hERG optimizations of IMB1603, discovery of alternative benzothiazinones as new antitubercular agents

Lv, Kai; Wang, Apeng; Tao, Zeyu; Fu, Ling; Liu, Hongtao; Wang, Bin; Ma, Chao; Wang, Hongjian; Ma, Xican; Han, Bing; Wang, Auyu; Zhang, Kai; Liu, Mingliang; Lu, Yu

doi:10.1016/j.ejmech.2019.06.053

Cited by 14 publications

(13 citation statements)

References 22 publications

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“…, IMB1603 ( 38 ) (Figure ). , Lead 38 exhibited potent activity against Mtb H37Rv (MIC 90 < 0.035 μM, the same as 24 in their assay) and minimal cytotoxicity against Vero cells (CC 50 811 μM). Comparable solubility values were measured for 24 and 38 at a pH value of ∼2.0 (2.0 and 2.1 mM, respectively), and the two molecules displayed almost identical mouse PK profiles .…”

Section: Preclinical Promisesmentioning

confidence: 99%

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%

Tuberculosis Drug Discovery: Challenges and New Horizons

et al. 2022

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“…Yield: 45%. 1 H NMR (400 MHz, CDCl 3 ) δ 9.24 (s, 1H), 9.00 (s, 1H), 8.08 (s, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.53 (t, J = 7.0 Hz, 2H), 7.49−7.43 (m, 1H), 5.94−5.92 (m, 1H), 3.18 (s, 3H), 1.82 (d, J = 8.0 Hz, 3H); 13 [1,3]thiazin-4-one (11). It was obtained as a yellow solid.…”

Section: -(((1-cyclohexylmentioning

confidence: 99%

“…This physicochemical liability apparently would lead to its low bioavailability, which may explain the failure of correlation of its extraordinary in vitro potency with the high in vivo dose application in animal models and clinical trials . To address the solubility issue, efforts have been focused on the modification of the side-chain portion, ,− while the 8-nitro-6-trifluoromethyl BTZ core was considered essential and should be maintained. Among these efforts, introduction of a hydrophilic sulfonamide group or disruption of the molecular planarity strategies was the most pronounced, and reported investigations have afforded compounds with good potency and improved physicochemical properties. ,, Toward this end, we sought to investigate the BTZ portion in combination with the side chain.…”

Section: Introductionmentioning

confidence: 99%

Structural and Activity Relationships of 6-Sulfonyl-8-Nitrobenzothiazinones as Antitubercular Agents

et al. 2021

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The benzothiazinone (BTZ) scaffold compound PBTZ169 kills Mycobacterium tuberculosis by inhibiting the essential flavoenzyme DprE1, consequently blocking the synthesis of the cell wall component arabinans. While extraordinarily potent against M. tuberculosis with a minimum inhibitory concentration (MIC) less than 0.2 ng/mL, its low aqueous solubility and bioavailability issues need to be addressed. Here, we designed and synthesized a series of 6-methanesulfonyl substituted BTZ analogues; further exploration introduced five-member aromatic heterocycles as linkers to attach an aryl group as the side chain. Our work led to the discovery of a number of BTZ derived compounds with potent antitubercular activity. The optimized compounds 6 and 38 exhibited MIC 47 and 30 nM, respectively. Compared to PBTZ169, both compounds displayed increased aqueous solubility and higher stability in human liver microsomes. This study suggested that an alternative side-chain modification strategy could be implemented to improve the druglike properties of the BTZ-based compounds.

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“…The initially reported structure-activity relationships (SAR) demonstrated a requirement for a nitro group at C-8, a strongly electron-withdrawing group at C-6, no substituents at C-5 or C-7, a carbonyl at C-4 and sulfur at the first position [12][13][14]. The amino group at the C-2 position is the most tolerant to modification, consequently this position has been the most extensively explored to modulate potency and drug disposition properties [3,6,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. However, the 8-nitro group remains a potential liability for idiosyncratic toxicity, metabolism by abundant commensal bacterial nitroreductases, reductive activation by glutathione and other biological thiolates and observed drug resistance by mutation of Cys387 to Ser387 [34][35][36][37].…”

Section: Introductionmentioning

confidence: 99%

8-cyanobenzothiazinone analogs with potent antitubercular activity

Zhang

Hegde

et al. 2021

Med Chem Res

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8-Nitrobenzothiazinones (BTZs) exemplified by macozinone are a new class of antitubercular agents with exceptionally potent activity. The aryl nitro group has been considered indispensable for activity since this is bioactivated within mycobacteria by the flavoenzyme DprE1 to a reactive nitroso metabolite that covalently labels Cys387. However, the aryl nitro group is a potential liability with regards to safety, stability, and resistance. In this paper, we introduced a nitrile as a bioisosteric replacement of the nitro group, which we hypothesize can maintain a similar covalent mechanism of inhibition, but mitigate against the aforementioned concerns. 8-cyanobenzothiazinone 1d displayed potent antitubercular activity with an MIC of 130 nM and had an improved volume of distribution in mice that increased the intrinsic half-life by twofold compared to macozinone. Analysis of the C-2 substituent of 1d revealed similar structure-activity relationships as observed for macozinone. Overall, the results confirm the 8-nitro group of benzothiazinones can be successfully replaced with a nitrile to retain useful activity and favorable pharmacokinetic properties.

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hERG optimizations of IMB1603, discovery of alternative benzothiazinones as new antitubercular agents

Cited by 14 publications

References 22 publications

Tuberculosis Drug Discovery: Challenges and New Horizons

Tuberculosis Drug Discovery: Challenges and New Horizons

Structural and Activity Relationships of 6-Sulfonyl-8-Nitrobenzothiazinones as Antitubercular Agents

8-cyanobenzothiazinone analogs with potent antitubercular activity

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