Design, synthesis, and biological evaluation of 1,2,4-triazole derivatives as potent antitubercular agents
Inhibition of mycobacterial membrane protein large 3 (MmpL3) thereby affecting the mycolic acid biosynthetic pathway has been proven to be an effective strategy for developing antitubercular drugs. Based on the X-ray crystal structure of MmpL3 inhibitor complexes, a series of novel 1,2,4-triazole de...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Wen, Yu [verfasserIn] Lun, Shichun [verfasserIn] Jiao, Yuxue [verfasserIn] Zhang, Wei [verfasserIn] Hu, Tianyu [verfasserIn] Liu, Ting [verfasserIn] Yang, Fan [verfasserIn] Tang, Jie [verfasserIn] Zhang, Bing [verfasserIn] Bishai, William R. [verfasserIn] Yu, Li-Fang [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2024 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Chinese chemical letters - Amsterdam : Elsevier, 1990, 35 |
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| Übergeordnetes Werk: |
volume:35 |
| DOI / URN: |
10.1016/j.cclet.2023.108464 |
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ELV067183700 |
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| 520 | |a Inhibition of mycobacterial membrane protein large 3 (MmpL3) thereby affecting the mycolic acid biosynthetic pathway has been proven to be an effective strategy for developing antitubercular drugs. Based on the X-ray crystal structure of MmpL3 inhibitor complexes, a series of novel 1,2,4-triazole derivatives were designed, synthesized and evaluated antitubercular activity against Mtb strain H37Rv. Comprehensive structure–activity relationship exploration resulted in the identification of compounds 21 and 28, which possess potent antitubercular activity against Mtb strain H37Rv [minimum inhibitory concentration (MIC) = 0.03–0.13 µg/mL] and the clinical isolates of multidrug resistance (MDR) and extensive drug resistance (XDR) tuberculosis (MIC = 0.06–1.0 µg/mL). Moreover, compounds 21 and 28 showed neglectable cytotoxicity (IC50 ≥ 32 µg/mL) to the mammalian Vero cells and favorable physicochemical and pharmacokinetic properties according to the in silico absorption, distribution, metabolism and excretion (ADME) prediction. Finally, the potential target of representative 1,2,4-triazole 28 was identified to be MmpL3 using a microscale thermophoresis (MST) assay. | ||
| 650 | 4 | |a Tuberculosis | |
| 650 | 4 | |a MDR and XDR-TB | |
| 650 | 4 | |a MmpL3 inhibitor | |
| 650 | 4 | |a 1,2,4-Triazole | |
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| 700 | 1 | |a Lun, Shichun |e verfasserin |4 aut | |
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10.1016/j.cclet.2023.108464 doi (DE-627)ELV067183700 (ELSEVIER)S1001-8417(23)00313-3 DE-627 ger DE-627 rda eng 540 VZ 6,25 ssgn ASIEN DE-1a fid 35.00 bkl 35.04 bkl Wen, Yu verfasserin aut Design, synthesis, and biological evaluation of 1,2,4-triazole derivatives as potent antitubercular agents 2024 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Inhibition of mycobacterial membrane protein large 3 (MmpL3) thereby affecting the mycolic acid biosynthetic pathway has been proven to be an effective strategy for developing antitubercular drugs. Based on the X-ray crystal structure of MmpL3 inhibitor complexes, a series of novel 1,2,4-triazole derivatives were designed, synthesized and evaluated antitubercular activity against Mtb strain H37Rv. Comprehensive structure–activity relationship exploration resulted in the identification of compounds 21 and 28, which possess potent antitubercular activity against Mtb strain H37Rv [minimum inhibitory concentration (MIC) = 0.03–0.13 µg/mL] and the clinical isolates of multidrug resistance (MDR) and extensive drug resistance (XDR) tuberculosis (MIC = 0.06–1.0 µg/mL). Moreover, compounds 21 and 28 showed neglectable cytotoxicity (IC50 ≥ 32 µg/mL) to the mammalian Vero cells and favorable physicochemical and pharmacokinetic properties according to the in silico absorption, distribution, metabolism and excretion (ADME) prediction. Finally, the potential target of representative 1,2,4-triazole 28 was identified to be MmpL3 using a