6-(Substituted methylene)penems, potent broad spectrum inhibitors of bacterial .BETA.-lactamase. III. Structure-activity relationships of the 5-membered heterocyclic derivatives.

Abstract

Sodium (5i?S)-Z-6-(heterocyclylmethylene)penem-3-carboxylates(2) are a series of extremely potent inhibitors of bacterial /Mactamases. A variety of 5-membered heteroaromatic derivatives have been prepared and structure-activity studies reveal a preferred substituent orientation. One of these derivatives, the 1-methyl-1,2,3-triazolyl compound (5m) is a more potent synergist of amoxycillin than clavulanic acid, sulbactamor tazobactam. 331 Earlier papers1>2) have described the synthesis and biological properties of a series of racemic 6-(substituted methylene)penems. Of particular interest was the 2-furyl derivative (1) which had the Z configuration about the C-6-C-8 double bond and was unsubstituted at the 2-position2). This paper outlines some of the further work on a series of penems (2) in which we sought to investigate the effect of varying aromatic heterocyclic substituents on the biological properties of the series. A number of 5-membered heterocycles have been synthesised and someconclusions on structure-activity relationships within this group of derivatives are presented. ChemistryThe Z-isomers (4a~4q) were prepared in excellent yield by treating the 2-unsubstituted penem acetates (3a~3q)3) with l ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at low temperature. Removal of the/>-nitrobenzyl (PNB) protecting group was readily achieved by hydrogenolysis over palladium on carbon followed by treatment with sodium hydrogen carbonate. The resulting sodium salts (5a~5q) were obtained as homogeneousfreeze-dried solids after chromatography on Biogel P2.The UV spectra of the penems (5a~5q) implied a degree of n orbital overlap between the aromatic heterocyclic ring and the exocyclic double bond consistent with a coplanar conformation. Molecular models suggested that in compounds bearing either a substituent or a proton at position 4' (see Fig. 1) conformation A could sshow fewer non-bonded interactions between the heterocycle and the penem nucleus than conformation B. Support for this view was also obtained from *HNMR data on someof these compounds (4g, 4j and 5m). NOE's were observed between the heterocyclic ring proton (4'-H) and both 8-H and 5-H. The results of the experiments are shown in Table 1 and may be interpreted as indicating a fast equilibrium between conformers A and B. Furthermore the differences in internuclear distances and the ratio of A :B from the NOEstudies imply that A is the major conformer4).

A copper(ii)–thioamide combination as a robust heterogeneous catalytic system for green synthesis of 1,4-disubstituted-1,2,3-triazoles under click conditions

“…1 shows representative bioactive 1,2,3-triazole-containing drugs. [7][8][9][10][11] Developing more efficient methods for the construction of compounds containing triazoles is a topic of immense importance. The synthesis of 1,2,3-triazoles strongly relies on copper(I)-catalyzed azide-alkyne [3 + 2] Huisgen cycloaddition reaction (CuAAC reaction) which is the best 'click' reaction to date, due to its wide range of applications in chemistry, biochemistry and polymer chemistry.…”

Cu(I)‐Catalyzed Regioselective and Highly Efficient One‐Pot Synthesis of Novel 1,2,3‐Triazoles Decorated with Pyridine and Heterocyclic Amines

“…It has also been demonstrated earlier that incorporation of 1,2,3‐triazole ring in a known drug often enhances its potential applications. For example, tazobactum and related triazole‐containing compounds are more potent s ‐lactamase inhibitor than clavulanic acid and sulbactam . Pyrimidine nucleosides have been studied as antiviral agents; however, introduction of triazoles in place of pyrimidine led to the compounds that showed both antiviral as well as cytotoxic activity .…”

Applications of Click Chemistry in Radiopharmaceutical Development

“…[10,11] The triazole moiety is also present in a commercially available b-lactamase inhibitor, tazobactam, as well as other triazole based b-lactamase inhibitors whose high potencies are credited to the triazole functional group. [12,13] Triazoles have been described as non-traditional amide bioisosteres and are typically substituted for potentially labile functional groups such as esters or amides. [10] Click chemistry has been demonstrated to be an efficient tool for in situ library screening as well as discovery high affinity ligands using in situ click chemistry.…”