Evaluation and Docking Study of Pyrazine Containing 1, 3, 4-Oxadiazoles Clubbed with Substituted Azetidin-2-one: A New Class of Potential Antimicrobial and Antitubercular

Drug Research ◽  
2020 ◽  
Vol 71 (01) ◽  
pp. 26-35
Author(s):  
Rina Das ◽  
Dinesh Kumar Mehta
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Aromatic Aldehydes ◽  
Antitubercular Activity ◽  
Docking Study ◽  
Drug Resistant ◽  
New Class ◽  
Heterocyclic Molecules ◽  
Amino Phenol ◽  
Tuberculosis Therapy ◽  
Pyrazinoic Acid

Abstract Background Tuberculosis (TB) caused by Mycobacterium tuberculosis is one of the main killers of people all over the world. The major hurdles with existing therapy are the lengthy regimen and appearance of multi drug resistant (MDR) and extensively drug resistant (XDR) strains of M.tuberculosis. Aims The present work was aimed to synthesize and determine antitubercular and antimicrobial potential of some novel 3-chloro-4-aryl-1-[4-(5-pyrazin-2-yl[1,3,4]oxadiazole-2-ylmethoxy)-phenyl]-azetidin-2-one derivatives 7(a-h) from pyrazinoic acid as precursor, which is a well-established antitubercular agent. Here we report the synthesis of a new class of heterocyclic molecules in which pyrazine, 1, 3, 4-oxadiazole and azetidinone moieties were present in one frame work. Methods Pyrazinoic acid (1) was esterified first (2) followed by amination to produce hydrazide (3) which was refluxed with POCl3 to obtain 2-chloromethyl-5pyrazino-1, 3, 4-oxadiazole (4). This was then further reacted with 4-amino phenol to obtain 4-[5-pyrazino-1, 3, 4-oxadiazol-2-yl-methoxy]-phenyl amine (5) which on condensation with various aromatic aldehydes afforded a series Schiff’s bases 6(a-h). Dehydrative annulations of 6(a-h) in the presence of chloroacetyl chloride and triethylamine yielded 3-chloro-4-aryl-1-[4-(5-pyrazin-2-yl-[1, 3, 4]oxadiazole-2-ylmethoxy)-phenyl]-azetidin-2-one derivatives 7(a-h). Antibacterial, antifungal and antitubercular potential of all the synthesized compounds were assessed. Docking study was performed using the software VLife Engine tools of Vlifemds 4.6 on the protein lumazine synthase of M. tuberculosis (PDB entry code 2C92). Results The present studies demonstrated that synthesized oxadiazole derivatives have good antimicrobial activity against the various microorganisms. Among the synthesized derivative, 7b and 7g were found to be prominent compounds which have potential antibacterial, antifungal and antitubercular activity (with MIC 3.12 µg/ml and high dock score ranging from −59.0 to −54.0) against Mycobacterium tuberculosis. Conclusions Derivatives 7b and 7g would be effective lead candidates for tuberculosis therapy.

scholarly journals Isoniazid-Isatin Hydrazone Derivatives: Synthesis, Antitubercular Activity and Molecular Docking Studies

2021 ◽  
Vol 18 (21) ◽  
pp. 39
Author(s):  
Mardi Santoso ◽  
Muhammad Riza Ghulam Fahmi ◽  
Yehezkiel Steven Kurniawan ◽  
Taslim Ersam ◽  
Sri Fatmawati ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Active Site ◽  
Antitubercular Activity ◽  
Docking Study ◽  
Positive Control ◽  
Tuberculosis H37rv ◽  
Molecular Docking Study

This study examined the synthesis of isoniazid-isatin hydrazone derivatives 5-7, followed by an investigation on the in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv, and molecular docking. A yield of 81 - 92 % of these compounds was achieved, with structural characterization by spectroscopic methods (FTIR, NMR, HRMS). The in vitro antitubercular activity was evaluated against M. tuberculosis H37Rv, and the highest effect was observed in compound 7, with a minimum inhibitory concentration (MIC) of 0.017 mM, lower than rifampicin (MIC 0.048 mM), which served as the positive control. In addition, the molecular docking of 5-7 was performed to visualize the interaction of isoniazid-isatin hydrazone derivatives with the active site of InhA receptor, which was in agreement with the experimental data. The hydrogen bonding with Ser94 and pi-pi interaction with Phe41 and/or Phe97 on the InhA active site was pivotal for the antitubercular activity. HIGHLIGHTS Tuberculosis caused by Mycobacterium tuberculosis is one of the top ten leading causes of death globally The first and second lines of antituberculosis drugs are the prevalent treatment for this disease, but they show several drawbacks and are exacerbated by the occurrence of drug resistance The isoniazid-isatin hydrazone derivatives were designed through molecular hybridization and synthesized effectively and exhibited moderate to high activity against tuberculosis H37Rv Molecular docking study demonstrated that the hydrogen bonding with Ser94 and the pi-pi interaction with Phe41 and/or Phe97 are important for antitubercular activity GRAPHICAL ABSTRACT