microscale thermophoresis (MST) assay. Tuberculosis MDR and XDR-TB MmpL3 inhibitor 1,2,4-Triazole Structure-based drug design Lun, Shichun verfasserin aut Jiao, Yuxue verfasserin (orcid)0000-0002-3282-6152 aut Zhang, Wei verfasserin aut Hu, Tianyu verfasserin aut Liu, Ting verfasserin aut Yang, Fan verfasserin aut Tang, Jie verfasserin aut Zhang, Bing verfasserin (orcid)0000-0001-8556-8049 aut Bishai, William R. verfasserin aut Yu, Li-Fang verfasserin (orcid)0000-0002-3250-6773 aut Enthalten in Chinese chemical letters Amsterdam : Elsevier, 1990 35 Online-Ressource (DE-627)358144019 (DE-600)2096242-3 (DE-576)267762151 1878-5964 nnns volume:35 GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-ASIEN GBV_ILN_31 GBV_ILN_95 GBV_ILN_150 GBV_ILN_2004 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2336 GBV_ILN_4251 35.00 Chemie: Allgemeines VZ 35.04 Ausbildung Beruf Organisationen Chemie VZ AR 35 |
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10.1016/j.cclet.2023.108464 doi (DE-627)ELV067183700 (ELSEVIER)S1001-8417(23)00313-3 DE-627 ger DE-627 rda eng 540 VZ 6,25 ssgn ASIEN DE-1a fid 35.00 bkl 35.04 bkl Wen, Yu verfasserin aut Design, synthesis, and biological evaluation of 1,2,4-triazole derivatives as potent antitubercular agents 2024 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Inhibition of mycobacterial membrane protein large 3 (MmpL3) thereby affecting the mycolic acid biosynthetic pathway has been proven to be an effective strategy for developing antitubercular drugs. Based on the X-ray crystal structure of MmpL3 inhibitor complexes, a series of novel 1,2,4-triazole derivatives were designed, synthesized and evaluated antitubercular activity against Mtb strain H37Rv. Comprehensive structure–activity relationship exploration resulted in the identification of compounds 21 and 28, which possess potent antitubercular activity against Mtb strain H37Rv [minimum inhibitory concentration (MIC) = 0.03–0.13 µg/mL] and the clinical isolates of multidrug resistance (MDR) and extensive drug resistance (XDR) tuberculosis (MIC = 0.06–1.0 µg/mL). Moreover, compounds 21 and 28 showed neglectable cytotoxicity (IC50 ≥ 32 µg/mL) to the mammalian Vero cells and favorable physicochemical and pharmacokinetic properties according to the in silico absorption, distribution, metabolism and excretion (ADME) prediction. Finally, the potential target of representative 1,2,4-triazole 28 was identified to be MmpL3 using a microscale thermophoresis (MST) assay. Tuberculosis MDR and XDR-TB MmpL3 inhibitor 1,2,4-Triazole Structure-based drug design Lun, Shichun verfasserin aut Jiao, Yuxue verfasserin (orcid)0000-0002-3282-6152 aut Zhang, Wei verfasserin aut Hu, Tianyu verfasserin aut Liu, Ting verfasserin aut Yang, Fan verfasserin aut Tang, Jie verfasserin aut Zhang, Bing verfasserin (orcid)0000-0001-8556-8049 aut Bishai, William R. verfasserin aut Yu, Li-Fang verfasserin (orcid)0000-0002-3250-6773 aut Enthalten in Chinese chemical letters Amsterdam : Elsevier, 1990 35 Online-Ressource (DE-627)358144019 (DE-600)2096242-3 (DE-576)267762151 1878-5964 nnns volume:35 GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-ASIEN GBV_ILN_31 GBV_ILN_95 GBV_ILN_150 GBV_ILN_2004 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2336 GBV_ILN_4251 35.00 Chemie: Allgemeines VZ 35.04 Ausbildung Beruf Organisationen Chemie VZ AR 35 |
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10.1016/j.cclet.2023.108464 doi (DE-627)ELV067183700 (ELSEVIER)S1001-8417(23)00313-3 DE-627 ger DE-627 rda eng 540 VZ 6,25 ssgn ASIEN DE-1a fid 35.00 bkl 35.04 bkl Wen, Yu verfasserin aut Design, synthesis, and biological evaluation of 1,2,4-triazole derivatives as potent antitubercular agents 2024 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Inhibition of mycobacterial membrane protein large 3 (MmpL3) thereby affecting the mycolic acid biosynthetic pathway has been proven to be an effective strategy for developing antitubercular drugs. Based on the X-ray crystal structure of MmpL3 inhibitor complexes, a series of novel 1,2,4-triazole derivatives were designed, synthesized and evaluated