Arylquinolinecarboxamides: Synthesis, in vitro and in silico studies against Mycobacterium tuberculosis
- Bokosi, Fostino R B, Beteck, Richard M, Jordaan, Audrey, Seldon, Ronnett, Warner, Digby F, Tshiwawa, Tendamudzimu, Lobb, Kevin A, Khanye, Setshaba D
- Authors: Bokosi, Fostino R B , Beteck, Richard M , Jordaan, Audrey , Seldon, Ronnett , Warner, Digby F , Tshiwawa, Tendamudzimu , Lobb, Kevin A , Khanye, Setshaba D
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451064 , vital:75015 , xlink:href="https://doi.org/10.1002/jhet.4340"
- Description: A series of fourteen 6-substituted-2-(methoxyquinolin-3-yl) methyl)-N-(pyridin-3-ylmethyl) benzamides was prepared from commercially available anilines infive simple and convenient synthetic steps. The structures of all new productswere confirmed by routine spectroscopic methods: IR,1Hand13 CNMR,andHRMS (electrospray ionization). The resulting arylquinolinecarboxamides weresubjected to biological screening assay forin vitroinhibitory activity againstMyco-bacterium tuberculosis (Mtb) H37Rv strain. Several compounds exhibited modestantitubercular activity with compounds8–11,15and19exhibiting MIC90valuesin the range of 32–85μM. The antitubercular data suggested that inhibition ofMtbcan be imparted by the introduction of a non-polar substituent on C-6 of thequinoline scaffold. Further, to understandthepossiblemodeofactionoftheseries, the reported compounds and bedaquiline were subjected toin silicodock-ing studies againstMtbATPase to determine their potential to interfere with themycobacterial adenosine triphosphate (ATP) synthase. The results showed thatthese compounds have the potential toserve as antimycobacterial agents.In silicoADME pharmacokinetic prediction results showed the ability of thesearylquinolinecarcboxamides to be absorbed, distributed, metabolized andexcreted efficiently.
- Full Text:
- Date Issued: 2021
- Authors: Bokosi, Fostino R B , Beteck, Richard M , Jordaan, Audrey , Seldon, Ronnett , Warner, Digby F , Tshiwawa, Tendamudzimu , Lobb, Kevin A , Khanye, Setshaba D
- Date: 2021
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/451064 , vital:75015 , xlink:href="https://doi.org/10.1002/jhet.4340"
- Description: A series of fourteen 6-substituted-2-(methoxyquinolin-3-yl) methyl)-N-(pyridin-3-ylmethyl) benzamides was prepared from commercially available anilines infive simple and convenient synthetic steps. The structures of all new productswere confirmed by routine spectroscopic methods: IR,1Hand13 CNMR,andHRMS (electrospray ionization). The resulting arylquinolinecarboxamides weresubjected to biological screening assay forin vitroinhibitory activity againstMyco-bacterium tuberculosis (Mtb) H37Rv strain. Several compounds exhibited modestantitubercular activity with compounds8–11,15and19exhibiting MIC90valuesin the range of 32–85μM. The antitubercular data suggested that inhibition ofMtbcan be imparted by the introduction of a non-polar substituent on C-6 of thequinoline scaffold. Further, to understandthepossiblemodeofactionoftheseries, the reported compounds and bedaquiline were subjected toin silicodock-ing studies againstMtbATPase to determine their potential to interfere with themycobacterial adenosine triphosphate (ATP) synthase. The results showed thatthese compounds have the potential toserve as antimycobacterial agents.In silicoADME pharmacokinetic prediction results showed the ability of thesearylquinolinecarcboxamides to be absorbed, distributed, metabolized andexcreted efficiently.
- Full Text:
- Date Issued: 2021
Quinolone-isoniazid hybrids: Synthesis and preliminary in vitro cytotoxicity and anti-tuberculosis evaluation
- Beteck, Richard M, Seldon, Ronnett, Khanye, Setshaba D, Legoabe, Lesetja J, Hoppe, Heinrich C, Laming, Dustin, Jordaan, Audrey, Warner, Digby F
- Authors: Beteck, Richard M , Seldon, Ronnett , Khanye, Setshaba D , Legoabe, Lesetja J , Hoppe, Heinrich C , Laming, Dustin , Jordaan, Audrey , Warner, Digby F
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123151 , vital:35410 , https://doi.org/10.1039/C8MD00480C
- Description: Herein, we propose novel quinolones incorporating an INH moiety as potential drug templates against TB. The quinolone-based compounds bearing an INH moiety attached via a hydrazide–hydrazone bond were synthesised and evaluated against Mycobacterium tuberculosis H37Rv (MTB). The compounds were also evaluated for cytotoxicity against HeLa cell lines. These compounds showed significant activity (MIC90) against MTB in the range of 0.2–8 μM without any cytotoxic effects. Compounds 10 (MIC90; 0.9 μM), 11 (MIC90; 0.2 μM), 12 (MIC90; 0.8 μM) and compound 15 (MIC90; 0.8 μM), the most active compounds in this series, demonstrate activities on par with INH and superior to those reported for the fluoroquinolones. The SAR analysis suggests that the nature of substituents at positions −1 and −3 of the quinolone nucleus influences anti-MTB activity. Aqueous solubility evaluation and in vitro metabolic stability of compound 12 highlights favourable drug-like properties for this compound class.
- Full Text:
- Date Issued: 2019
- Authors: Beteck, Richard M , Seldon, Ronnett , Khanye, Setshaba D , Legoabe, Lesetja J , Hoppe, Heinrich C , Laming, Dustin , Jordaan, Audrey , Warner, Digby F
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123151 , vital:35410 , https://doi.org/10.1039/C8MD00480C
- Description: Herein, we propose novel quinolones incorporating an INH moiety as potential drug templates against TB. The quinolone-based compounds bearing an INH moiety attached via a hydrazide–hydrazone bond were synthesised and evaluated against Mycobacterium tuberculosis H37Rv (MTB). The compounds were also evaluated for cytotoxicity against HeLa cell lines. These compounds showed significant activity (MIC90) against MTB in the range of 0.2–8 μM without any cytotoxic effects. Compounds 10 (MIC90; 0.9 μM), 11 (MIC90; 0.2 μM), 12 (MIC90; 0.8 μM) and compound 15 (MIC90; 0.8 μM), the most active compounds in this series, demonstrate activities on par with INH and superior to those reported for the fluoroquinolones. The SAR analysis suggests that the nature of substituents at positions −1 and −3 of the quinolone nucleus influences anti-MTB activity. Aqueous solubility evaluation and in vitro metabolic stability of compound 12 highlights favourable drug-like properties for this compound class.
- Full Text:
- Date Issued: 2019
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