Design, synthesis and antimycobacterial evaluation of novel adamantane and adamantanol analogues effective against drug-resistant tuberculosis
The treacherous nature of tuberculosis (TB) combined with the ubiquitous presence of the drug-resistant (DR) forms pose this disease as a growing public health menace. Therefore, it is imperative to develop new chemotherapeutic agents with a novel mechanism of action to circumvent the cross-resistan...
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| Format: | Journal Article |
| Language: | English |
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ACADEMIC PRESS INC ELSEVIER SCIENCE
2021
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| Online Access: | http://purl.org/au-research/grants/arc/DE160100482 http://hdl.handle.net/20.500.11937/90998 |
| _version_ | 1848765481701343232 |
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| author | Alsayed, S.S.R. Lun, S. Payne, Alan Bishai, W.R. Gunosewoyo, Hendra |
| author_facet | Alsayed, S.S.R. Lun, S. Payne, Alan Bishai, W.R. Gunosewoyo, Hendra |
| author_sort | Alsayed, S.S.R. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | The treacherous nature of tuberculosis (TB) combined with the ubiquitous presence of the drug-resistant (DR) forms pose this disease as a growing public health menace. Therefore, it is imperative to develop new chemotherapeutic agents with a novel mechanism of action to circumvent the cross-resistance problems. The unique architecture of the Mycobacterium tuberculosis (M. tb) outer envelope plays a predominant role in its pathogenesis, contributing to its intrinsic resistance against available therapeutic agents. The mycobacterial membrane protein large 3 (MmpL3), which is a key player in forging the M. tb rigid cell wall, represents an emerging target for TB drug development. Several indole-2-carboxamides were previously identified in our group as potent anti-TB agents that act as inhibitor of MmpL3 transporter protein. Despite their highly potent in vitro activities, the lingering Achilles heel of these indoleamides can be ascribed to their high lipophilicity as well as low water solubility. In this study, we report our attempt to improve the aqueous solubility of these indole-2-carboxamides while maintaining an adequate lipophilicity to allow effective M. tb cell wall penetration. A more polar adamantanol moiety was incorporated into the framework of several indole-2-carboxamides, whereupon the corresponding analogues were tested for their anti-TB activity against drug-sensitive (DS) M. tb H37Rv strain. Three adamantanol derivatives 8i, 8j and 8l showed nearly 2- and 4-fold higher activity (MIC = 1.32 – 2.89 µM) than ethambutol (MIC = 4.89 µM). Remarkably, the most potent adamantanol analogue 8j demonstrated high selectivity towards DS and DR M. tb strains over mammalian cells [IC50 (Vero cells) ≥ 169 µM], evincing its lack of cytotoxicity. The top eight active compounds 8b, 8d, 8f, 8i, 8j, 8k, 8l and 10a retained their in vitro potency against DR M. tb strains and were docked into the MmpL3 active site. The most potent adamantanol/adamantane-based indoleamides 8j/8k displayed a two-fold surge in potency against extensively DR (XDR) M. tb strains with MIC values of 0.66 and 0.012 µM, respectively. The adamantanol-containing indole-2-carboxamides exhibited improved water solubility both in silico and experimentally, relative to the adamantane counterparts. Overall, the observed antimycobacterial and physicochemical profiles support the notion that adamantanol moiety is a suitable replacement to the adamantane scaffold within the series of indole-2-carboxamide-based MmpL3 inhibitors. |
| first_indexed | 2025-11-14T11:35:56Z |
| format | Journal Article |