antitubercular activity against Mtb strain H37Rv. Comprehensive structure–activity relationship exploration resulted in the identification of compounds 21 and 28, which possess potent antitubercular activity against Mtb strain H37Rv [minimum inhibitory concentration (MIC) = 0.03–0.13 µg/mL] and the clinical isolates of multidrug resistance (MDR) and extensive drug resistance (XDR) tuberculosis (MIC = 0.06–1.0 µg/mL). Moreover, compounds 21 and 28 showed neglectable cytotoxicity (IC50 ≥ 32 µg/mL) to the mammalian Vero cells and favorable physicochemical and pharmacokinetic properties according to the in silico absorption, distribution, metabolism and excretion (ADME) prediction. Finally, the potential target of representative 1,2,4-triazole 28 was identified to be MmpL3 using a microscale thermophoresis (MST) assay. Tuberculosis MDR and XDR-TB MmpL3 inhibitor 1,2,4-Triazole Structure-based drug design Lun, Shichun verfasserin aut Jiao, Yuxue verfasserin (orcid)0000-0002-3282-6152 aut Zhang, Wei verfasserin aut Hu, Tianyu verfasserin aut Liu, Ting verfasserin aut Yang, Fan verfasserin aut Tang, Jie verfasserin aut Zhang, Bing verfasserin (orcid)0000-0001-8556-8049 aut Bishai, William R. verfasserin aut Yu, Li-Fang verfasserin (orcid)0000-0002-3250-6773 aut Enthalten in Chinese chemical letters Amsterdam : Elsevier, 1990 35 Online-Ressource (DE-627)358144019 (DE-600)2096242-3 (DE-576)267762151 1878-5964 nnns volume:35 GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-ASIEN GBV_ILN_31 GBV_ILN_95 GBV_ILN_150 GBV_ILN_2004 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2336 GBV_ILN_4251 35.00 Chemie: Allgemeines VZ 35.04 Ausbildung Beruf Organisationen Chemie VZ AR 35 |
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10.1016/j.cclet.2023.108464 doi (DE-627)ELV067183700 (ELSEVIER)S1001-8417(23)00313-3 DE-627 ger DE-627 rda eng 540 VZ 6,25 ssgn ASIEN DE-1a fid 35.00 bkl 35.04 bkl Wen, Yu verfasserin aut Design, synthesis, and biological evaluation of 1,2,4-triazole derivatives as potent antitubercular agents 2024 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Inhibition of mycobacterial membrane protein large 3 (MmpL3) thereby affecting the mycolic acid biosynthetic pathway has been proven to be an effective strategy for developing antitubercular drugs. Based on the X-ray crystal structure of MmpL3 inhibitor complexes, a series of novel 1,2,4-triazole derivatives were designed, synthesized and evaluated antitubercular activity against Mtb strain H37Rv. Comprehensive structure–activity relationship exploration resulted in the identification of compounds 21 and 28, which possess potent antitubercular activity against Mtb strain H37Rv [minimum inhibitory concentration (MIC) = 0.03–0.13 µg/mL] and the clinical isolates of multidrug resistance (MDR) and extensive drug resistance (XDR) tuberculosis (MIC = 0.06–1.0 µg/mL). Moreover, compounds 21 and 28 showed neglectable cytotoxicity (IC50 ≥ 32 µg/mL) to the mammalian Vero cells and favorable physicochemical and pharmacokinetic properties according to the in silico absorption, distribution, metabolism and excretion (ADME) prediction. Finally, the potential target of representative 1,2,4-triazole 28 was identified to be MmpL3 using a microscale thermophoresis (MST) assay. Tuberculosis MDR and XDR-TB MmpL3 inhibitor 1,2,4-Triazole Structure-based drug design Lun, Shichun verfasserin aut Jiao, Yuxue verfasserin (orcid)0000-0002-3282-6152 aut Zhang, Wei verfasserin aut Hu, Tianyu verfasserin aut Liu, Ting verfasserin aut Yang, Fan verfasserin aut Tang, Jie verfasserin aut Zhang, Bing verfasserin (orcid)0000-0001-8556-8049 aut Bishai, William R. verfasserin aut Yu, Li-Fang verfasserin (orcid)0000-0002-3250-6773 aut Enthalten in Chinese chemical letters Amsterdam : Elsevier, 1990 35 Online-Ressource (DE-627)358144019 (DE-600)2096242-3 (DE-576)267762151 1878-5964 nnns volume:35 GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-ASIEN GBV_ILN_31 GBV_ILN_95 GBV_ILN_150 GBV_ILN_2004 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2336 GBV_ILN_4251 35.00 Chemie: Allgemeines VZ 35.04 Ausbildung Beruf Organisationen Chemie VZ AR 35 |
