6-(Substituted methylene)penems, potent broad spectrum inhibitors of bacterial .BETA.-lactamase. V. Chiral 1,2,3-triazolyl derivatives.

Abstract

Structure-activity relationships in a series of (5i?)-6-triazolylmethylene penems with potent /Mactamase inhibitory activity are described. In most cases, their in vitro synergistic activity with amoxycillin is superior to that of clavulanic acid, sulbactam and tazobactam (YTR830). Against an Escherichia coli TEM-1infection in mice, the compoundsshowed a broad range of potencies; an optimum polarity was found, however, which gave maximumpotency.Earlier papers in this series1~4) have described the synthesis and biological properties of a series of racemic 6-(substituted methylene)penems. Of particular interest was the triazolylmethylene penem (5b), and this paper outlines some further work on a series of triazolyl derivatives with a chiral centre at C-5. ChemistryThe (5i?,6Z)penems (5) were prepared using two routes. Route A (Scheme 1) has been described for the preparation of 5b5) and is shown schematically in full elsewhere6): it requires a 1,2,3-triazolecarboxylic Scheme 1.

Pharmacological significance of triazole scaffold

“…This drug is marketed in combination with the broad spectrum antibiotic piperacillin and has turned out to be a potent β-lactamase inhibitor with higher potency than clavulanic acid and sulbactam. The triazole ring appears to play a very pivotal role for its potency [134,135]. Giffin et al reported a triazole containing compound (49) as an effective molecule against the single point protease inhibitor mutants, V82F, V82A, and G48V.…”

Synthesis, characterization and biological evaluation of 7-substituted- 4-((1-aryl-1H-1,2,3-triazol-4-yl) methyl)-2H-benzo[b][1,4]oxazin- 3(4H)-ones as anticancer agents

“…In particular, by combining 1,2,3-triazoles with other pharmacophore via click chemistry, a number of compounds with potent biological active compounds were synthesized (Stefely et al, 2010;Reddy et al, 2011;Singh et al, 2012). 1,2,3-triazole moiety containing drug molecules such as tazobactam (Bennet et al, 1991), cefatrizine (Stilwell et al, 1975) and carboxyamidotriazole (Soltis et al, 1996) are available (Fig. 2).…”

ZnO nanoparticles-mediated regioselective synthesis of methyl-N-alkylated 1,2,3-triazole-4-carboxylates

“…Russell et al identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo [3,4-a] phthalazines as potent partial agonists of the a 3 receptor subtype with fivefold selectivity in binding affinity over the a 1 receptor. Triazole-based compounds are known to be involved in many biochemical processes [14][15][16][17], and a wide range of 1,2,3-triazole-derived compounds are important to medicinal, agricultural, and organic chemists. The N-substituted aziridines are versatile intermediates of many biologically active compounds [18].…”