Novel lead generation of an anti-tuberculosis agent active against non-replicating mycobacteria: exploring hybridization of pyrazinamide with multiple fragments

Markad, Shankar D.; Kaur, Parvinder; Reddy, B. Kasi; Chinnapattu, Murugan; Raichurkar, Anandkumar; Nandishaiah, Radha; Panda, Manoranjan; Iyer, Pravin S.

doi:10.1007/s00044-015-1352-6

Cited by 12 publications

(6 citation statements)

References 20 publications

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“…Next, to explore the scope of the reaction, a set of acrylate intermediates differently functionalized at the arene ring ( 3 , 4 , 5 and 6 ; Table , entries 1–4, [TBMA][MsO]) or at the acrylic nitrogen ( 7 and 8 ; Table , entries 5 and 6, [TBMA][MsO]) were cyclized in [TBMA][MsO] as reaction medium in the presence of K 2 CO 3 at 80 °C. Also, the results were compared with those derived from parallel reactions conducted in DMF (entries 1–6, DMF).…”

Section: Resultsmentioning

confidence: 99%

“…Also, the results were compared with those derived from parallel reactions conducted in DMF (entries 1–6, DMF). Overall, [TBMA][MsO] proved a good choice for the cyclization of all the acrylates 3 – 8 to the corresponding quinolones 9 , 10 , 11 , 12 , 13 and 14 , (entries 1–6, [TBMA][MsO]) which were obtained in good yields (68–80 %) and in short reaction times (2–5 h). Compared with the cyclization reactions in DMF, (entries 1–6, DMF) in general, the use of the IL gave slightly higher yields.…”

Section: Resultsmentioning

confidence: 99%

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Advantageous Use of Ionic Liquids for the Synthesis of Pharmaceutically Relevant Quinolones

et al. 2018

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The advantageous use of ionic liquids (ILs) as alternatives to common DMF as solvent in the Grohe cycloaracylation for the synthesis of pharmaceutically relevant quinolones is reported. ILs showed in many cases shorter reaction times and higher yields, complete conversions of the reactants and easy work‐up procedures compared with DMF. Of the ILs screened, tributylmethylammonium methanesulfonate ([TBMA][MsO]) was selected as the most suitable for further studies. Interestingly, a wide substrate scope was observed and the IL was recycled by a green process. A further step forward in the use of [TBMA][MsO] for quinolone synthesis was the preparation by a one‐pot/three‐step procedure of the representative 3‐carboxy‐4‐quinolone acid 16, which was obtained in high yield in a short time. The greener properties of ILs in comparison with DMF and their non‐volatility appoint this method as a potentially efficient and alternative approach to the industrial production of quinolones.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Advantageous Use of Ionic Liquids for the Synthesis of Pharmaceutically Relevant Quinolones

et al. 2018

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“…The alarming statistics [ 1 ] on drug resistance in TB demand novel PZA-like sterilizing drugs that work best in low/acidic pH, kill non-replicating populations of Mtb and shorten the treatment duration [ 38 , 68 ]. In a separate study, we have demonstrated the importance of low pH screens by selecting PZA-hybrid molecules in-vitro [ 69 ]. Recently, PZA was also reported to enhance the cidality of various combinations of existing drugs [ 70 ]and is an integral component of emerging novel combinations in the clinic like PAMZ (PA-824, Moxi, PZA), in STAND (Shortening Treatment by Advancing New Drugs, www.clinicaltrial.com ) clinical trial.…”

Section: Discussionmentioning

confidence: 99%

Unravelling the Secrets of Mycobacterial Cidality through the Lens of Antisense

Kaur¹,

Datta²,

Shandil³

et al. 2016

PLoS ONE

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One of the major impediments in anti-tubercular drug discovery is the lack of a robust grammar that governs the in-vitro to the in-vivo translation of efficacy. Mycobacterium tuberculosis (Mtb) is capable of growing both extracellular as well as intracellular; encountering various hostile conditions like acidic milieu, free radicals, starvation, oxygen deprivation, and immune effector mechanisms. Unique survival strategies of Mtb have prompted researchers to develop in-vitro equivalents to simulate in-vivo physiologies and exploited to find efficacious inhibitors against various phenotypes. Conventionally, the inhibitors are screened on Mtb under the conditions that are unrelated to the in-vivo disease environments. The present study was aimed to (1). Investigate cidality of Mtb targets using a non-chemical inhibitor antisense-RNA (AS-RNA) under in-vivo simulated in-vitro conditions.(2). Confirm the cidality of the targets under in-vivo in experimental tuberculosis. (3). Correlate in-vitro vs. in-vivo cidality data to identify the in-vitro condition that best predicts in-vivo cidality potential of the targets. Using cidality as a metric for efficacy, and AS-RNA as a target-specific inhibitor, we delineated the cidality potential of five target genes under six different physiological conditions (replicating, hypoxia, low pH, nutrient starvation, nitrogen depletion, and nitric oxide).In-vitro cidality confirmed in experimental tuberculosis in BALB/c mice using the AS-RNA allowed us to identify cidal targets in the rank order of rpoB>aroK>ppk>rpoC>ilvB. RpoB was used as the cidality control. In-vitro and in-vivo studies feature aroK (encoding shikimate kinase) as an in-vivo mycobactericidal target suitable for anti-TB drug discovery. In-vitro to in-vivo cidality correlations suggested the low pH (R = 0.9856) in-vitro model as best predictor of in-vivo cidality; however, similar correlation studies in pathologically relevant (Kramnik) mice are warranted. In the acute infection phase for the high fidelity translation, the compound efficacy may also be evaluated in the low pH, in addition to the standard replication condition.

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“…Markad and corworkers investigated quinolone–pyrazinamide hybrid 64 as potential antituberculosis drug candidate. This compound exhibited improved antitubercular activity in comparison with pyrazinamide and wide antibacterial action against common bacterial pathogens; however, it was inactive in DNA supercoiling assay indicating novel mechanism of action [ 146 ] (Fig. 17 ).…”

Section: Hybrid Drugsmentioning

confidence: 99%

Modifications of quinolones and fluoroquinolones: hybrid compounds and dual-action molecules

Fedorowicz

Sączewski

2018

Monatsh Chem

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This review is aimed to provide extensive survey of quinolones and fluoroquinolones for a variety of applications ranging from metal complexes and nanoparticle development to hybrid conjugates with therapeutic uses. The review covers the literature from the past 10 years with emphasis placed on new applications and mechanisms of pharmacological action of quinolone derivatives. The following are considered: metal complexes, nanoparticles and nanodrugs, polymers, proteins and peptides, NO donors and analogs, anionic compounds, siderophores, phosphonates, and prodrugs with enhanced lipophilicity, phototherapeutics, fluorescent compounds, triazoles, hybrid drugs, bis-quinolones, and other modifications. This review provides a comprehensive resource, summarizing a broad range of important quinolone applications with great utility as a resource concerning both chemical modifications and also novel hybrid bifunctional therapeutic agents.Graphical abstract

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Novel lead generation of an anti-tuberculosis agent active against non-replicating mycobacteria: exploring hybridization of pyrazinamide with multiple fragments

Cited by 12 publications

References 20 publications

Advantageous Use of Ionic Liquids for the Synthesis of Pharmaceutically Relevant Quinolones

Advantageous Use of Ionic Liquids for the Synthesis of Pharmaceutically Relevant Quinolones

Unravelling the Secrets of Mycobacterial Cidality through the Lens of Antisense

Modifications of quinolones and fluoroquinolones: hybrid compounds and dual-action molecules

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