scholarly journals Pantothenate and Pantetheine Antagonize the Antitubercular Activity of Pyrazinamide

2014 ◽  
Vol 58 (12) ◽  
pp. 7258-7263 ◽  
Author(s):  
Nicholas A. Dillon ◽  
Nicholas D. Peterson ◽  
Brandon C. Rosen ◽  
Anthony D. Baughn
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Nicotinic Acid ◽  
Active Form ◽  
Laboratory Strain ◽  
Antitubercular Activity ◽  
First Line ◽  
Auxotrophic Strain ◽  
Content Type ◽  
Related Compounds ◽  
Pyrazinoic Acid

ABSTRACTPyrazinamide (PZA) is a first-line tuberculosis drug that inhibits the growth ofMycobacterium tuberculosisvia an as yet undefined mechanism. AnM. tuberculosislaboratory strain that was auxotrophic for pantothenate was found to be insensitive to PZA and to the active form, pyrazinoic acid (POA). To determine whether this phenotype was strain or condition specific, the effect of pantothenate supplementation on PZA activity was assessed using prototrophic strains ofM. tuberculosis. It was found that pantothenate and other β-alanine-containing metabolites abolished PZA and POA susceptibility, suggesting that POA might selectively target pantothenate synthesis. However, when the pantothenate-auxotrophic strain was cultivated using a subantagonistic concentration of pantetheine in lieu of pantothenate, susceptibility to PZA and POA was restored. In addition, we found that β-alanine could not antagonize PZA and POA activity against the pantothenate-auxotrophic strain, indicating that the antagonism is specific to pantothenate. Moreover, pantothenate-mediated antagonism was observed for structurally related compounds, includingn-propyl pyrazinoate, 5-chloropyrazinamide, and nicotinamide, but not for nicotinic acid or isoniazid. Taken together, these data demonstrate that while pantothenate can interfere with the action of PZA, pantothenate synthesis is not directly targeted by PZA. Our findings suggest that targeting of pantothenate synthesis has the potential to enhance PZA efficacy and possibly to restore PZA susceptibility in isolates withpanD-linked resistance.

First-line tuberculosis therapy and drug-resistant Mycobacterium tuberculosis in prisons

The Lancet ◽  
1999 ◽  
Vol 353 (9157) ◽  
pp. 969-973 ◽  
Author(s):  
R Coninx ◽  
C Mathieu ◽  
M Debacker ◽  
F Mirzoev ◽  
A Ismaelov ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Resistant ◽  
First Line ◽  
Tuberculosis Therapy

scholarly journals Bengamides display potent activity against drug-resistant Mycobacterium tuberculosis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Diana H. Quan ◽  
Gayathri Nagalingam ◽  
Ian Luck ◽  
Nicholas Proschogo ◽  
Vijaykumar Pillalamarri ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
New Drugs ◽  
Bioactive Molecules ◽  
Aminopeptidase Activity ◽  
Drug Resistant ◽  
Lead Compounds ◽  
New Class ◽  
Tb Treatment ◽  
Bioassay Guided Fractionation

