Design, synthesis and SAR of antitubercular benzylpiperazine ureas

Satish, Sohal; Chitral, Rohan; Kori, Amitkumar; Sharma, Basantkumar; Puttur, Jayashree; Khan, Afreen A.; Desle, Deepali; Raikuvar, Kavita; Korkegian, Aaron; Martis, Elvis A. F.; Iyer, Kaushik A.; Coutinho, Evans C.; Parish, Tanya; Nandan, Santosh

doi:10.1007/s11030-020-10158-3

Cited by 6 publications

(10 citation statements)

References 22 publications

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“…To the best of our knowledge, ML based approaches have not been applied to QcrB inhibitors. We had earlier published a the synthesis and SAR of benzyl piperazine ureas 9 with insilico studies suggesting QcrB as the target. The 55 molecules of that study are also part of this study.…”

Section: One Of the Evolving Arms Of Computer Aided Drug Discovery Is...mentioning

confidence: 99%

Prediction Of QcrB Inhibition As A Measure Of Antitubercular Activity With Machine Learning Protocols.

Khan

Bhave

Poojary

et al. 2022

Preprint

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Mycobacterium tuberculosis has been a challenging target with respect to developing interventional therapies. Over the years, several attempts at developing anti-tubercular agents have hit a dead-end due to the propensity of the tubercular bacilli to mutate rapidly. Recently, cytochrome bcc complex (QcrB) has shown some promise as a novel target of the tubercular bacilli; with Q203 being the first molecule acting on this target. In this paper, we report the deployment of several ML-based approaches to design molecules against QcrB. Machine Learning (ML) models were developed based on a large dataset of 350 molecules using three different sets of molecular features, i.e. MACCS keys, ECFP6 fingerprints and Mordred descriptors. Each feature set was trained on eight ML classifier algorithms and optimised to classify molecules accurately. Of the 24 models generated, the best performing model was one built with support vector machine and based on the ECFP6 feature set. A further screening of the known imidazopyridine amide inhibitors demonstrated that the model correctly classified the most potent molecules as actives. Thus validating the model for future applications.

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Section: One Of the Evolving Arms Of Computer Aided Drug Discovery Is...mentioning

confidence: 99%

Prediction Of QcrB Inhibition As A Measure Of Antitubercular Activity With Machine Learning Protocols.

Khan

Bhave

Poojary

et al. 2022

Preprint

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“…In addition, in a complete genome sequencing study, resistant mutants strains of H37Rv of M. tuberculosis were used with the 11,626,142 quinazoline derivative (Table 1) and revealed that the main target for this compound is the cytochrome bc 1 complex of M. tuberculosis [92]. In 2021, Satish et al discovered benzylpiperazine ureas which have good antitubercular activity [93]. The bioisosteric substitute of the heterocyclic furan ring with a phenyl ring and removal of the conjugated double bond in the GSK Tres Cantos molecules resulted in a novel molecule (I) (Table 1) which has good activity, metabolic stability, and specificity against M. tuberculosis H37Rv strain along with low cellular toxicity [93].…”

Section: Tablementioning

confidence: 99%

“…In 2021, Satish et al discovered benzylpiperazine ureas which have good antitubercular activity [93]. The bioisosteric substitute of the heterocyclic furan ring with a phenyl ring and removal of the conjugated double bond in the GSK Tres Cantos molecules resulted in a novel molecule (I) (Table 1) which has good activity, metabolic stability, and specificity against M. tuberculosis H37Rv strain along with low cellular toxicity [93]. SAR analysis of 55 synthesized derivatives of the molecule (I) indicated that benzylpiperazinyl urea and piperonyl moieties are the essential features for the activity.…”

Section: Tablementioning

confidence: 99%

“…The docking study results yielded novel insights and paved the way for the structure-based development of new hypothetical IPA analogues as anti-tubercular drug candidates [118]. In 2021, the molecular docking study showed that the benzylpiperazine urea derivative molecule (I) and Q203 bind to a similar binding site (Q 0 site, the stigmatellin binding site) into the QcrB homology model [93].…”

Section: Computational Approaches For Prediction Of the Binding Site In Qcrbmentioning

confidence: 99%

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Targeting the cytochrome bc1 complex for drug development in M. tuberculosis: review

Wani

Dhaked

2021

Mol Divers

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The terminal oxidases of the oxidative phosphorylation pathway play a significant role in the survival and growth of M. tuberculosis, targeting these components lead to inhibition of M. tuberculosis. Many drug candidates targeting various components of the electron transport chain in M. tuberculosis have recently been discovered. The cytochrome bc 1 -aa 3 supercomplex is one of the most important components of the electron transport chain in M. tuberculosis, and it has emerged as the novel target for several promising candidates. There are two cryo-electron microscopy structures (PDB IDs: 6ADQ and 6HWH) of the cytochrome bc 1 -aa 3 supercomplex that aid in the development of effective and potent inhibitors for M. tuberculosis. In recent years, a number of potential candidates targeting the QcrB subunit of the cytochrome bc 1 complex have been developed. In this review, we describe the recently identified inhibitors that target the electron transport chain's terminal oxidase enzyme in M. tuberculosis, specifically the QcrB subunit of the cytochrome bc 1 complex.

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“…One serious challenge in the treatment of tuberculosis is the emergence of multi-drug-resistant strains of Mtb which arises due to improper use of both traditional first-line and second-line antituberculosis drugs [ 5 ]. Globally in 2019, approximately half a million people developed rifampicin-resistant TB (RR-TB), with 78% of patients presenting with multidrug-resistant TB (MDR-TB).…”

Section: Introductionmentioning

confidence: 99%

Exploration of 4-aminopyrrolo[2,3-d]pyrimidine as antitubercular agents

et al. 2022

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Tuberculosis (TB) is one of the leading causes of death worldwide. Developing new anti-TB compounds using cost-effective processes is critical to reduce TB incidence and accomplish the End TB Strategy milestone. Herein, we describe the synthesis and structure–activity relationships of a library of thirty 7H -Pyrrolo[2,3- d ]pyrimidine derivatives providing insights into the contributions of different aromatic, aryl and alkyl substitution at the C-4 position of the 7-deazapurine ring. The minimum inhibitory concentration (MIC) of the compounds against the green fluorescent protein (GFP) reporter strain of Mycobacterium tuberculosis was assayed using the standard broth microdilution method, and cell toxicity was determined using the MTT assay. Sixteen compounds displayed in vitro activity against the GFP reporter strain of Mycobacterium tuberculosis with MIC 90 values of 0.488–62.5 µM. This study highlights the most potent derivative, N-(4-phenoxy phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine with a MIC 90 value of 0.488 µM and was non-cytotoxic to the Vero cell line. Moreover, all the potent compounds from this series have a ClogP value less than 4 and molecular weight < 400; thus, likely to maintain drug-likeness during lead optimisation. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11030-022-10453-1.

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Design, synthesis and SAR of antitubercular benzylpiperazine ureas

Cited by 6 publications

References 22 publications

Prediction Of QcrB Inhibition As A Measure Of Antitubercular Activity With Machine Learning Protocols.

Prediction Of QcrB Inhibition As A Measure Of Antitubercular Activity With Machine Learning Protocols.

Targeting the cytochrome bc1 complex for drug development in M. tuberculosis: review

Exploration of 4-aminopyrrolo[2,3-d]pyrimidine as antitubercular agents

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