Lead identification and optimization of bacterial glutamate racemase inhibitors

Malapati, Prasanthi; Krishna, Vagolu Siva; Nallangi, Radhika; Meda, Nikhila; Srilakshmi, Rudraraju Reshma; Sriram, Dharmarajan

doi:10.1016/j.bmc.2017.11.031

Cited by 11 publications

(4 citation statements)

References 24 publications

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“…In recent past, MurI in Staphylococcus aureus and Helicobacter pylori was shown to be inhibited by 8-benzyl pteridine-6,7-diones and pyridodiazepine amines respectively 37,38 . Inhibitory effect of some of the benzoxazole and indazole derivatives were also reported against TB 39,40 . However, extensive studies are not in place to establish these compounds as inhibitors of racemization activity of MTB-MurI.…”

Section: Discussionmentioning

confidence: 95%

Screening of natural compounds that targets glutamate racemase of Mycobacterium tuberculosis reveals the anti-tubercular potential of flavonoids

Pawar

Jha

Chopra

et al. 2020

Sci Rep

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tuberculosis (tB) is caused by Mycobacterium tuberculosis (MTB), a highly infectious disease accounting for nearly 1.5 million deaths every year and has been a major global concern. Moreover, resistance to anti-TB drugs is an arduous obstacle to effective prevention, TB care and management. Therefore, incessant attempts are being made to identify novel drug targets and newer anti-tubercular drugs to fight with this deadly pathogen. Increasing resistance, adverse effects and costly treatment by conventional therapeutic agents have been inclining the researchers to search for an alternative source of medicine. In this regard natural compounds have been exploited extensively for their therapeutic interventions targeting cellular machinery of MTB. Glutamate racemase (MurI) is an enzyme involved in peptidoglycan (PG) biosynthesis and has become an attractive target due to its moonlighting property. We screened various classes of natural compounds using computational approach for their binding to MTB-MurI. Shortlisted best docked compounds were evaluated for their functional, structural and anti-mycobacterial activity. The results showed that two flavonoids (naringenin and quercetin) exhibited best binding affinity with MTB-MurI and inhibited the racemization activity with induced structural perturbation. In addition, fluorescence and electron microscopy were employed to confirm the membrane and cell wall damages in mycobacterial cells on exposure to flavonoids. Together, these observations could provide impetus for further research in better understanding of anti-tubercular mechanisms of flavonoids and establishing them as lead molecules for TB treatment.

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Section: Discussionmentioning

confidence: 95%

Screening of natural compounds that targets glutamate racemase of Mycobacterium tuberculosis reveals the anti-tubercular potential of flavonoids

Pawar

Jha

Chopra

et al. 2020

Sci Rep

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“…Aliquots of these cultures were then treated with standard drugs (isoniazid, ciprofloxacin, rifampicin and moxifloxacin) and 4c for 7 days at a concentration of 10 μg/ml. The frequency of persistors was enumerated by MPN (most probable number) assay 23,24 .…”

Section: Nutrient Starvation Modelmentioning

confidence: 99%

Design, Synthesis and Antimycobacterial Activity of 2-(Benzimidazol-2-yl)-propanenitrile Analogs

Tan¹,

Sirim²,

Vagolu³

et al. 2022

Hacettepe University Journal of the Faculty of Pharmacy

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This paper reports the synthesis and evaluation of six new 2-(benzimidazol-2-yl)-3-(4-(4-substitutedpiperazin-1-yl)phenyl)propanenitrile derivatives (4a-f) for their in vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv. The target compounds (4a-f) were characterized using IR, 1H and 13C NMR, mass spectral data as well as elemental analysis. Among them, 4c (2was found to be the most active compound with MIC of 1.56 μg/mL against M. tuberculosis. In addition, 4c showed 2.1 log reduction against nutrient starved M. tuberculosis which is more potent than first line drugs. Based on their predicted physicochemical values, the compounds obeyed the Lipinski's "rule of five," and TPSA/nROT limits. Molecular docking studies were performed to estimate the orientation of 4c at the active site of M. tuberculosis LAT enzyme. These results suggest that 4c may be a good candidate for drug development owing to potential against both active and dormant forms of M. tuberculosis.

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“…21). [246][247][248] Structure-activity relationship (SAR) studies led to inhibitors 117-119 with low mM IC 50 values. Non-competitive inhibition was assigned based on the observed changes within the thermal shift assay, although this was not confirmed by enzyme activity assays.…”

Section: Cofactor-independent Racemases and Epimerasesmentioning

confidence: 99%

Racemases and epimerases operating through a 1,1-proton transfer mechanism: reactivity, mechanism and inhibition

et al. 2021

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Lead identification and optimization of bacterial glutamate racemase inhibitors

Cited by 11 publications

References 24 publications

Screening of natural compounds that targets glutamate racemase of Mycobacterium tuberculosis reveals the anti-tubercular potential of flavonoids

Screening of natural compounds that targets glutamate racemase of Mycobacterium tuberculosis reveals the anti-tubercular potential of flavonoids

Design, Synthesis and Antimycobacterial Activity of 2-(Benzimidazol-2-yl)-propanenitrile Analogs

Racemases and epimerases operating through a 1,1-proton transfer mechanism: reactivity, mechanism and inhibition

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