Abstract Mycobacterium tuberculosis infects over 10 million people annually and kills more people each year than any other human pathogen. The current tuberculosis (TB) vaccine is only partially effective in preventing infection, while current TB treatment is problematic in terms of length, complexity and patient compliance. There is an urgent need for new drugs to combat the burden of TB disease and the natural environment has re-emerged as a rich source of bioactive molecules for development of lead compounds. In this study, one species of marine sponge from the Tedania genus was found to yield samples with exceptionally potent activity against M. tuberculosis. Bioassay-guided fractionation identified bengamide B as the active component, which displayed activity in the nanomolar range against both drug-sensitive and drug-resistant M. tuberculosis. The active compound inhibited in vitro activity of M. tuberculosis MetAP1c protein, suggesting the potent inhibitory action may be due to interference with methionine aminopeptidase activity. Tedania-derived bengamide B was non-toxic against human cell lines, synergised with rifampicin for in vitro inhibition of bacterial growth and reduced intracellular replication of M. tuberculosis. Thus, bengamides isolated from Tedania sp. show significant potential as a new class of compounds for the treatment of drug-resistant M. tuberculosis.

scholarly journals Synthesis and antitubercular activity of 1- and 3-substituted benzo[g]isoquinoline-5,10-diones

2019 ◽  
Vol 17 (11) ◽  
pp. 2923-2939 ◽  
Author(s):  
Robert J. Smets ◽  
Eveline Torfs ◽  
Filip Lemière ◽  
Paul Cos ◽  
Davie Cappoen ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Antitubercular Activity ◽  
New Class

The synthesis of a new class of 1- and 3-substituted benzo[g]isoquinoline-5,10-diones and their anti-mycobacterial activities againstMycobacterium tuberculosisH37Rv is reported.

scholarly journals Pyrazinoic Acid Inhibits the Bifunctional Enzyme (Rv2783) in Mycobacterium tuberculosis by Competing with tmRNA

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 230 ◽  
Author(s):  
Lei He ◽  
Peng Cui ◽  
Wanliang Shi ◽  
Qiong Li ◽  
Wenhong Zhang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Mechanism ◽  
Messenger Rna ◽  
Mutant Allele ◽  
Active Form ◽  
Antitubercular Activity ◽  
Bifunctional Enzyme ◽  
Catalytic Activities ◽  
Insight Into ◽  
Pyrazinoic Acid

Pyrazinamide (PZA) is a key drug for tuberculosis treatment. The active form of PZA, pyrazinoic acid (POA), appears to inhibit multiple targets in M. tuberculosis. Recently, the bifunctional enzyme Rv2783 was reported as a new target of POA. However, the mechanism by which POA inhibits Rv2783 is not yet clear. Here, we report how a new A2104C substitution in Rv2783c, identified in PZA-resistant clinical isolates, conferred resistance to PZA in M. tuberculosis. Expression of the mutant allele recapitulated the PZA resistance. All catalytic activities of Rv2783, but not the mutant, were inhibited by POA. Additionally, POA competed with transfer-messenger RNA (tmRNA) for binding to Rv2783, other than the mutant. These results provide new insight into the molecular mechanism of the antitubercular activity of PZA.

scholarly journals Screening and Evaluation of Multi Drug Resistance Activity of Various 1,2,4-Triazoles Derivatives through in Vitro Anti tubercular

2019 ◽  
Vol 8 (2S6) ◽  
pp. 530-534
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Isonicotinic Acid ◽  
Acid Hydrazide ◽  
Antitubercular Activity ◽  
Docking Study ◽  
Docking Studies ◽  
Multi Drug Resistance ◽  
Log P ◽  
Rapid Decline

Isoniazid (Isonicotinic acid hydrazide, INH) has been significantly used to treat Mycobacterium tuberculosis. Introduction of drugs like INH, Rifmapicin, Pyrazinamide and Streptomycin resulted in rapid decline in TB cases worldwide. Several factors lead to the emergence of resistant strains of Mycobacterium tuberculosis. HIV infection also contributed to the escalating burden of tuberculosis. In the present examination 1,2,4-triazole subordinates were planned, incorporated and exposed to in vitro antitubercular screening against Mycobacterium tuberculosis H37Rv.Lipophilicity (log P) of the compounds were also determined to establish a correlation ship between physicochemical properties and antitubercular activity. Mtb CYP121 and CYP125 are considered to be potential targets for drug design. Binding study of azoles with these enzymes have also been reported. However, enough reports are not available on Mtb CYP-ligand binding requirements to improve the MIC of Azole based antitubercular agents. Hence we conducted the docking study of our synthesized triazoles against both Mtb CYP 121 and CYP125 to establish a correlationship between antitubercular activity and receptor binding interactions. In this paper we discuss about the molecular docking studies of the synthesized mercapto and benzthio 1,2,4-triazole compounds 13-18 with different enzyme target which we have employed.

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