Challenging the Biginelli scaffold to surpass the first line antitubercular drugs: Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) inhibition activity and molecular modelling studies
New Biginelli adducts were rationalised, via the introduction of selected anti-tubercular (TB) pharmacophores into the dihydropyrimidine (DHPM) ring of deoxythymidine monophosphate (dTMP), the natural substrate of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt). Repurposing was on...
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Taylor & Francis Group
2024-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2024.2386668 |
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| author | Mai S. El-Shoukrofy Amal Atta Salwa Fahmy Dharmarajan Sriram Michael G. Shehat Ibrahim M. Labouta Mona A. Mahran |
| author_facet | Mai S. El-Shoukrofy Amal Atta Salwa Fahmy Dharmarajan Sriram Michael G. Shehat Ibrahim M. Labouta Mona A. Mahran |
| author_sort | Mai S. El-Shoukrofy |
| collection | DOAJ |
| description | New Biginelli adducts were rationalised, via the introduction of selected anti-tubercular (TB) pharmacophores into the dihydropyrimidine (DHPM) ring of deoxythymidine monophosphate (dTMP), the natural substrate of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt). Repurposing was one of the design rationale strategies for some selected mimics of the designed compounds. The anti-TB activity was screened against the Mtb H37Rv strain where 11a was superior to ethambutol (EMB), and was 9-fold more potent than pyrazinamide (PZA). Additionally, compounds 11b, 4a, 4b, 13a, 13b and 14a elicited higher anti-TB activity than PZA, showing better safety profiles than EMB against RAW 264.7 cells’ growth. The in vitro TMPKmt inhibition assay released compounds 11a, 11b and 13b as the most potent inhibitors. Docking studies presumed the binding modes and molecular dynamics (MD) simulation revealed the dynamic stability of 11a-TMPKmt complex over 100 ns. In silico prediction of the chemo-informatics properties of the most active compounds was conducted. |
| format | Article |
| id | doaj-art-c8a522259c9d48deaa89756aeec51448 |
| institution | DOAJ |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-c8a522259c9d48deaa89756aeec514482025-08-20T02:40:33ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742024-12-0139110.1080/14756366.2024.2386668Challenging the Biginelli scaffold to surpass the first line antitubercular drugs: Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) inhibition activity and molecular modelling studiesMai S. El-Shoukrofy0Amal Atta1Salwa Fahmy2Dharmarajan Sriram3Michael G. Shehat4Ibrahim M. Labouta5Mona A. Mahran6Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, EgyptMedicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science, Pilani, IndiaDepartment of Microbiology and Immunology, Faculty of Pharmacy, Alexandria University, Alexandria, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, EgyptNew Biginelli adducts were rationalised, via the introduction of selected anti-tubercular (TB) pharmacophores into the dihydropyrimidine (DHPM) ring of deoxythymidine monophosphate (dTMP), the natural substrate of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt). Repurposing was one of the design rationale strategies for some selected mimics of the designed compounds. The anti-TB activity was screened against the Mtb H37Rv strain where 11a was superior to ethambutol (EMB), and was 9-fold more potent than pyrazinamide (PZA). Additionally, compounds 11b, 4a, 4b, 13a, 13b and 14a elicited higher anti-TB activity than PZA, showing better safety profiles than EMB against RAW 264.7 cells’ growth. The in vitro TMPKmt inhibition assay released compounds 11a, 11b and 13b as the most potent inhibitors. Docking studies presumed the binding modes and molecular dynamics (MD) simulation revealed the dynamic stability of 11a-TMPKmt complex over 100 ns. In silico prediction of the chemo-informatics properties of the most active compounds was conducted.https://www.tandfonline.com/doi/10.1080/14756366.2024.2386668TetrahydropyrimidineBiginelliantitubercular activityMycobacterium tuberculosis thymidine monophosphate kinasemolecular dynamics simulation |
| spellingShingle | Mai S. El-Shoukrofy Amal Atta Salwa Fahmy Dharmarajan Sriram Michael G. Shehat Ibrahim M. Labouta Mona A. Mahran Challenging the Biginelli scaffold to surpass the first line antitubercular drugs: Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) inhibition activity and molecular modelling studies Journal of Enzyme Inhibition and Medicinal Chemistry Tetrahydropyrimidine Biginelli antitubercular activity Mycobacterium tuberculosis thymidine monophosphate kinase molecular dynamics simulation |
| title | Challenging the Biginelli scaffold to surpass the first line antitubercular drugs: Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) inhibition activity and molecular modelling studies |
| title_full | Challenging the Biginelli scaffold to surpass the first line antitubercular drugs: Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) inhibition activity and molecular modelling studies |
| title_fullStr | Challenging the Biginelli scaffold to surpass the first line antitubercular drugs: Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) inhibition activity and molecular modelling studies |
| title_full_unstemmed | Challenging the Biginelli scaffold to surpass the first line antitubercular drugs: Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) inhibition activity and molecular modelling studies |
| title_short | Challenging the Biginelli scaffold to surpass the first line antitubercular drugs: Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) inhibition activity and molecular modelling studies |
| title_sort | challenging the biginelli scaffold to surpass the first line antitubercular drugs mycobacterium tuberculosis thymidine monophosphate kinase tmpkmt inhibition activity and molecular modelling studies |
| topic | Tetrahydropyrimidine Biginelli antitubercular activity Mycobacterium tuberculosis thymidine monophosphate kinase molecular dynamics simulation |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2024.2386668 |
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