| id | curtin-20.500.11937-90998 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T11:35:56Z |
| publishDate | 2021 |
| publisher | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| recordtype | eprints |
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| spelling | curtin-20.500.11937-909982023-05-24T01:03:33Z Design, synthesis and antimycobacterial evaluation of novel adamantane and adamantanol analogues effective against drug-resistant tuberculosis Alsayed, S.S.R. Lun, S. Payne, Alan Bishai, W.R. Gunosewoyo, Hendra Science & Technology Life Sciences & Biomedicine Physical Sciences Biochemistry & Molecular Biology Chemistry, Organic Chemistry Tuberculosis MmpL3 Indoleamides Adamantane Adamantanol MDR-TB XDR-TB Cytotoxicity Water solubility MYCOLIC ACID TRANSPORT MYCOBACTERIUM-TUBERCULOSIS MULTIDRUG-RESISTANT BIOLOGICAL EVALUATION MEMBRANE TRANSPORTER CELL-WALL MMPL3 DISCOVERY TARGETS DERIVATIVES Adamantane Adamantanol Cytotoxicity Indoleamides MDR-TB MmpL3 Tuberculosis Water solubility XDR-TB Adamantane Antitubercular Agents Dose-Response Relationship, Drug Drug Design Microbial Sensitivity Tests Models, Molecular Molecular Structure Mycobacterium tuberculosis Structure-Activity Relationship Tuberculosis, Multidrug-Resistant Mycobacterium tuberculosis Tuberculosis, Multidrug-Resistant Adamantane Antitubercular Agents Microbial Sensitivity Tests Molecular Structure Structure-Activity Relationship Dose-Response Relationship, Drug Drug Design Models, Molecular The treacherous nature of tuberculosis (TB) combined with the ubiquitous presence of the drug-resistant (DR) forms pose this disease as a growing public health menace. Therefore, it is imperative to develop new chemotherapeutic agents with a novel mechanism of action to circumvent the cross-resistance problems. The unique architecture of the Mycobacterium tuberculosis (M. tb) outer envelope plays a predominant role in its pathogenesis, contributing to its intrinsic resistance against available therapeutic agents. The mycobacterial membrane protein large 3 (MmpL3), which is a key player in forging the M. tb rigid cell wall, represents an emerging target for TB drug development. Several indole-2-carboxamides were previously identified in our group as potent anti-TB agents that act as inhibitor of MmpL3 transporter protein. Despite their highly potent in vitro activities, the lingering Achilles heel of these indoleamides can be ascribed to their high lipophilicity as well as low water solubility. In this study, we report our attempt to improve the aqueous solubility of these indole-2-carboxamides while maintaining an adequate lipophilicity to allow effective M. tb cell wall penetration. A more polar adamantanol moiety was incorporated into the framework of several indole-2-carboxamides, whereupon the corresponding analogues were tested for their anti-TB activity against drug-sensitive (DS) M. tb H37Rv strain. Three adamantanol derivatives 8i, 8j and 8l showed nearly 2- and 4-fold higher activity (MIC = 1.32 – 2.89 µM) than ethambutol (MIC = 4.89 µM). Remarkably, the most potent adamantanol analogue 8j demonstrated high selectivity towards DS and DR M. tb strains over mammalian cells [IC50 (Vero cells) ≥ 169 µM], evincing its lack of cytotoxicity. The top eight active compounds 8b, 8d, 8f, 8i, 8j, 8k, 8l and 10a retained their in vitro potency against DR M. tb strains and were docked into the MmpL3 active site. The most potent adamantanol/adamantane-based indoleamides 8j/8k displayed a two-fold surge in potency against extensively DR (XDR) M. tb strains with MIC values of 0.66 and 0.012 µM, respectively. The adamantanol-containing indole-2-carboxamides exhibited improved water solubility both in silico and experimentally, relative to the adamantane counterparts. Overall, the observed antimycobacterial and physicochemical profiles support the notion that adamantanol moiety is a suitable replacement to the adamantane scaffold within the series of indole-2-carboxamide-based MmpL3 inhibitors. 2021 Journal Article http://hdl.handle.net/20.500.11937/90998 10.1016/j.bioorg.2020.104486 English http://purl.org/au-research/grants/arc/DE160100482 http://creativecommons.org/licenses/by-nc-nd/4.0/ ACADEMIC PRESS INC ELSEVIER SCIENCE fulltext |
