Evaluation of substituted triazol-1-yl-pyrimidines as inhibitors of Bacillus anthracis acetohydroxyacid synthase

Gedi, Vinayakumar; Jayaraman, Kunthala; Kalme, Satish; Park, Hye-Yeon; Park, Hae-Chul; La, Im-Joung; Hahn, Hoh‐Gyu; Yoon, Moon‐Young

doi:10.1016/j.bbapap.2010.02.002

Cited by 8 publications

(12 citation statements)

References 22 publications

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“…The discontinuous colourimetric method employs a high‐throughput format where various chemical compound libraries are screened against several bacterial AHASs with the aim of developing antimicrobial agents. This strategy has been applied against the purified AHAS of several pathogenic bacteria, including M. tuberculosis , B. anthracis , H. influenza , P. aeruginosa , S. sonnei and E. coli K‐12 isozyme I [8,30,44,89,91,92]. The screening identified several inhibitors, each representing a structural class, including 3‐phenyl‐[1,2,4]triazol‐1‐yl, substituted triazol‐1‐yl‐pyrimidine derivatives and phenyl‐2,3‐dihydro‐isothiazole derivatives [8,44,92].…”

Section: Inhibitorsmentioning

confidence: 99%

“…8). A total of four compounds, including AVS2397, AVS2087, AVS2236 and AVS2093, are found to inhibit B. anthracis AHAS with IC 50 values in the low micromolar range (1.0–2.1 μ m ) [44]. The basic scaffold of AVS chemicals is similar to the triazolopyrimidines, consisting of a di‐ or tri‐substituted aromatic ring linked by a short bridge to a substituted 2‐[1,2,4]‐triazol‐1‐yl‐pyrimidine.…”

Section: Inhibitorsmentioning

confidence: 99%

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Bacterial acetohydroxyacid synthase and its inhibitors – a summary of their structure, biological activity and current status

Gedi

Yoon

2012

The FEBS Journal

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Acetohydroxyacid synthase (anabolic AHAS; http://www.chem.qmul.ac.uk/iubmb/enzyme/EC2/2/1/6.html) is a thiamin diphosphate‐dependent enzyme that catalyzes the first step in the branched‐chain amino acid (BCAA) biosynthesis pathway. BCAAs are synthesized by plants, algae, fungi and bacteria, although not by animals. Thus, the enzymes of the BCAA biosynthetic pathway are potential targets in the development of herbicides, fungicides and antimicrobial compounds. Plant AHASs are well studied in this regard because specific plant AHAS inhibitors are considered to comprise the most potent herbicides. These inhibitors are also effective against bacterial AHASs, inhibit the growth of several bacterial strains and have little to no toxicity in mammals. This review provides an overview of bacterial AHASs with an update of the current status of AHAS inhibitors.

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Section: Inhibitorsmentioning

confidence: 99%

Section: Inhibitorsmentioning

confidence: 99%

Bacterial acetohydroxyacid synthase and its inhibitors – a summary of their structure, biological activity and current status

Gedi

Yoon

2012

The FEBS Journal

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“…In addition, these compounds also found to inhibit the various bacterial AHASs with similar sub-micromolar level inhibition. 20,21 Further, the molecular docking simulations of four AVS compounds with catalytic subunit of Mtb-AHAS revealed the details of their interactions. The docking data suggests the possible location of AVS compounds at different binding sites and exploits an inhibitory mechanism that can be instrumental in further developing inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Mechanism Studies of Substituted Triazol-1-yl-pyrimidine Derivatives Inhibition on Mycobacterium tuberculosis Acetohydroxyacid Synthase

Chien¹,

Jung²,

Reddy³

et al. 2012

Bulletin of the Korean Chemical Society

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The first step in the common pathway for the biosynthesis of branched chain amino acids is catalyzed by acetohydroxyacid synthase (AHAS). The AHAS is found in plants, fungi and bacteria. With an aim to identify new anti-tuberculosis drugs that inhibit branched chain amino acid biosynthesis, we screened a chemical library against Mycobacterium tuberculosis AHAS. The screening identified four compounds, AVS 2087, AVS 2093, AVS 2236, and AVS 2387 with IC 50 values of 0.28, 0.21, 3.88, and 0.25 µM, respectively. Moreover, these four compounds also showed strong inhibition against reconstituted AHAS with IC 50 values of 0.37, 0.26, 1.0, and 1.18 µM, respectively. The basic scaffold of the AVS group consists of 1-pyrimidin-2-yl-1H-[1,2,4]-triazole-3-sulfonamide. The most active compound, AVS 2387, showed the lowest total interaction energy -8.75 Kcal/mol and illustrates its binding mode by hydrogen bonding with Hε of Gln517 with the distance of 2.24 Å.

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“…Herbicide sulfonylureas can inhibit the Mycobacterium avium AHAS 24. Several efficient inhibitors against AHAS from M. tuberculosis (for exmple, KHG20612, Figure 3a) and Bacillus anthracis are documented 9, 10, 25, 26.…”

Section: Thdp-dependent Enzymes Are Crucial For Pathogensmentioning

confidence: 99%

Thiamin (Vitamin B1) Biosynthesis and Regulation: A Rich Source of Antimicrobial Drug Targets?

Du¹,

Wang²,

Xie³

2011

Int. J. Biol. Sci.

144

121

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Drug resistance of pathogens has necessitated the identification of novel targets for antibiotics. Thiamin (vitamin B1) is an essential cofactor for all organisms in its active form thiamin diphosphate (ThDP). Therefore, its metabolic pathways might be one largely untapped source of antibiotics targets. This review describes bacterial thiamin biosynthetic, salvage, and transport pathways. Essential thiamin synthetic enzymes such as Dxs and ThiE are proposed as promising drug targets. The regulation mechanism of thiamin biosynthesis by ThDP riboswitch is also discussed. As drug targets of existing antimicrobial compound pyrithiamin, the ThDP riboswitch might serves as alternative targets for more antibiotics.

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Evaluation of substituted triazol-1-yl-pyrimidines as inhibitors of Bacillus anthracis acetohydroxyacid synthase

Cited by 8 publications

References 22 publications

Bacterial acetohydroxyacid synthase and its inhibitors – a summary of their structure, biological activity and current status

Bacterial acetohydroxyacid synthase and its inhibitors – a summary of their structure, biological activity and current status

Mechanism Studies of Substituted Triazol-1-yl-pyrimidine Derivatives Inhibition on Mycobacterium tuberculosis Acetohydroxyacid Synthase

Thiamin (Vitamin B1) Biosynthesis and Regulation: A Rich Source of Antimicrobial Drug Targets?

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