Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents
Our group has previously reported several indolecarboxamides exhibiting potent antitubercular activity. Herein, we rationally designed several arylcarboxamides based on our previously reported homology model and the recently published crystal structure of the mycobacterial membrane protein large 3 (...
| Main Authors: | , , , , , , , |
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| Format: | Journal Article |
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RSC
2020
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| Online Access: | http://purl.org/au-research/grants/arc/DE160100482 http://hdl.handle.net/20.500.11937/78250 |
| _version_ | 1848763946169794560 |
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| author | Alsayed, Shahinda SR Lun, Shichun Luna, Giuseppe Beh, Chau Chun Payne, Alan D Foster, Neil R Bishai, William R Gunosewoyo, Hendra |
| author_facet | Alsayed, Shahinda SR Lun, Shichun Luna, Giuseppe Beh, Chau Chun Payne, Alan D Foster, Neil R Bishai, William R Gunosewoyo, Hendra |
| author_sort | Alsayed, Shahinda SR |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Our group has previously reported several indolecarboxamides exhibiting potent antitubercular activity. Herein, we rationally designed several arylcarboxamides based on our previously reported homology model and the recently published crystal structure of the mycobacterial membrane protein large 3 (MmpL3). Many analogues showed considerable anti-TB activity against drug-sensitive (DS) Mycobacterium tuberculosis (M. tb) strain. Naphthamide derivatives 13c and 13d were the most active compounds in our study (MIC: 6.55, 7.11 μM, respectively), showing comparable potency to the first line anti-tuberculosis (anti-TB) drug ethambutol (MIC: 4.89 μM). In addition to the naphthamide derivatives, we also identified the quinolone-2-carboxamides and 4-arylthiazole-2-carboxamides as potential MmpL3 inhibitors in which compounds 8i and 18b had MIC values of 9.97 and 9.82 μM, respectively. All four compounds retained their high activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tb strains. It is worth noting that the two most active compounds 13c and 13d also exhibited the highest selective activity towards DS, MDR and XDR M. tb strains over mammalian cells [IC50 (Vero cells) ≥ 227 μM], indicating their potential lack of cytotoxicity. The four compounds were docked into the MmpL3 active site and were studied for their drug-likeness using Lipinski's rule of five. |
| first_indexed | 2025-11-14T11:11:32Z |
| format | Journal Article |
| id | curtin-20.500.11937-78250 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T11:11:32Z |
| publishDate | 2020 |
| publisher | RSC |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-782502020-10-06T08:09:44Z Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents Alsayed, Shahinda SR Lun, Shichun Luna, Giuseppe Beh, Chau Chun Payne, Alan D Foster, Neil R Bishai, William R Gunosewoyo, Hendra Our group has previously reported several indolecarboxamides exhibiting potent antitubercular activity. Herein, we rationally designed several arylcarboxamides based on our previously reported homology model and the recently published crystal structure of the mycobacterial membrane protein large 3 (MmpL3). Many analogues showed considerable anti-TB activity against drug-sensitive (DS) Mycobacterium tuberculosis (M. tb) strain. Naphthamide derivatives 13c and 13d were the most active compounds in our study (MIC: 6.55, 7.11 μM, respectively), showing comparable potency to the first line anti-tuberculosis (anti-TB) drug ethambutol (MIC: 4.89 μM). In addition to the naphthamide derivatives, we also identified the quinolone-2-carboxamides and 4-arylthiazole-2-carboxamides as potential MmpL3 inhibitors in which compounds 8i and 18b had MIC values of 9.97 and 9.82 μM, respectively. All four compounds retained their high activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tb strains. It is worth noting that the two most active compounds 13c and 13d also exhibited the highest selective activity towards DS, MDR and XDR M. tb strains over mammalian cells [IC50 (Vero cells) ≥ 227 μM], indicating their potential lack of cytotoxicity. The four compounds were docked into the MmpL3 active site and were studied for their drug-likeness using Lipinski's rule of five. 2020 Journal Article http://hdl.handle.net/20.500.11937/78250 10.1039/C9RA10663D http://purl.org/au-research/grants/arc/DE160100482 http://creativecommons.org/licenses/by-nc/4.0/ RSC fulltext |
| spellingShingle | Alsayed, Shahinda SR Lun, Shichun Luna, Giuseppe Beh, Chau Chun Payne, Alan D Foster, Neil R Bishai, William R Gunosewoyo, Hendra Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents |
| title | Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents |
| title_full | Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents |
| title_fullStr | Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents |
| title_full_unstemmed | Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents |
| title_short | Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents |
| title_sort | design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents |
| url | http://purl.org/au-research/grants/arc/DE160100482 http://hdl.handle.net/20.500.11937/78250 |