| spellingShingle | Science & Technology Life Sciences & Biomedicine Physical Sciences Biochemistry & Molecular Biology Chemistry, Organic Chemistry Tuberculosis MmpL3 Indoleamides Adamantane Adamantanol MDR-TB XDR-TB Cytotoxicity Water solubility MYCOLIC ACID TRANSPORT MYCOBACTERIUM-TUBERCULOSIS MULTIDRUG-RESISTANT BIOLOGICAL EVALUATION MEMBRANE TRANSPORTER CELL-WALL MMPL3 DISCOVERY TARGETS DERIVATIVES Adamantane Adamantanol Cytotoxicity Indoleamides MDR-TB MmpL3 Tuberculosis Water solubility XDR-TB Adamantane Antitubercular Agents Dose-Response Relationship, Drug Drug Design Microbial Sensitivity Tests Models, Molecular Molecular Structure Mycobacterium tuberculosis Structure-Activity Relationship Tuberculosis, Multidrug-Resistant Mycobacterium tuberculosis Tuberculosis, Multidrug-Resistant Adamantane Antitubercular Agents Microbial Sensitivity Tests Molecular Structure Structure-Activity Relationship Dose-Response Relationship, Drug Drug Design Models, Molecular Alsayed, S.S.R. Lun, S. Payne, Alan Bishai, W.R. Gunosewoyo, Hendra Design, synthesis and antimycobacterial evaluation of novel adamantane and adamantanol analogues effective against drug-resistant tuberculosis |
| title | Design, synthesis and antimycobacterial evaluation of novel adamantane and adamantanol analogues effective against drug-resistant tuberculosis |
| title_full | Design, synthesis and antimycobacterial evaluation of novel adamantane and adamantanol analogues effective against drug-resistant tuberculosis |
| title_fullStr | Design, synthesis and antimycobacterial evaluation of novel adamantane and adamantanol analogues effective against drug-resistant tuberculosis |
| title_full_unstemmed | Design, synthesis and antimycobacterial evaluation of novel adamantane and adamantanol analogues effective against drug-resistant tuberculosis |
| title_short | Design, synthesis and antimycobacterial evaluation of novel adamantane and adamantanol analogues effective against drug-resistant tuberculosis |
| title_sort | design, synthesis and antimycobacterial evaluation of novel adamantane and adamantanol analogues effective against drug-resistant tuberculosis |
| topic | Science & Technology Life Sciences & Biomedicine Physical Sciences Biochemistry & Molecular Biology Chemistry, Organic Chemistry Tuberculosis MmpL3 Indoleamides Adamantane Adamantanol MDR-TB XDR-TB Cytotoxicity Water solubility MYCOLIC ACID TRANSPORT MYCOBACTERIUM-TUBERCULOSIS MULTIDRUG-RESISTANT BIOLOGICAL EVALUATION MEMBRANE TRANSPORTER CELL-WALL MMPL3 DISCOVERY TARGETS DERIVATIVES Adamantane Adamantanol Cytotoxicity Indoleamides MDR-TB MmpL3 Tuberculosis Water solubility XDR-TB Adamantane Antitubercular Agents Dose-Response Relationship, Drug Drug Design Microbial Sensitivity Tests Models, Molecular Molecular Structure Mycobacterium tuberculosis Structure-Activity Relationship Tuberculosis, Multidrug-Resistant Mycobacterium tuberculosis Tuberculosis, Multidrug-Resistant Adamantane Antitubercular Agents Microbial Sensitivity Tests Molecular Structure Structure-Activity Relationship Dose-Response Relationship, Drug Drug Design Models, Molecular |
| url | http://purl.org/au-research/grants/arc/DE160100482 http://hdl.handle.net/20.500.11937/90998 |