Arun C. Kaura

Penem inhibitors of bacterial signal peptidase

Abstract C(3)-Penem esters and amides having the (5S)-configuration at the bridgehead are inhibitors of Escherichia coli leader peptidase, the best activity being seen with a 6-(1-acetoxyethyl) derivative having the (5S, 6S, 8R)-stereochemistry. These compounds represent the first examples of potent inhibitors of bacterial signal peptidase.

Benzothiopyran-4-one based reversible inhibitors of the human cytomegalovirus (HCMV) protease

A novel class of CMV protease inhibitors based on a benzothiopyran-S,S-dioxide nucleus has been discovered. Enzyme kinetic data supports a reversible mode of inhibition for a representative member of this class, 2-(3-pyridyl-N-oxide)benzothiopyran-4-one-S,S-dioxide, 1. Experiments in the presence and absence of the disulfide reducing agent DTT suggest that the inhibition by 1 is not due to oxidative inactivation of the enzyme. Also presented are results of some SAR studies of the benzothiopyranone ring system.

SYNTHESIS OF 6-HYDROXY-2-METHYL-3-THIOXO-2H-1,2,4-TRIAZIN-5-ONE

Abstract The title compound has been prepared in three steps from 2-methylthiosemicarbazide following acylation, cyclisation and cation exchange chromatography. It was fully characterised by the usual spectroscopic means as well as by 15N nmr spectroscopy and X-ray crystallographic analysis.

Metal mediated protease inhibition: design and synthesis of inhibitors of the human cytomegalovirus (hCMV) protease.

A versatile synthetic route to a novel series of bis-imidazolemethanes designed to inhibit the hCMV protease has been developed and a series of potential metal binding inhibitors has been identified. In selectivity assays, the compounds were highly specific for CMV protease and showed no inhibition (IC50 > 100 microM) of other prototypical serine proteases such as trypsin, elastase, and chymotrypsin. Although the presence of free zinc ions was found to be an absolute requirement for the in vitro biological activity of this class of inhibitor, the potency of the inhibitors could not be improved beyond the micromolar level.

Novel Synthesis of 5-Amino-3-bromo-1-(tert-butyl)-1H-pyrazole-4-carbonitrile: A Versatile Intermediate for the Preparation of 5-Amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides

A simple, novel, and efficient route for the synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 has been devised. Preparation of pyrazole bromide 3 from potassium tricyanomethanide can be accomplished in only two steps in good yield and features a selective Sandmeyer reaction on the corresponding diaminopyrazole. This allows for a more versatile synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 than was previously possible.

Ozonolysis of ethylidene azetidinones; ozonide fragmentation to α-amino acid-N-carboxyanhydrides

Ozonolysis of α-ethylidene azetidinones (1) and (10) did not provide the expected α-oxoazetidinones, but afforded α-amino acid-N-carboxyanhydrides (3) and (11). Ozonolysis of α-ethylidene azetidinone (1) did not provide an oxoazetidinone (6) but gave the α-amino acid-N-carboxyanhydride (3).

Olivanic acid analogues. Part 11. Ozonolysis of α-ethylideneazetidinones: ozonide fragmentation to α-amino acid-N-carboxyanhydrides

Ozonolysis of (E)-7-ethylidene[3-oxa-1-azabicyclo[4.2.0]octane-2-spirocyclohexan]-8-one failed to provide the α-oxoazetidinone 2, but afforded an α-amino acid-N-carboxyanhydride [3,8-dioxa-1-azabicyclo[4.3.0]nonane-2-spirocyclohexane]-7,9-dione 5. [3-Oxa-1-azabicyclo[4.2.0]octane-2-spirocyclohexane]-7,8-dione 2 was instead obtained from the trans-ketone 9 by a sequence involving Baeyer–Villiger oxidation of the azido ketone 10.

A convenient large scale synthesis of 7α-formamido cephalosporins

Abstract The development of a convenient “one pot” synthesis of 7α-formamido ACA(12) from 7-ACA(2) via quinone methide methodology is described.

Design and synthesis of conformationally restricted eight-Membered ring diketones as potential serine protease inhibitors

The design of conformationally restricted eight-membered ring diketones as transition state mimics of the mechanism of action of cyclotheonamides on serine proteases is described. Two target compounds are prepared from mutilin, derived from the natural product pleuromutilin. Compound 3 shows significant inhibition of plasmin and urokinase in enzyme rate assays, but an analogue 4 in which the amide moiety has been omitted does not. An X-ray crystal structure of the diketone 3 confirms the conformational predictions made by molecular modelling.

Synthesis and antibacterial activity of two catechol-bearing penems

Abstract The penems ( 2 ) and ( 4 ), attached to a catechol group via an ester linkage at C-2, have been prepared and evaluated as antibacterial agents.