Design, synthesis and biological evaluation of (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives as inhibitors of Mycobacterium tuberculosis bd oxidase
New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Kumar, Amit [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2022transfer abstract |
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| Schlagwörter: |
(4-oxoquinazoline-3(4H)-yl)acetamide |
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| Übergeordnetes Werk: |
Enthalten in: Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles - Jose, Ajay ELSEVIER, 2018, Amsterdam [u.a.] |
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| Übergeordnetes Werk: |
volume:242 ; year:2022 ; day:15 ; month:11 ; pages:0 |
| Links: |
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| DOI / URN: |
10.1016/j.ejmech.2022.114639 |
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| 245 | 1 | 0 | |a Design, synthesis and biological evaluation of (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives as inhibitors of Mycobacterium tuberculosis bd oxidase |
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| 520 | |a New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc 1 -aa 3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc 1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc 1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc 1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203. | ||
| 520 | |a New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc 1 -aa 3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc 1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc 1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc 1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203. | ||
| 650 | 7 | |a (4-oxoquinazoline-3(4H)-yl)acetamide |2 Elsevier | |
| 650 | 7 | |a Mycobacterium tuberculosis bd-oxidase |2 Elsevier | |
| 650 | 7 | |a (Quinazoline 4-yloxy)acetamide |2 Elsevier | |
| 700 | 1 | |a Kumari, Neetu |4 oth | |
| 700 | 1 | |a Bhattacherjee, Sandeep |4 oth | |
| 700 | 1 | |a Venugopal, Umamageswaran |4 oth | |
| 700 | 1 | |a Parwez, Shahid |4 oth | |
| 700 | 1 | |a Siddiqi, Mohammad Imran |4 oth | |
| 700 | 1 | |a Krishnan, Manju Y. |4 oth | |
| 700 | 1 | |a Panda, Gautam |4 oth | |
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10.1016/j.ejmech.2022.114639 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001896.pica (DE-627)ELV058886575 (ELSEVIER)S0223-5234(22)00541-4 DE-627 ger DE-627 rakwb eng 570 540 VZ BIODIV DE-30 fid 42.00 bkl Kumar, Amit verfasserin aut Design, synthesis and biological evaluation of (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives as inhibitors of Mycobacterium tuberculosis bd oxidase 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc 1 -aa 3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc 1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc 1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc 1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203. New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc 1 -aa 3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc 1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc 1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc 1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203. (4-oxoquinazoline-3(4H)-yl)acetamide Elsevier Mycobacterium tuberculosis bd-oxidase Elsevier (Quinazoline 4-yloxy)acetamide Elsevier Kumari, Neetu oth Bhattacherjee, Sandeep oth Venugopal, Umamageswaran oth Parwez, Shahid oth Siddiqi, Mohammad Imran oth Krishnan, Manju Y. oth Panda, Gautam oth Enthalten in Elsevier Science Jose, Ajay ELSEVIER Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles 2018 Amsterdam [u.a.] (DE-627)ELV000457477 volume:242 year:2022 day:15 month:11 pages:0 https://doi.org/10.1016/j.ejmech.2022.114639 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 42.00 Biologie: Allgemeines VZ AR 242 2022 15 1115 0 |
| spelling |
10.1016/j.ejmech.2022.114639 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001896.pica (DE-627)ELV058886575 (ELSEVIER)S0223-5234(22)00541-4 DE-627 ger DE-627 rakwb eng 570 540 VZ BIODIV DE-30 fid 42.00 bkl Kumar, Amit verfasserin aut Design, synthesis and biological evaluation of (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives as inhibitors of Mycobacterium tuberculosis bd oxidase 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc 1 -aa 3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc 1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc 1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc 1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203. New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc 1 -aa 3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc 1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc 1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc 1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203. (4-oxoquinazoline-3(4H)-yl)acetamide Elsevier Mycobacterium tuberculosis bd-oxidase Elsevier (Quinazoline 4-yloxy)acetamide Elsevier Kumari, Neetu oth Bhattacherjee, Sandeep oth Venugopal, Umamageswaran oth Parwez, Shahid oth Siddiqi, Mohammad Imran oth Krishnan, Manju Y. oth Panda, Gautam oth Enthalten in Elsevier Science Jose, Ajay ELSEVIER Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles 2018 Amsterdam [u.a.] (DE-627)ELV000457477 volume:242 year:2022 day:15 month:11 pages:0 https://doi.org/10.1016/j.ejmech.2022.114639 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 42.00 Biologie: Allgemeines VZ AR 242 2022 15 1115 0 |
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10.1016/j.ejmech.2022.114639 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001896.pica (DE-627)ELV058886575 (ELSEVIER)S0223-5234(22)00541-4 DE-627 ger DE-627 rakwb eng 570 540 VZ BIODIV DE-30 fid 42.00 bkl Kumar, Amit verfasserin aut Design, synthesis and biological evaluation of (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives as inhibitors of Mycobacterium tuberculosis bd oxidase 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc 1 -aa 3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc 1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc 1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc 1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203. New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc 1 -aa 3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc 1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc 1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc 1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203. (4-oxoquinazoline-3(4H)-yl)acetamide Elsevier Mycobacterium tuberculosis bd-oxidase Elsevier (Quinazoline 4-yloxy)acetamide Elsevier Kumari, Neetu oth Bhattacherjee, Sandeep oth Venugopal, Umamageswaran oth Parwez, Shahid oth Siddiqi, Mohammad Imran oth Krishnan, Manju Y. oth Panda, Gautam oth Enthalten in Elsevier Science Jose, Ajay ELSEVIER Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles 2018 Amsterdam [u.a.] (DE-627)ELV000457477 volume:242 year:2022 day:15 month:11 pages:0 https://doi.org/10.1016/j.ejmech.2022.114639 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 42.00 Biologie: Allgemeines VZ AR 242 2022 15 1115 0 |
