The structural use of carbostyril in physiologically active substances

Tashima, Toshihiko

doi:10.1016/j.bmcl.2015.06.027

Cited by 42 publications

(13 citation statements)

References 32 publications

(25 reference statements)

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“…Here, we presented data to show that a new carbostyril derivative, OPC-167832, is a novel anti-TB drug candidate that can potentially be combined with DMD and other newer anti-TB agents. OPC-167832 shares the same carbostyril structure with several drugs in other therapeutic areas that are known to have good PK and safety profiles (5), thus giving the hope that it may share the same favorable characteristics.…”

Section: Discussionmentioning

confidence: 99%

“…As part of our ongoing TB drug discovery efforts, we used phenotypic screening methods to identify and optimize compounds with anti-TB activities from a core carbostyril structure, which has been recognized as having good absorption, distribution, metabolism, excretion, and toxicity profiles, and has been used as the backbone of numerous drugs (5). These efforts led to a promising compound, OPC-167832 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

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OPC-167832, a Novel Carbostyril Derivative with Potent Antituberculosis Activity as a DprE1 Inhibitor

Hariguchi

Chen

Hayashi

et al. 2020

Antimicrob Agents Chemother

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There is an urgent need for new, potent antituberculosis (anti-TB) drugs with novel mechanisms of action that can be included in new regimens to shorten the treatment period for TB. After screening a library of carbostyrils, we optimized 3,4-dihydrocarbostyril derivatives and identified OPC-167832 as having potent antituberculosis activity. The MICs of the compound for Mycobacterium tuberculosis ranged from 0.00024 to 0.002 μg/ml. It had bactericidal activity against both growing and intracellular bacilli, and the frequency of spontaneous resistance for M. tuberculosis H37Rv was less than 1.91 × 10−7. It did not show antagonistic effects with other anti-TB agents in an in vitro checkerboard assay. Whole-genome and targeted sequencing of isolates resistant to OPC-167832 identified decaprenylphosphoryl-β-d-ribose 2′-oxidase (DprE1), an essential enzyme for cell wall biosynthesis, as the target of the compound, and further studies demonstrated inhibition of DprE1 enzymatic activity by OPC-167832. In a mouse model of chronic TB, OPC-167832 showed potent bactericidal activities starting at a dose of 0.625 mg/kg of body weight. Further, it exhibited significant combination effects in 2-drug combinations with delamanid, bedaquiline, or levofloxacin. Finally, 3- or 4-drug regimens comprised of delamanid and OPC-167832 as the core along with bedaquiline, moxifloxacin, or linezolid showed efficacy in reducing the bacterial burden and preventing relapse superior to that of the standard treatment regimen. In summary, these results suggest that OPC-167832 is a novel and potent anti-TB agent, and regimens containing OPC-167832 and new or repurposed anti-TB drugs may have the potential to shorten the duration of treatment for TB.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

OPC-167832, a Novel Carbostyril Derivative with Potent Antituberculosis Activity as a DprE1 Inhibitor

Hariguchi

Chen

Hayashi

et al. 2020

Antimicrob Agents Chemother

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“…We quickly recognized that this undesired result could be harnessed for the syntheses of multi-functionalized 2-quinolinones,the privileged heterocyclic structures in medicinal chemistry. [11] While numerous synthetic methods for the preparation of 2-quinolinones have been reported, [12] few of them could allow for the introduction of several functional groups into the heterocyclic scaffold. Thef unctional groups on am edicinally important architecture could be used either individually as synthetic handles or for functional-group-pairing reactions, [13] generating compound libraries through diversity-oriented synthesis.…”

mentioning

confidence: 99%

Bio‐Inspired Fragmentations: Rapid Assembly of Indolones, 2‐Quinolinones, and (−)‐Goniomitine

Peng

Jiang

et al. 2017

Angew Chem Int Ed

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Inspired by the biogenetic origin of goniomitine, new synthetic bio-inspired fragmentation strategies for the synthesis of functionalized 2-quinolinones and indolones have been developed. Remarkable synthetic efficiency was achieved by telescoping several transformations into one-pot reactions, allowing for the direct coupling of 2-alkynyl-anilines and diazo ketones. The synthetic utility was demonstrated by the 5-step asymmetric total synthesis of (-)-goniomitine from 2-ethyl-cyclopentanone.

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“…Further, chemistry and biological profiles of various pharmacophores of 1‐aza coumarin derivatives, which ultimately metabolize as the corresponding 8‐hydroxy coumarins in the biological system and therefore found to be very good anti‐inflammatory agent . Both coumarin and 1‐aza coumarin have been widely reported to exhibit anti‐microbial activity [20] owing to its unique structural features …”

Section: Introductionmentioning

confidence: 99%

Synthesis and Molecular Modeling Studies of Coumarin‐ and 1‐Aza‐Coumarin‐Linked Miconazole Analogues and Their Antifungal Activity

et al. 2018

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A series of new coumarin and 1‐aza coumarin analogues of miconazole (6 a‐j) were synthesized from 3‐bromoacetyl coumarins. Further diversification was achieved by synthesizing coumarin‐benzimidazole hybrids of miconazole (7 a‐j) and evaluated for in‐vitro anti‐microbial activities. Amongst the tested compounds, 7 d was found to be particularly effective as anti‐fungal agents against C. albicans and C. krusei, with activity comparable to that of the standard. Comparative Docking studies with mevalonate‐5‐diphosphatedecarboxylase shows better binding affinity than imidazole counterparts which is primarily attributed to extended π‐alkyl interactions facilitated by benzimidazole.

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The structural use of carbostyril in physiologically active substances

Cited by 42 publications

References 32 publications

OPC-167832, a Novel Carbostyril Derivative with Potent Antituberculosis Activity as a DprE1 Inhibitor

OPC-167832, a Novel Carbostyril Derivative with Potent Antituberculosis Activity as a DprE1 Inhibitor

Bio‐Inspired Fragmentations: Rapid Assembly of Indolones, 2‐Quinolinones, and (−)‐Goniomitine

Synthesis and Molecular Modeling Studies of Coumarin‐ and 1‐Aza‐Coumarin‐Linked Miconazole Analogues and Their Antifungal Activity

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