1,2,4-Triazole-3-thione Compounds as Inhibitors of Dizinc Metallo-β-lactamases

ChemMedChem
Laurent SevailleJean-François Hernandez

Abstract

Metallo-β-lactamases (MBLs) cause resistance of Gram-negative bacteria to β-lactam antibiotics and are of serious concern, because they can inactivate the last-resort carbapenems and because MBL inhibitors of clinical value are still lacking. We previously identified the original binding mode of 4-amino-2,4-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione (compound IIIA) within the dizinc active site of the L1 MBL. Herein we present the crystallographic structure of a complex of L1 with the corresponding non-amino compound IIIB (1,2-dihydro-5-(2-methylphenyl)-3H-1,2,4-triazole-3-thione). Unexpectedly, the binding mode of IIIB was similar but reverse to that of IIIA. The 3 D structures suggested that the triazole-thione scaffold was suitable to bind to the catalytic site of dizinc metalloenzymes. On the basis of these results, we synthesized 54 analogues of IIIA or IIIB. Nineteen showed IC50 values in the micromolar range toward at least one of five representative MBLs (i.e., L1, VIM-4, VIM-2, NDM-1, and IMP-1). Five of these exhibited a significant inhibition of at least four enzymes, including NDM-1, VIM-2, and IMP-1. Active compounds mainly featured either halogen or bulky bicyclic aryl substituents. Finally, some compou...Continue Reading

References

Feb 1, 1995·Protein Engineering·A C WallaceJ M Thornton
Jan 1, 1997·Antimicrobial Agents and Chemotherapy·D J PayneJ Marchand-Brynaert
Jun 29, 1999·Il Farmaco·G Turan-ZitouniF S Kiliç
Jun 6, 2000·Journal of Biomolecular Screening·J H ZhangK R Oldenburg
Jun 8, 2001·The Journal of Biological Chemistry·J H ToneyY D Gao
Sep 21, 2001·The Journal of Biological Chemistry·C MollardG C Roberts
May 23, 2002·Antimicrobial Agents and Chemotherapy·David J PayneAlfonso Rivera-Sagredo
May 25, 2002·The Journal of Biological Chemistry·Andreas VogelWolfram Meyer-Klaucke
Jun 8, 2002·Current Medicinal Chemistry·Vincent P Sandanayaka, Amar S Prashad
Jul 18, 2002·Antimicrobial Agents and Chemotherapy·Stefan SiemannGary I Dmitrienko
Jun 9, 2004·Biochemical and Biophysical Research Communications·Zareen AmtulSupino Rosanna
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Apr 16, 2005·Clinical Microbiology Reviews·Timothy R WalshPatrice Nordmann
Dec 28, 2005·Bioorganic & Medicinal Chemistry·Lars OlsenFlemming S Jørgensen
Jan 13, 2006·Angewandte Chemie·James Spencer, Timothy R Walsh
Aug 11, 2006·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Maja BabicRobert A Bonomo
Dec 13, 2006·Bioorganic & Medicinal Chemistry Letters·Benoît M R LiénardChristopher J Schofield
Feb 20, 2007·Antimicrobial Agents and Chemotherapy·L E HorsfallM Galleni
Mar 10, 2007·European Journal of Medicinal Chemistry·Mithun AshokBoja Poojary
Jun 20, 2007·Bioorganic & Medicinal Chemistry Letters·John L GilmoreJames J-W Duan
Jan 22, 2008·Journal of Medicinal Chemistry·Benoît M R LiénardChristopher J Schofield
Apr 29, 2008·European Journal of Medicinal Chemistry·Anelia Ts MavrovaPavletta Denkova
Jun 20, 2008·Organic & Biomolecular Chemistry·Benoît M R LiénardChristopher J Schofield
Jun 26, 2009·Bioorganic & Medicinal Chemistry·Dmitriy MinondPeter Hodder
Jul 28, 2009·Bioorganic & Medicinal Chemistry Letters·Yukiko HiraiwaToshiaki Kudo
Aug 6, 2009·Journal of the American Chemical Society·Robert M BreeceDavid L Tierney
Sep 22, 2009·RNA·Flore SinturelLionel Bénard
Jan 13, 2010·Clinical Microbiology Reviews·Sarah M Drawz, Robert A Bonomo
Feb 4, 2010·Journal of Medicinal Chemistry·Peter OelschlaegerJeffrey H Toney
Jun 10, 2010·Journal of Medicinal Chemistry·Patricia LassauxCarine Bebrone
Sep 18, 2010·Bioorganic & Medicinal Chemistry Letters·Lucie MaingotBenoit Deprez

❮ Previous
Next ❯

Citations

Oct 17, 2018·Expert Review of Anti-infective Therapy·Matthew W McCarthy, Thomas J Walsh
Oct 24, 2018·Antimicrobial Agents and Chemotherapy·Antonela R PalaciosAlejandro J Vila
Jan 25, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ahmed T A BoraeiAssem Barakat
Mar 30, 2019·Chemical Biology & Drug Design·Cheng ShiHeng Zheng
Oct 6, 2018·MedChemComm·Kamaleddin H M E Tehrani, Nathaniel I Martin
Oct 28, 2020·Journal of Biomolecular Structure & Dynamics·Y Sheena MaryB Narayana
Apr 24, 2018·Trends in Pharmacological Sciences·Lin-Cheng JuMichael W Crowder
Sep 17, 2020·European Journal of Medicinal Chemistry·Laurent GavaraJean-François Hernandez
Jun 12, 2021·Bioorganic Chemistry·Laurent GavaraJean-François Hernandez
Aug 19, 2017·ACS Infectious Diseases·Kamaleddin Haj Mohammad Ebrahim Tehrani, Nathaniel I Martin
Jan 20, 2018·ACS Medicinal Chemistry Letters·Francesca SpyrakisDonatella Tondi
Sep 8, 2018·Chemical Reviews·Allie Y ChenSeth M Cohen

❮ Previous
Next ❯

Related Concepts

Related Feeds

Beta-lactamase Inhibitors (ASM)

Beta-lactamase inhibitors are a class of antibiotics that inhibit beta-lactamases, a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. Here is the latest research.

Carbapenems

Carbapenems are members of the beta lactam class of antibiotics and are used for the treatment of severe or high-risk bacterial infections. Discover the latest research on carbapenems here.

Carbapenems (ASM)

Carbapenems are members of the beta lactam class of antibiotics and are used for the treatment of severe or high-risk bacterial infections. Discover the latest research on carbapenems here.

Beta-lactamase Inhibitors

Beta-lactamase inhibitors are a class of antibiotics that inhibit beta-lactamases, a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. Here is the latest research.