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10.1016/j.ejmech.2022.114639 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001896.pica (DE-627)ELV058886575 (ELSEVIER)S0223-5234(22)00541-4 DE-627 ger DE-627 rakwb eng 570 540 VZ BIODIV DE-30 fid 42.00 bkl Kumar, Amit verfasserin aut Design, synthesis and biological evaluation of (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives as inhibitors of Mycobacterium tuberculosis bd oxidase 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc 1 -aa 3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc 1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc 1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc 1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203. New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc 1 -aa 3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc 1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc 1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc 1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203. (4-oxoquinazoline-3(4H)-yl)acetamide Elsevier Mycobacterium tuberculosis bd-oxidase Elsevier (Quinazoline 4-yloxy)acetamide Elsevier Kumari, Neetu oth Bhattacherjee, Sandeep oth Venugopal, Umamageswaran oth Parwez, Shahid oth Siddiqi, Mohammad Imran oth Krishnan, Manju Y. oth Panda, Gautam oth Enthalten in Elsevier Science Jose, Ajay ELSEVIER Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles 2018 Amsterdam [u.a.] (DE-627)ELV000457477 volume:242 year:2022 day:15 month:11 pages:0 https://doi.org/10.1016/j.ejmech.2022.114639 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 42.00 Biologie: Allgemeines VZ AR 242 2022 15 1115 0 |
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10.1016/j.ejmech.2022.114639 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001896.pica (DE-627)ELV058886575 (ELSEVIER)S0223-5234(22)00541-4 DE-627 ger DE-627 rakwb eng 570 540 VZ BIODIV DE-30 fid 42.00 bkl Kumar, Amit verfasserin aut Design, synthesis and biological evaluation of (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives as inhibitors of Mycobacterium tuberculosis bd oxidase 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc 1 -aa 3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc 1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc 1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc 1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203. New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc 1 -aa 3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc 1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc 1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc 1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203. (4-oxoquinazoline-3(4H)-yl)acetamide Elsevier Mycobacterium tuberculosis bd-oxidase Elsevier (Quinazoline 4-yloxy)acetamide Elsevier Kumari, Neetu oth Bhattacherjee, Sandeep oth Venugopal, Umamageswaran oth Parwez, Shahid oth Siddiqi, Mohammad Imran oth Krishnan, Manju Y. oth Panda, Gautam oth Enthalten in Elsevier Science Jose, Ajay ELSEVIER Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles 2018 Amsterdam [u.a.] (DE-627)ELV000457477 volume:242 year:2022 day:15 month:11 pages:0 https://doi.org/10.1016/j.ejmech.2022.114639 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 42.00 Biologie: Allgemeines VZ AR 242 2022 15 1115 0 |
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design, synthesis and biological evaluation of (quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4h)-yl)acetamide derivatives as inhibitors of mycobacterium tuberculosis bd oxidase |
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Design, synthesis and biological evaluation of (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives as inhibitors of Mycobacterium tuberculosis bd oxidase |
| abstract |
New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc 1 -aa 3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc 1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc 1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc 1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203. |
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New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc 1 -aa 3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc 1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc 1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc 1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203. |
| abstract_unstemmed |
New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc 1 -aa 3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc 1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc 1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc 1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203. |
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Design, synthesis and biological evaluation of (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives as inhibitors of Mycobacterium tuberculosis bd oxidase |
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This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc 1 -aa 3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc 1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc 1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc 1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203.</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">(4-oxoquinazoline-3(4H)-yl)acetamide</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">Mycobacterium tuberculosis bd-oxidase</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">(Quinazoline 4-yloxy)acetamide</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Kumari, Neetu</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Bhattacherjee, Sandeep</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Venugopal, Umamageswaran</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Parwez, Shahid</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Siddiqi, Mohammad Imran</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Krishnan, Manju Y.</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Panda, Gautam</subfield><subfield code="4">oth</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="n">Elsevier Science</subfield><subfield code="a">Jose, Ajay ELSEVIER</subfield><subfield code="t">Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles</subfield><subfield code="d">2018</subfield><subfield code="g">Amsterdam [u.a.]</subfield><subfield code="w">(DE-627)ELV000457477</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:242</subfield><subfield code="g">year:2022</subfield><subfield code="g">day:15</subfield><subfield code="g">month:11</subfield><subfield code="g">pages:0</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.1016/j.ejmech.2022.114639</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_U</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ELV</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_U</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">FID-BIODIV</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHA</subfield></datafield><datafield tag="936" ind1="b" ind2="k"><subfield code="a">42.00</subfield><subfield code="j">Biologie: Allgemeines</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">242</subfield><subfield code="j">2022</subfield><subfield code="b">15</subfield><subfield code="c">1115</subfield><subfield code="h">0</subfield></datafield></record></collection>
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