Thiophene containing trisubstituted methanes [TRSMs] as identified lead against Mycobacterium tuberculosis

Singh, Priyanka; Manna, Sudipta Kumar; Jana, Amit Kumar; Saha, Tiash; Mishra, Pankaj; Bera, Saurav; Parai, Maloy Kumar; M, Srinivas Lavanya Kumar; Mondal, Samrat; Trivedi, Priyanka; Chaturvedi, Vinita; Singh, Shyam; Sinha, Sudhir; Panda, Gautam

doi:10.1016/j.ejmech.2015.03.036

Cited by 32 publications

(16 citation statements)

References 11 publications

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“…Antitubercular activity of the S006-830 racemate has previously been reported by us. 4 Therefore, we presently explored whether there was a difference in the potencies of its enantiomers. In drug-free cultures, the Mtb inoculums (∼10 6 colony-forming units, cfu) multiplied nearly 2.5 logs (∼5 × 10 8 cfu) over a period of 7 days ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…In our earlier studies, the S006-830 racemate had shown an impressive bactericidal activity against drug-sensitive as well as drug-resistant Mtb. 4 It had produced over 10-fold reduction in viable bacterial counts in the lungs of mice infected with Mtb, an activity comparable with some of the candidate antitubercular drugs currently under trial. 1 This in vivo activity was attained despite relatively high (compared with other drug candidates) MIC and MBC of the compound, owing perhaps to its good oral bioavailability.…”

Section: Discussionmentioning

confidence: 97%

“…In addition, the compound also showed bactericidal activity against MDR, RR, and INHR (INH-resistant) clinical isolates of Mtb. 4 In preclinical evaluations, the compound demonstrated good pharmacokinetic (PK) properties with rapid intestinal absorption. 6 , 7 Peak plasma concentration was achieved at <1 h post oral dose, the elimination half-life was ∼9 h, the mean residence time was ∼11 h, plasma protein binding was ∼60%, and bioavailability was in the range of 45–50%.…”

Section: Introductionmentioning

confidence: 99%

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S-Enantiomer of the Antitubercular Compound S006-830 Complements Activity of Frontline TB Drugs and Targets Biogenesis of Mycobacterium tuberculosis Cell Envelope

Singh¹,

Kumar²,

Maurya

et al. 2017

ACS Omega

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A synthetic molecule S006-830, belonging to the class of thiophene-containing trisubstituted methanes, had shown good in vitro and in vivo bactericidal activity against drug-sensitive and drug-resistant Mycobacterium tuberculosis (Mtb). The molecule had also shown good druglike pharmacokinetic properties. However, S006-830 is a racemic mixture of two enantiomers, one of which could possess a better pharmacological profile than the other. We purified both the enantiomers on a chiral column and observed that S-enantiomer has a significantly higher inhibitory and cidal activity against Mtb than the R-enantiomer. Action of S-S006-830 was “synergistic” for rifampicin and “additive” for isoniazid and ethambutol. The combination of S-S006-830 and rifampicin produced 100% kill of Mtb within 8 days. In a chemical proteomics approach using matrix-bound compound to pull down its target protein(s) from Mtb membrane, FabG4 (β-ketoacyl CoA reductase, EC 1.1.1.100) emerged as the most likely target for S-S006-830. In target validation assays, the compound exhibited 2-fold higher inhibitory concentration for an Mtb construct overexpressing FabG4. In addition, it inhibited mycolic acid biosynthesis and formation of biofilms by Mtb. Molecular docking of S-S006-830 with FabG4 was consistent with the experimental data. These results support the development of S-S006-830 as a novel lead against tuberculosis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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S-Enantiomer of the Antitubercular Compound S006-830 Complements Activity of Frontline TB Drugs and Targets Biogenesis of Mycobacterium tuberculosis Cell Envelope

Singh¹,

Kumar²,

Maurya

et al. 2017

ACS Omega

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“…6 Our research group is consistently working in the area of development of new antitubercular agents (Das et al, 2007;Karkara et al, 2020;Panda et al, 2005Panda et al, , 2007Parai et al, 2008;Saha et al, 2017). Because of our constant efforts, we have reported CDRI S006-830 as lead molecule for Mtb (Singh, Manna, et al, 2015). The purpose of this review is to focus on the synthesis, biological target existing clinical evidence and completed and ongoing clinical trials for various drugs in pipeline for development for treatment of Mtb.…”

Section: Introductionmentioning

confidence: 99%

Novel candidates in the clinical development pipeline for TB drug development and their synthetic approaches

2021

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Tuberculosis (TB) is an infection caused by Mycobacterium tuberculosis (Mtb) and one of the deadliest infectious diseases in the world. Mtb has the ability to become dormant within the host and to develop resistance. Hence, new antitubercular agents are required to overcome problems in the treatment of multi-drug-resistant Tb (MDR-Tb) and extensively drug-resistant Tb (XDR-Tb) along with shortening the treatment time. Several efforts are being made to develop very effective new drugs for Tb, within the pharmaceutical industry, the academia and through public-private partnerships. This review will address the antitubercular activities, biological target, mode of action, synthetic approaches and thoughtful concept for the development of several new drugs currently in the clinical trial pipeline (up to October 2019) for tuberculosis. The aim of this review may be very useful in scheming new chemical entities (NCEs) for Mtb.

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“…The bisphenol motif is prevalent in a number of natural and manual products, which display appealing biological activities, such as antioxidant, antitumor, antiviral, antitubercular activities, and restraint activity for histidine protein kinases . For instance, Selaginpulvilins A shows remarkable suppressin-g activities against phosphodiesterase-4 (PDE4) and have been used as a drug target to treat asthma and chronic obstructive pulmonary disease (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Organocatalytic Asymmetric Synthesis of Biologically Relevant 3,3- Dihydroxyphenyloxindoles via para-Quinone Methides Derived from Isatins

Qin

Gao

et al. 2021

J. Org. Chem.

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The first asymmetric synthetic approach to biologically relevant 3,3-diphenyloloxindoles was developed using paraquinone methides derived from isatins and phenols. Chiral phosphoric acid efficiently catalyzed the reaction and delivered 3,3diphenyloloxindoles under mild conditions with up to an equivalent yield and excellent enantioselectivity (up to >99% ee). The chirality was maintained in further synthesis. Article pubs.acs.org/joc

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Thiophene containing trisubstituted methanes [TRSMs] as identified lead against Mycobacterium tuberculosis

Cited by 32 publications

References 11 publications

S-Enantiomer of the Antitubercular Compound S006-830 Complements Activity of Frontline TB Drugs and Targets Biogenesis of Mycobacterium tuberculosis Cell Envelope

S-Enantiomer of the Antitubercular Compound S006-830 Complements Activity of Frontline TB Drugs and Targets Biogenesis of Mycobacterium tuberculosis Cell Envelope

Novel candidates in the clinical development pipeline for TB drug development and their synthetic approaches

Organocatalytic Asymmetric Synthesis of Biologically Relevant 3,3- Dihydroxyphenyloxindoles via para-Quinone Methides Derived from Isatins

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