Seeking potent anti-tubercular agents: design and synthesis of substituted-<i>N</i>-(6-(4-(pyrazine-2-carbonyl)piperazine/homopiperazine-1-yl)pyridin-3-yl)benzamide derivatives as anti-tubercular agents

Srinivasarao, Singireddi; Nandikolla, Adinarayana; Suresh, A.; Calster, Kevin Van; Voogt, Linda De; Cappoen, Davie; Ghosh, Balaram; Aggarwal, Himanshu; Murugesan, Sankaranarayanan; Sekhar, Kondapalli Venkata Gowri Chandra

doi:10.1039/d0ra01348j

Cited by 14 publications

(10 citation statements)

References 33 publications

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“…Compounds containing derivatives of piperidine, morpholine, or piperazine are prone to show antitubercular activities. , Considering their biological importance, we attempted to synthesize dihydro-quinazolino[4,3- b ]quinazolin-8-one derivatives containing a piperidine, morpholine, or piperazine motif to study their fluorescence properties. Toward this, a series of aldehydes ( 2a′–2e′ ) were synthesized and subjected to a reaction with compound 1a .…”

Section: Resultsmentioning

confidence: 99%

An Aldehyde-Driven, Fe(0)-Mediated, One-Pot Reductive Cyclization: Direct Access to 5,6-Dihydro-quinazolino[4,3-b]quinazolin-8-ones and Photophysical Study

2023

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A short, proficient, and regioselective synthesis of biheterocyclic 5,6-dihydro-quinazolino[4,3-b]quinazolin-8-ones has been revealed via an Fe(0)-powder-mediated, one-pot reductive cyclization protocol. Mechanistic investigation proved that water acts as a source of hydrogen for the reduction of the nitro group and the reaction rate was accelerated by an aldehyde. The designed transformation works under aerobic conditions, providing a series of bio-inspired molecular scaffolds. In addition, the photophysical study showed blue fluorescence emission with a good fluorescence quantum yield.

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Section: Resultsmentioning

confidence: 99%

An Aldehyde-Driven, Fe(0)-Mediated, One-Pot Reductive Cyclization: Direct Access to 5,6-Dihydro-quinazolino[4,3-b]quinazolin-8-ones and Photophysical Study

2023

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“…Srinivasarao et al [9] designed a novel series of N-(6-(4-[pyrazine-2-carbonyl]piperazine) substituted benzamide derivatives using Scheme 1. In the first step, 2-chloro-5-nitropyridine was treated with 1-Boc-piperazine/1-Boc-homopiperazine at 110 C and then deprotection of Boc group was done using EDC.HCl, HOBt, and base.…”

Section: The Antitubercular Activity Of Pyrazinamide Derivativesmentioning

confidence: 99%

Synthesis and antimycobacterial evaluation of pyrazinamide, benzimidazole and carboxamide derivatives

Shah

Kumar

et al. 2022

Journal of Heterocyclic Chem

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Due to the unusual structure and chemical composition of the mycobacterial cell wall, it is difficult to develop effective antitubercular treatment as it leads to many antibiotics not working and preventing drug entry. It also leads to the problem of more drug resistance. Tuberculosis (TB) is still the second most contagious disease with about 33% of the world's population being affected mainly by drug-resistant TB (MDR, XDR), chronic infections, and the combination of TB and human immunodeficiency virus (HIV). Therefore, there is an urgent need for the development of novel antitubercular drugs that will shorten the total duration of effective treatment taken under directly observed treatment, short-course (DOTS) guidance, solve the problem of multiple drug resistance, and provide effective treatment for TB diseases. In this review, we considered various synthetic schemes of pyrazinamide, benzimidazole, and carboxamide derivatives that have antitubercular properties that can overcome the resistance to parental drugs and thus act as an effective alternative.

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“…Several inhibitors that target MtPanC have been identified through various screening methods (White et al, 2007;Velaparthi et al, 2008;Yang et al, 2011;Kumar et al, 2013;Ntie-Kang et al, 2013;Samala et al, 2013;Naidu et al, 2014;Samala et al, 2014;Naidu et al, 2016;Naidu et al, 2016;Amaroju et al, 2017;Pradhan and Sinha, 2018;Kumar et al, 2019;Hassan et al, 2020;Singireddi et al, 2020). White et al (2007) developed an automated high-throughput screen (HTS) by adapting the coupled assay first used by Zheng and Blanchard (2001), and used it to identify known drugs that inhibit MtPanC.…”

Section: Panc Inhibitors Identified By Screeningmentioning

confidence: 99%

Vitamin in the Crosshairs: Targeting Pantothenate and Coenzyme A Biosynthesis for New Antituberculosis Agents

Butman

Kotze

Dowd

et al. 2020

Front. Cell. Infect. Microbiol.

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Despite decades of dedicated research, there remains a dire need for new drugs against tuberculosis (TB). Current therapies are generations old and problematic. Resistance to these existing therapies results in an ever-increasing burden of patients with disease that is difficult or impossible to treat. Novel chemical entities with new mechanisms of action are therefore earnestly required. The biosynthesis of coenzyme A (CoA) has long been known to be essential in Mycobacterium tuberculosis (Mtb), the causative agent of TB. The pathway has been genetically validated by seminal studies in vitro and in vivo. In Mtb, the CoA biosynthetic pathway is comprised of nine enzymes: four to synthesize pantothenate (Pan) from l-aspartate and α-ketoisovalerate; five to synthesize CoA from Pan and pantetheine (PantSH). This review gathers literature reports on the structure/mechanism, inhibitors, and vulnerability of each enzyme in the CoA pathway. In addition to traditional inhibition of a single enzyme, the CoA pathway offers an antimetabolite strategy as a promising alternative. In this review, we provide our assessment of what appear to be the best targets, and, thus, which CoA pathway enzymes present the best opportunities for antitubercular drug discovery moving forward.

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Seeking potent anti-tubercular agents: design and synthesis of substituted-N-(6-(4-(pyrazine-2-carbonyl)piperazine/homopiperazine-1-yl)pyridin-3-yl)benzamide derivatives as anti-tubercular agents

Abstract: We herein report 27 pyrazinamide analogues as anti-tubercular agents, of which six exhibited excellent activity with IC50 ≤ 2.18 μM and these were less toxic against HEK 293 cells.

Cited by 14 publications

References 33 publications

An Aldehyde-Driven, Fe(0)-Mediated, One-Pot Reductive Cyclization: Direct Access to 5,6-Dihydro-quinazolino[4,3-b]quinazolin-8-ones and Photophysical Study

An Aldehyde-Driven, Fe(0)-Mediated, One-Pot Reductive Cyclization: Direct Access to 5,6-Dihydro-quinazolino[4,3-b]quinazolin-8-ones and Photophysical Study

Synthesis and antimycobacterial evaluation of pyrazinamide, benzimidazole and carboxamide derivatives

Vitamin in the Crosshairs: Targeting Pantothenate and Coenzyme A Biosynthesis for New Antituberculosis Agents

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