Development of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives as novel Mycobacterium tuberculosis pantothenate synthetase inhibitors

Samala, Ganesh; Devi, Parthiban Brindha; Nallangi, Radhika; Yogeeswari, Perumal; Sriram, Dharmarajan

doi:10.1016/j.ejmech.2013.08.036

Cited by 32 publications

(14 citation statements)

References 12 publications

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“…Samala and coworkers have reported the synthesis and evaluation of the bioactivity of 3-phenyl-4,5,6,7-tetrahydro-1 H -pyrazolo[4,3- c ]pyridine derivatives against M. tuberculosis (MTB) pantothenate synthetase Trypanosoma. Among the compounds, 358 was found to be the most active compound with IC 50 of 21.8 µM against MTB PS [ 259 ].…”

Section: Pharmacological Activitiesmentioning

confidence: 99%

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

et al. 2018

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Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug rimonabant, difenamizole, an analgesic, betazole, a H2-receptor agonist and the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety. Owing to this diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This review highlights the different synthesis methods and the pharmacological properties of pyrazole derivatives. Studies on the synthesis and biological activity of pyrazole derivatives developed by many scientists around the globe are reported.

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Section: Pharmacological Activitiesmentioning

confidence: 99%

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

et al. 2018

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“…Therefore, PS is very good drug target for developing new drugs against TB 13 . Many inhibitors against PS has been reported which include pyrazolo[4,3-c]pyridine carboxamides derivatives 39 , 3-Biphenyl-4-Cyanopyrrole-2-Carboxylic Acids derivatives 40 , and 2,6-disubstituted 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide derivatives 41 . There is a dire necessity for investigating the mechanism to reduce the catalytic activity of enzymes which are crucial targets against tuberculosis.…”

Section: Discussionmentioning

confidence: 99%

Alanine mutation of the catalytic sites of Pantothenate Synthetase causes distinct conformational changes in the ATP binding region

Pandey

Grover

Goyal

et al. 2018

Sci Rep

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The enzyme Pantothenate synthetase (PS) represents a potential drug target in Mycobacterium tuberculosis. Its X-ray crystallographic structure has demonstrated the significance and importance of conserved active site residues including His44, His47, Asn69, Gln72, Lys160 and Gln164 in substrate binding and formation of pantoyl adenylate intermediate. In the current study, molecular mechanism of decreased affinity of the enzyme for ATP caused by alanine mutations was investigated using molecular dynamics (MD) simulations and free energy calculations. A total of seven systems including wildtype + ATP, H44A + ATP, H47A + ATP, N69A + ATP, Q72A + ATP, K160A + ATP and Q164A + ATP were subjected to 50 ns MD simulations. Docking score, MM-GBSA and interaction profile analysis showed weak interactions between ATP (substrate) and PS (enzyme) in H47A and H160A mutants as compared to wild-type, leading to reduced protein catalytic activity. However, principal component analysis (PCA) and free energy landscape (FEL) analysis revealed that ATP was strongly bound to the catalytic core of the wild-type, limiting its movement to form a stable complex as compared to mutants. The study will give insight about ATP binding to the PS at the atomic level and will facilitate in designing of nonreactive analogue of pantoyl adenylate which will act as a specific inhibitor for PS.The causative agent of tuberculosis (TB) is Mycobacterium tuberculosis (Mtb), a major infectious bacterium which spreads through droplets in the air. TB is second only to HIV/AIDS as the major killer across the globe 1 . Multi-drug resistant Mtb is becoming a regular health problem especially in immuno-compromised individuals with HIV 2 . This form of TB is more difficult to treat and as a result has higher mortality rate. Because of this, the discovery of drugs targeting novel pathways such as the synthesis of pantothenate has become increasingly important. The World Health statistics report in 2014 stated that 9.6 million people were diagnosed with TB of which 1.5 million people died 3 . PanC gene encodes Pantothenate Synthetase (PS; EC 6.3.2.1) responsible for producing pantothenate (vitamin B5), is a promising drug target owing to a few important reasons 4 . Firstly, it is present in all bacteria but absent in mammals, a key factor for the selective activity of drug molecule 5 . Secondly, Pantothenate is notable for its role in the synthesis of coenzyme A (CoA) and acyl carrier protein (ACP), essential components of fatty acid synthesis which maintain persistent growth and pathogenicity of the M. tuberculosis 6 . Lastly, Jacob et al., conducted research on a TB vaccine which compromised panC auxotrophs' growth and virulence rigorously supporting the theory of functional necessity of Pantothenate Synthetase pathway and enhancing its attractiveness as a potential antimicrobial target 7 . PS proceeds by Bi Uni Uni Bi Ping Pong kinetic reactions; it catalyzes the ATP dependent condensation of pantoate with beta-alanine via a pantoyl adenylate intermediate as follo...

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“…The test plate was immediately transferred to a microplate reader and absorbance was measured at 340 nm after every 12 s for 120 s. Each plate had 16 control wells in the two outside columns, of which 12 contained the complete reaction mixture with a DMSO carrier control (full reaction) and four without PS. The following formula was used to calculate percent inhibition % inhibi tion = 100 Â (1 À compound rate À background rate)/(full reaction rate À background rate) [38,39].…”

Section: Mycobacterial Pantothenate Synthetase Assaymentioning

confidence: 99%

Synthesis and evaluation of antimicrobial, antitubercular and anticancer activities of benzimidazole derivatives

Yadav

Narasimhan

Lim

et al. 2018

Egyptian Journal of Basic and Applied Sciences

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A series of benzimidazole derivatives (1-20) was synthesized and evaluated for its in vitro antimicrobial, antitubercular and anticancer activities. Compound 10 was found to be the most active antibacterial agent. The compounds active in in vitro evaluation against M. tuberculosis were further assessed for their in vivo activity in mice and for their capacity to inhibit the vital mycobacterial enzymes viz., isocitrate lyase, pantothenate synthetase and chorismate mutase. The dose of the compounds in antitubercular evaluation that proved fatal and highly toxic to mice was 5.67 mg/kg while lethal dose varied from 1.82 mg/kg to 3.23 mg/kg body weight of the mice. A dose of 1.34 mg/kg was found to be safe for each of the compounds. All compounds inhibited the mycobacterial enzymes but to a lesser extent than streptomycin sulphate used as positive control. Compound 19, exhibiting inhibition of 67.56%, 53.45%, and 47.56% against isocitrate lyase, pantothenate synthetase and chorismate mutase, respectively is the most potent antitubercular compound among the synthesized benzimidazole derivatives. Further, compound 19 also emerged as a potent anticancer agent (IC 50 = 0.0013 mM) than 5-flourouracil against breast cancer cell line (MCF 7).

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Development of 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives as novel Mycobacterium tuberculosis pantothenate synthetase inhibitors

Cited by 32 publications

References 12 publications

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

Alanine mutation of the catalytic sites of Pantothenate Synthetase causes distinct conformational changes in the ATP binding region

Synthesis and evaluation of antimicrobial, antitubercular and anticancer activities of benzimidazole derivatives

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