Hideaki Imamura

Dicationic dithiocarbamate carbapenems with anti-MRSA activity.

A new class of 1 beta-methylcarbapenems bearing a doubly quaternarized 1,4-diazabicyclooctane (DABCO) substituted dithiocarbamate moiety at the C-2 side chain was prepared, and the biological profiles of the compounds, including in vitro and in vivo anti-MRSA activity and DHP-I susceptibility, were evaluated to identify a carbapenem derivative that was superior to BO-3482 (1). As a result, we discovered a 1 beta-methyl-2-[4-(4-carbamoylmethyl-1,4-diazabicyclo[2,2,2]octanediium-1-yl)methyl-1,2,3,6-tetrahydropyridinylthiocarbonylthio]carbapenem, 14a showing greater than 2-fold better anti-MRSA activity in a mouse infection model and 3-fold better DHP-I susceptibility as compared with BO-3482 (1).

Enzymatic transformation of glyceroglycolipids into sn-1 and sn-2 lysoglyceroglycolipids by use of Rhizopus arrhizus lipase

Abstract Lipase from Rhizopus arrhizus catalyzed deacylation of two classes of glyceroglycolipids, monogalactosyl diacylglycerol(MGDG). and digalactosyl diacylglycerol(DGDG), proceeded regiospecifically to furnish sn-1 lysoglyceroglycolipids quantitatively. The lipase also catalyzed complete acyl migration of sn-1 lysoglycerogalactolipids leading to sn-2 lysoglycerogalactolipids.

In Vitro Activities of Novel trans-3,5-Disubstituted Pyrrolidinylthio-1β-Methylcarbapenems with Potent Activities against Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa

ABSTRACT The in vitro activities of the novel 1β-methylcarbapenems J-111,225, J-114,870, and J-114,871, which have a structurally unique side chain that consists of a trans-3,5-disubstituted 5-arylpyrrolidin-3-ylthio moiety at the C-2 position, were compared with those of reference antibiotics. Among isolates of both methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCoNS), 90% were inhibited by J-111,347 (prototype), J-111,225, J-114,870, and J-114,871 at concentrations of 2, 4, 4, and 4 μg/ml (MICs at which 90% of isolates are inhibited [MIC90s]), respectively, indicating that these agents were 32- to 64-fold more potent than imipenem, which has an MIC90 of 128 μg/ml. Although these drugs were less active in vitro than vancomycin, which had MIC90s of 1 and 2 μg/ml for MRSA and MRCoNS, respectively, the new carbapenems displayed better killing kinetics than vancomycin. The potent anti-MRSA activity was ascribed to the excellent affinities of the new carbapenems for penicillin-binding protein 2a of MRSA. Since the new carbapenems also exhibited good activity against gram-positive and -negative bacteria including clinically important pathogens such as penicillin-resistantStreptococcus pneumoniae, Haemophilus influenzae, members of the family Enterobacteriaceae,Pseudomonas aeruginosa, and Clostridium difficile, as well as MRSA, the novel carbapenems are worthy of further evaluation.

Stereoselective Synthesis of a Broad Spectrum 1β-Methylcarbapenem, J-114,870

Abstract An ultra-broad spectrum carbapenem, J-114,870 (1), was synthesized from the corresponding C-2 side chain and 1β-methylcarbapenem enolphosphate. Synthesis of the C-2 side chain was accomplished by installation of the benzene part to (4R)-hydroxy-2-pyrrolidone 3, affording 2-phenylpyrrolidine 8a, and asymmetric Michael addition of chiral amine to α,β-unsaturated ester derived from 8a.

Selective preparation of sn-1 and sn-2 lysogalactolipids by enzymatic hydrolysis using lipase (from Rhizopus arrhizus)

Abstract Selective and quantitative transformations of galactolipids into sn -1 and sn -2 lysogalactolipids by the use of lipase (from Rhizopus arrhizus ) were developed.

Structure–Activity Relationships of 1β-Methyl-2-(5-phenylpyrrolidin-3-ylthio)carbapenems

Structure--activity relationship studies of 1beta-methyl-2-[(3S,5R)-5-(4-aminomethylphenyl)pyrrolidin-3-ylthio]carbapenems, especially those pertaining to the relationship between antibacterial activity and side-chain structure were conducted. These studies suggested that the trans-(3S,5R)-5-phenylpyrrolidin-3-ylthio side-chain and the aminomethyl group at the 4-position of the phenyl ring play a key role in enhancing the antibacterial activity against the MRSA and Pseudomonas aeruginosa strains. In particular, the basicity of a substituent at the 4-position of the phenyl ring were shown to greatly contribute to the antibacterial activity against MRSA and methicillin-resistant Staphyloccocus epidermidis strains. In contrast, the amidine group was shown to lead to potent antibacterial activity against P. aeruginosa strains comparable to that of imipenem, however, a good correlation between the basicity of the 4-substituent and antipseudomonal activity was not observed. In conclusion, the 4-aminomethyl or methylaminomethyl group on the phenyl ring was the best substituent for antipseudomonal activity.

Discovery of novel trans-3,5-disubstituted pyrrolidinylthio-1β-methylcarbapenems

Novel trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems were designed and synthesized to provide J-111,347 (1a) as the first example of an exceptionally broad-spectrum antibiotic, showing activity against methicillin-resistant Staphyloccocus aureus (MRSA) as well as Pseudomonas aeruginosa. Further derivation of 1a afforded J-111,225 (2a), J-114,870 (3a), and J-114,871 (3b). which showed improved safety profiles and retained broad-spectrum antibacterial activities.

Structure–activity relationships of trans-3,5-disubstituted pyrrolidinylthio-1β-methylcarbapenems. Part 2: J-111,225, J-114,870, J-114,871 and related compounds

Through further derivatization of J-111,347 (1a), a trans-3,5-disubstituted pyrrolidinylthio-1β-methylcarbapenem, undesired epileptogenicity in a rat intracerebroventricular assay (200 μg/rat) could be eliminated to afford J-111,225 (2a), J-114,870 (3a) and J-114,871 (3b) which preserved comparable broad antimicrobial activity.