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10.1016/j.cclet.2023.108464 doi (DE-627)ELV067183700 (ELSEVIER)S1001-8417(23)00313-3 DE-627 ger DE-627 rda eng 540 VZ 6,25 ssgn ASIEN DE-1a fid 35.00 bkl 35.04 bkl Wen, Yu verfasserin aut Design, synthesis, and biological evaluation of 1,2,4-triazole derivatives as potent antitubercular agents 2024 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Inhibition of mycobacterial membrane protein large 3 (MmpL3) thereby affecting the mycolic acid biosynthetic pathway has been proven to be an effective strategy for developing antitubercular drugs. Based on the X-ray crystal structure of MmpL3 inhibitor complexes, a series of novel 1,2,4-triazole derivatives were designed, synthesized and evaluated antitubercular activity against Mtb strain H37Rv. Comprehensive structure–activity relationship exploration resulted in the identification of compounds 21 and 28, which possess potent antitubercular activity against Mtb strain H37Rv [minimum inhibitory concentration (MIC) = 0.03–0.13 µg/mL] and the clinical isolates of multidrug resistance (MDR) and extensive drug resistance (XDR) tuberculosis (MIC = 0.06–1.0 µg/mL). Moreover, compounds 21 and 28 showed neglectable cytotoxicity (IC50 ≥ 32 µg/mL) to the mammalian Vero cells and favorable physicochemical and pharmacokinetic properties according to the in silico absorption, distribution, metabolism and excretion (ADME) prediction. Finally, the potential target of representative 1,2,4-triazole 28 was identified to be MmpL3 using a microscale thermophoresis (MST) assay. Tuberculosis MDR and XDR-TB MmpL3 inhibitor 1,2,4-Triazole Structure-based drug design Lun, Shichun verfasserin aut Jiao, Yuxue verfasserin (orcid)0000-0002-3282-6152 aut Zhang, Wei verfasserin aut Hu, Tianyu verfasserin aut Liu, Ting verfasserin aut Yang, Fan verfasserin aut Tang, Jie verfasserin aut Zhang, Bing verfasserin (orcid)0000-0001-8556-8049 aut Bishai, William R. verfasserin aut Yu, Li-Fang verfasserin (orcid)0000-0002-3250-6773 aut Enthalten in Chinese chemical letters Amsterdam : Elsevier, 1990 35 Online-Ressource (DE-627)358144019 (DE-600)2096242-3 (DE-576)267762151 1878-5964 nnns volume:35 GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-ASIEN GBV_ILN_31 GBV_ILN_95 GBV_ILN_150 GBV_ILN_2004 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2336 GBV_ILN_4251 35.00 Chemie: Allgemeines VZ 35.04 Ausbildung Beruf Organisationen Chemie VZ AR 35 |
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design, synthesis, and biological evaluation of 1,2,4-triazole derivatives as potent antitubercular agents |
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Design, synthesis, and biological evaluation of 1,2,4-triazole derivatives as potent antitubercular agents |
| abstract |
Inhibition of mycobacterial membrane protein large 3 (MmpL3) thereby affecting the mycolic acid biosynthetic pathway has been proven to be an effective strategy for developing antitubercular drugs. Based on the X-ray crystal structure of MmpL3 inhibitor complexes, a series of novel 1,2,4-triazole derivatives were designed, synthesized and evaluated antitubercular activity against Mtb strain H37Rv. Comprehensive structure–activity relationship exploration resulted in the identification of compounds 21 and 28, which possess potent antitubercular activity against Mtb strain H37Rv [minimum inhibitory concentration (MIC) = 0.03–0.13 µg/mL] and the clinical isolates of multidrug resistance (MDR) and extensive drug resistance (XDR) tuberculosis (MIC = 0.06–1.0 µg/mL). Moreover, compounds 21 and 28 showed neglectable cytotoxicity (IC50 ≥ 32 µg/mL) to the mammalian Vero cells and favorable physicochemical and pharmacokinetic properties according to the in silico absorption, distribution, metabolism and excretion (ADME) prediction. Finally, the potential target of representative 1,2,4-triazole 28 was identified to be MmpL3 using a microscale thermophoresis (MST) assay. |
| abstractGer |
