Giuseppe Pagani

Modulation of penicillin acylase properties via immobilization techniques: one-pot chemoenzymatic synthesis of cephamandole from cephalosporin C

The modulation of penicillin G acylase (PGA) properties via immobilization techniques has been performed studying the acylation of 7-aminocephalosporanic acid with R-mandelic acid methyl ester. PGA from Escherichia coli, immobilized onto agarose activated with glycidol (glyoxyl-agarose), has been used for the design of a novel one-pot synthesis of Cephamandole in aqueous medium and without isolation of intermediates, through three consecutive biotransformations catalyzed by D-amino acid oxidase, glutaryl acylase and PGA.

Evaluation of different enzymes as catalysts for the production of β-lactam antibiotics following a kinetically controlled strategy

Abstract Several β-lactam acylases produced by different microorganisms ( Escherichia coli , Kluyvera citrophila , Acetobacter turbidans , and Bacillus megaterium ) have been evaluated as catalysts for the syntheses of relevant β-lactam antibiotics (ampicillin, cephalexin, and cefamandole). These enzymes displayed very different synthetic properties showing large differences in synthetic yields (by a 4- to 5-fold factor) depending on the antibiotic and the enzyme. The enzyme from A. turbidans presented the best properties for the synthesis of ampicillin, which is a low activity in the hydrolysis of the antibiotic and a high specificity for the transformation of the ester into antibiotic. Although this enzyme was able to transform approximately 80% of phenylglycine methyl ester into ampicillin, it was unsuitable for the synthesis of cephalexin and cefamandole. In fact, all of the enzymes showed significant hydrolysis rates of the antibiotics compared to the synthetic activity, although the enzyme from E. coli exhibited the highest specificity for the transformation of esters into these antibiotics. To prevent the hydrolysis of the antibiotic, a two-phase aqueous system was used to extract the antibiotic from the enzyme environment. In this way, high synthetic yields could be obtained, e.g. 80% of phenylglycine methyl ester was transformed into cephalexin using the enzyme from E. coli .

3H-[1,2]Dithiolo[3,4-b]pyridine-3-thione and its derivatives Synthesis and antimicrobial activity

A series of 2-substituted isothiazolo[5,4-b]pyridine-3(2H)-thiones, isothiazolo[5,4-b]pyridin-3(2H)-ones, N-substituted 2-sulfanylnicotinamides and the corresponding carbothioamide derivatives were synthesized and evaluated for their antimicrobial activity against several strains of Gram+ and Gram- bacteria and fungi. Chemical syntheses were resumed into a comprehensive cyclic route that enables the reversible conversion for each derivative of the series considered. Among the tested compounds the N-(aralkyl)-2-sulfanylnicotinamides show the highest fungitoxicity (MIC = 1.25-5 microg/ml). The best activity towards Gram-positive bacteria was in the range of 2.5-5 microg/ml. Activity against Gram-negative bacteria was generally very poor for all compounds.

Regioselective hydrolysis of peracetylated α-D-glucopyranose catalyzed by immobilized lipases in aqueous medium. A facile preparation of useful intermediates for oligosaccharide synthesis

Penta-O-acetyl-alpha-D-glucopyranose was selectively deacetylated in aqueous media by lipases from Candida cilindracea (CCL) adsorbed on octyl-agarose support. Enzymatic hydrolyses was regioselective at the 4-position under neutral pH and towards the 6 position under acidic conditions. This enzymatic approach allows the one step synthesis of 1,2,3,6-tetra-O-acetyl-alpha-D-glucopyranoses 1, a useful intermediate in oligosaccharide synthesis.

New N-alkyl-1,2-dihydro-2-thioxo-3-pyridinecarbothioamides as antituberculous agents with improved pharmacokinetics

Infections caused by multidrug-resistant Mycobacterium tuberculosis (MT) and non-tuberculous mycobacteria are difficult to treat and, indeed, new therapeutic agents are being sought. As a part of an ongoing research in our laboratories, novel N-alkyl-1,2-dihydro-2-thioxo-3-pyridinecarbothioamides have been synthesized and evaluated against several strains of MT and Mycobacterium avium complex (MAC). The pharmacokinetics and relative bioavailability after intravenous administration of three derivatives have been investigated. Introduction of a hydroxyl or a tertiary amino group in the N-alkyl chain resulted in an improved pharmacokinetic profile without affecting sensitively the antituberculous potency.

1,2-Dithiolan-3-ones and derivatives structurally related to leinamycin. Synthesis and biological evaluation

Leinamycin, an antitumor antibiotic isolated from Streptomyces sp., shows a 1,2-dithiolan-3-one 1-oxide heterocycle that appears to be involved in the biological activity. Several derivatives related to 1,2-dithiolan-3-one 1-oxide have been prepared and their activity as antineoplastic agents have been investigated. The synthesized compounds did not display a significative antitumor or cytotoxic activity in vitro.