was tested against HPL1D cells, demonstrating low cytotoxicity with high selectivity indices. Furthermore, these compounds were also evaluated on two additional human cancerous cell lines (A549 and MDA-MB-231), confirming their anticancer effectiveness. The in vitro hemolysis assay also showed the non-toxicity of these compounds on normal uninfected human RBCs. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS. The in silico ADMET profiling also revealed promising physicochemical and pharmacokinetic parameters for the most active hybrids, which provide strong vision for further development of potential antimalarials.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:248 |
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| Enthalten in: |
European journal of medicinal chemistry - 248(2023) vom: 15. Feb., Seite 115055 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Pal, Kavita [VerfasserIn] |
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| Links: |
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| Themen: |
ADMET properties |
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| Anmerkungen: |
Date Completed 31.01.2023 Date Revised 02.02.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2022.115055 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Copyright © 2022. Published by Elsevier Masson SAS. | ||
| 520 | |a Malaria is the most lethal parasitic infections in the world. To address the emergence of drug resistance to current antimalarials, here we report the design and synthesis of new series of tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide hybrids by using multicomponent Petasis reaction as the key step and evaluated in vitro for their antimalarial effectiveness. The structure of all the compounds were confirmed by NMR Spectroscopy and mass spectrometry. Most of the compounds showed potent antimalarial activity against both CQ-sensitive (3D7) and CQ-resistant (W2) strains. A8, A5, and A4 are the most potent compounds that showed excellent anti-plasmodial activity against CQ-resistant strain in the nanomolar range with IC50 values 55.7 nM, 60.8 nM, and 68.0 nM respectively. To assess the parasite selectivity, the in vitro cytotoxicity of selected compounds (A3-A6, A8) was tested against HPL1D cells, demonstrating low cytotoxicity with high selectivity indices. Furthermore, these compounds were also evaluated on two additional human cancerous cell lines (A549 and MDA-MB-231), confirming their anticancer effectiveness. The in vitro hemolysis assay also showed the non-toxicity of these compounds on normal uninfected human RBCs. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS. The in silico ADMET profiling also revealed promising physicochemical and pharmacokinetic parameters for the most active hybrids, which provide strong vision for further development of potential antimalarials | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ADMET properties | |
| 650 | 4 | |a Antimalarial activity | |
| 650 | 4 | |a Docking study | |
| 650 | 4 | |a Hemolysis assay | |
| 650 | 4 | |a Petasis reaction | |
| 650 | 4 | |a Tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide | |
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| 650 | 7 | |a Pyrimidines |2 NLM | |
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| 700 | 1 | |a Legac, Jenny |e verfasserin |4 aut | |
| 700 | 1 | |a Rahman, Abdur |e verfasserin |4 aut | |
| 700 | 1 | |a Manzoor, Shoaib |e verfasserin |4 aut | |
| 700 | 1 | |a Bhattacharjee, Souvik |e verfasserin |4 aut | |
| 700 | 1 | |a Rosenthal, Philip J |e verfasserin |4 aut | |
| 700 | 1 | |a Hoda, Nasimul |e verfasserin |4 aut | |
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