Inhibition of mycobacterial membrane protein large 3 (MmpL3) thereby affecting the mycolic acid biosynthetic pathway has been proven to be an effective strategy for developing antitubercular drugs. Based on the X-ray crystal structure of MmpL3 inhibitor complexes, a series of novel 1,2,4-triazole derivatives were designed, synthesized and evaluated antitubercular activity against Mtb strain H37Rv. Comprehensive structure–activity relationship exploration resulted in the identification of compounds 21 and 28, which possess potent antitubercular activity against Mtb strain H37Rv [minimum inhibitory concentration (MIC) = 0.03–0.13 µg/mL] and the clinical isolates of multidrug resistance (MDR) and extensive drug resistance (XDR) tuberculosis (MIC = 0.06–1.0 µg/mL). Moreover, compounds 21 and 28 showed neglectable cytotoxicity (IC50 ≥ 32 µg/mL) to the mammalian Vero cells and favorable physicochemical and pharmacokinetic properties according to the in silico absorption, distribution, metabolism and excretion (ADME) prediction. Finally, the potential target of representative 1,2,4-triazole 28 was identified to be MmpL3 using a microscale thermophoresis (MST) assay. |
| abstract_unstemmed |
Inhibition of mycobacterial membrane protein large 3 (MmpL3) thereby affecting the mycolic acid biosynthetic pathway has been proven to be an effective strategy for developing antitubercular drugs. Based on the X-ray crystal structure of MmpL3 inhibitor complexes, a series of novel 1,2,4-triazole derivatives were designed, synthesized and evaluated antitubercular activity against Mtb strain H37Rv. Comprehensive structure–activity relationship exploration resulted in the identification of compounds 21 and 28, which possess potent antitubercular activity against Mtb strain H37Rv [minimum inhibitory concentration (MIC) = 0.03–0.13 µg/mL] and the clinical isolates of multidrug resistance (MDR) and extensive drug resistance (XDR) tuberculosis (MIC = 0.06–1.0 µg/mL). Moreover, compounds 21 and 28 showed neglectable cytotoxicity (IC50 ≥ 32 µg/mL) to the mammalian Vero cells and favorable physicochemical and pharmacokinetic properties according to the in silico absorption, distribution, metabolism and excretion (ADME) prediction. Finally, the potential target of representative 1,2,4-triazole 28 was identified to be MmpL3 using a microscale thermophoresis (MST) assay. |
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Design, synthesis, and biological evaluation of 1,2,4-triazole derivatives as potent antitubercular agents |
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Lun, Shichun Jiao, Yuxue Zhang, Wei Hu, Tianyu Liu, Ting Yang, Fan Tang, Jie Zhang, Bing Bishai, William R. Yu, Li-Fang |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">ELV067183700</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20240225093002.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">240225s2024 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1016/j.cclet.2023.108464</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)ELV067183700</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(ELSEVIER)S1001-8417(23)00313-3</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rda</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">540</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">6,25</subfield><subfield code="2">ssgn</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">ASIEN</subfield><subfield code="q">DE-1a</subfield><subfield code="2">fid</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">35.00</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">35.04</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Wen, Yu</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Design, synthesis, and biological evaluation of 1,2,4-triazole derivatives as potent antitubercular agents</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2024</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">zzz</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Inhibition of mycobacterial membrane protein large 3 (MmpL3) thereby affecting the mycolic acid biosynthetic pathway has been proven to be an effective strategy for developing antitubercular drugs. 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