Yang-I Lin

Muraymycins, novel peptidoglycan biosynthesis inhibitors: semisynthesis and SAR of their derivatives.

Sixteen muraymycin derivatives 2-17 were synthesized based on selective reactions of the primary and secondary amino groups of muraymycin C1 (1) with isocyanates and aldehydes. Disubstituted derivatives 3-9 demonstrated no activity against either MraY or MurG at <or=100 microg/mL whereas mono substituted derivatives 11-17 demonstrated good inhibitory activity, well correlated with the lipophilicity of the substituent introduced. In particular, the activity of derivatives 13 and 14 was comparable to that of muraymycin C1 in this assay.

2-Phenyl-5,6-dihydro-2H-thieno[3,2-c]pyrazol-3-ol derivatives as new inhibitors of bacterial cell wall biosynthesis

Twenty-five 2-phenyl-5,6-dihydro-2H-thieno[3,2-c]pyrazol-3-ol derivatives were synthesized for evaluation as new inhibitors of bacterial cell wall biosynthesis. Many of them demonstrated good inhibitory activity against Staphylococcus aureus MurB, MurC and MurD enzymes in vitro and antimicrobial activity against gram-positive bacteria including MRSA, VRE and PRSP. However, when they were tested in the presence of 4% bovine serum albumin, the MIC values increased to greater than 128 microg/mL against PRSP. None of the compounds demonstrated activity against gram-negative bacteria at MIC <32 microg/mL.

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.

Preparation of novel tricyclic diazo carbapenems: Application of inverse electron demand Diels-Alder reactions of 3,6-bis(methylthio)-1,2,4,5-tetrazine

Abstract The syntheses of novel tricyclic diazo carbapenem precursor 17 , and the deprotected carbapenems 2 and 3 are described. The construction of the tricyclic carbapenem was accomplished by an intramolecular nucleophilic substitution of the diazine sulfone 16 which was obtained from an inverse electron demand Diels-Alder reaction of the alkynyl azetidinone 13 with 3,6-bis(methylthio)-1,2,4,5-tetrazine (4) .

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.