Identification of novel benzothiopyranones with ester and amide motifs derived from active metabolite as promising leads against Mycobacterium tuberculosis

Wang, Bin; Fu, Ling; Guo, Kaijing; Ma, Chen; Wang, Baolian; Lin, Ziyun; Li, Gang; Huang, Haihong; Lu, Yu

doi:10.1016/j.ejmech.2021.113603

Cited by 8 publications

(10 citation statements)

References 28 publications

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“…The same investigators have recently reported a new study based on one of the proposed metabolites of 42 in hepatocytes, alcohol 43 (Figure ). This active metabolite (MIC 90 0.15 μM against Mtb H37Rv) was considerably less lipophilic than 42 (ClogP was lowered by 2 log units) and had much better solubility in water (18 μM vs <0.2 μM for 42 ). These results prompted an assessment of its in vivo efficacy using the acute Mtb infection BALB/c mouse model.…”

Section: Preclinical Promisesmentioning

confidence: 99%

“…However, in comparison to 42 , alcohol 43 showed only modest utility, with oral dosing at 100 mg/kg for 3 weeks giving a 0.9 log 10 reduction in lung CFU. New ester and amide leads based on 43 are now being evaluated …”

Section: Preclinical Promisesmentioning

confidence: 99%

“…New ester and amide leads based on 43 are now being evaluated. 166 Meanwhile, Borthwick et al disclosed novel morpholinopyrimidine derivatives 45 and 46 (Figure 5) as potent noncovalent DprE1 inhibitors with enhanced physicochemical properties in comparison to the original HTS hit, 44 (Figure 5). 167 Compounds 45 and 46 respectively exhibited MIC 90 values of 0.6 and 1.7 μM against Mtb H37Rv and IC 50 values of 0.025 and 0.050 μM against the DprE1 enzyme.…”

Section: Compounds Targeting Cell Wallmentioning

confidence: 99%

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Tuberculosis Drug Discovery: Challenges and New Horizons

et al. 2022

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Over the past 2000 years, tuberculosis (TB) has claimed more lives than any other infectious disease. In 2020 alone, TB was responsible for 1.5 million deaths worldwide, comparable to the 1.8 million deaths caused by COVID-19. The World Health Organization has stated that new TB drugs must be developed to end this pandemic. After decades of neglect in this field, a renaissance era of TB drug discovery has arrived, in which many novel candidates have entered clinical trials. However, while hundreds of molecules are reported annually as promising anti-TB agents, very few successfully progress to clinical development. In this Perspective, we critically review those anti-TB compounds published in the last 6 years that demonstrate good in vivo efficacy against Mycobacterium tuberculosis. Additionally, we highlight the main challenges and strategies for developing new TB drugs and the current global pipeline of drug candidates in clinical studies to foment fresh research perspectives.

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Section: Preclinical Promisesmentioning

confidence: 99%

Section: Preclinical Promisesmentioning

confidence: 99%

Section: Compounds Targeting Cell Wallmentioning

confidence: 99%

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Tuberculosis Drug Discovery: Challenges and New Horizons

et al. 2022

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“…Recently, some novel benzothiopyranones have revealed in vitro biological activities against a range of Mycobacterium tuberculosis strains [ 24 ]. For these reasons, the promising metabolite M-1 from [ 24 ] and other high-potent inhibitors, such as macozinone ( PBTZ169 ) and TBA-7371 were re-docked by AutoDock Vina to be comparable with our docking results ( Figure 2 and Table 2 ). According to the U.S. National Library of Medicine ( ), TBA-7371 (Identifier: NCT04176250) is currently at Phase 2 of the early bactericidal activity against Pulmonary tuberculosis .…”

Section: Resultsmentioning

confidence: 99%

“… The best-docking-scored reference compounds from [ 6 , 24 ] and other known inhibitors for the mycobacterial DHFR, such as methotrexate (MTX), macozinone ( PBTZ169 ), and TBA-7371 . Heteroatoms and key functional groups are color-coded.…”

Section: Figures Schemes and Tablesmentioning

confidence: 99%

Synthesis of Novel Derivatives of 5,6,7,8-Tetrahydroquinazolines Using α-Aminoamidines and In Silico Screening of Their Biological Activity

Snizhko

Kyrychenko

Gladkov

2022

IJMS

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α-Aminoamidines are promising reagents for the synthesis of a diverse family of pyrimidine ring derivatives. Here, we demonstrate the use of α-aminoamidines for the synthesis of a new series of 5,6,7,8-tetrahydroquinazolines by their reaction with bis-benzylidene cyclohexanones. The reaction occurs in mild conditions and is characterized by excellent yields. It has easy workup, as compared to the existing methods of tetrahydroquinazoline preparation. Newly synthesized derivatives of 5,6,7,8-tetrahydroquinazoline bear protecting groups at the C2-tert-butyl moiety of a quinazoline ring, which can be easily cleaved, opening up further opportunities for their functionalization. Moreover, molecular docking studies indicate that the synthesized compounds reveal high binding affinity toward some essential enzymes of Mycobacterial tuberculosis, such as dihydrofolate reductase (DHFR), pantothenate kinase (MtPanK), and FAD-containing oxidoreductase DprE1 (MtDprE1), so that they may be promising candidates for the molecular design and the development of new antitubercular agents against multidrug-resistant strains of the Tubercle bacillus. Finally, the high inhibition activity of the synthesized compounds was also predicted against β-glucosidase, suggesting a novel tetrahydroquinazoline scaffold for the treatment of diabetes.

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