Panayota Bitha

6-(1-hydroxyalkyl)penam sulfone derivatives as inhibitors of class a and class C β-lactamases I

Two stereoselective processes for the synthesis of novel 3,6-disubstituted penam sulfone derivatives were developed. One 6beta-(1-hydroxyethyl) and four 6beta-hydroxymethyl penam sulfone derivatives were synthesized. All four 6beta-(hydroxymethyl)penam sulfone derivatives demonstrated good IC50 against both TEM-1 and AmpC beta-lactamases. Of these, 6beta-hydroxymethyl penam sulfone derivative 25 was the most active inhibitor which was able to restore the activity of piperacillin in vitro and in vivo against both TEM-1 and AmpC beta-lactamases producing organisms.

Synthesis of (alkoxycarbonyloxy)methyl, (acyloxy)methyl and (oxodioxolenyl)methyl carbamates as bioreversible prodrug moieties for amines

Abstract Synthesis of (alkoxycarbonyloxy)methyl carbamates of secondary amines was developed, and it was extended to (acyloxy)methylation of benzylmethylamine and (oxodioxolenyl)methylation of benzylamine, benzylmethylamine, and L-phenylalanine.

Peptidic prodrugs of novel aminomethyl-THF 1β-methylcarbapenems

Abstract Peptidic prodrugs of the five most active aminomethyl-THF 1β-methylcarbapenems were synthesized. Of these, only L-amino acid derivatives from 1a demonstrated an improved oral activity. These results indicate that the L-amino acid derivatives from 1a are orally absorbed most likely through the dipeptide and tripeptide transport mechanism.

Synthesis and structure-activity relationships of novel THF 1β-methylcarbapenems II

Abstract A series of twelve highly active aminomethyl-THF 1β-methylcarbapenems 3a-1 were synthesized. Of these, carbapenems 3a-f demonstrated a spectrum of antimicrobial activity comparable to those of imipenem and meropenem with the exception of only moderate anti-pseudomonal activity. Most importantly, they demonstrated moderate intrinsic oral activity against an E. coli infection in mice.

An intramolecular addition-elimination strategy for the synthesis of carbapenems

Abstract The synthesis of 2-[(4-fluorophenylsulfonyl)methyl] carbapenem carboxylate 20 is described. The key step is a base mediated addition-elimination ring closure of a iodovinyl sulfone 12.

Synthesis and structure-activity relationships of some novel oxetane carbapenems

Six disubstituted oxetane carbapenems were synthesized and their antibacterial profile compared with the lead amino methyl THF carbapenem as well as imipenem. The oxetane carbapenems had comparable or less activity against the Gram(−) bacteria and had reduced activity against Gram(+) bacteria in comparison with imipenem and the THF carbapenem CL 191, 121, but were highly stable to hydrolysis by hog kidney dehydropeptidase (DHP).

Mono and bis double ester prodrugs of novel aminomethyl-THF 1β-methylcarbapenems

Mono and bis double ester prodrugs of aminomethyl THF 1β-methylcarbapenems 1 were synthesized. Mono double ester derivatives (2, 4 and 7) did not demonstrate significantly improved oral activity due to the presence of the charged species. However, bis double ester derivatives (3 and 5) demonstrated enhanced oral activity.

Suppression of Ethyl Migration in the Synthesis of 2,5-Anhydro-1-Amino-1,4-Dideoxy-3-Thio-D-Threo-Pentitol Hydrochloride, A Key Intermediate for Oral the 1β-Methylcarbapenems

Abstract A reproducible synthesis of 2,5-anhydro-1-amino-1,4-dideoxy-3-thio-D-threo-pentitol hydrochloride (2b) via the Staudinger reaction with triethyl phosphite was developed. An unexpected ethyl migration from an oxygen to the nitrogen of iminophosphorane 7 was observed.

EFFICIENT SYNTHESIS OF ORAL THF 1β-METHYLCARBAPENEM (OCA-983) VIA THE WITTIG PROCESS

An efficient and reproducible synthesis of orally active 2-tetrahydrofuranylthio-1β-methylcarbapenem 16 (OCA-983) via the Wittig process was developed. The intramolecular reductive cyclization of the thioester-oxalimide 13 with triethyl phosphite to the 2-tetrahydrofuranylthio-1β-methylcarbapenem 14 was carried out in two steps in order to obtain a reproducible yield.