Abstract

A new series of 1β-methyl carbapenems possessing a 6,7-disubstituted imidazo[5,1-b]thiazol-2-yl group directly attached to the C-2 position of the carbapenem nucleus was prepared, and the activities of these compounds against methicillin-resistant Staphylococcus aureus (MRSA) were evaluated. To study the effect of basic moieties on anti-MRSA activity, we introduced an amino, or imino, or amidino group at the 6-position of imidazo[5,1-b]thiazole in place of the carbamoylmethyl moiety of CP5068. Anti-MRSA activities of almost all basic group-substituted carbapenems were improved, though some of the compounds showed stronger acute toxicity in mice than IPM. In order to decrease the toxicity without decreasing the activity, we introduced various additional functionalities around the basic moiety. Finally, we obtained CP5484, which has excellent anti-MRSA activity and low acute toxicity.

Graphical abstract

A new series of 1β-methyl carbapenems possessing a 6,7-disubstituted imidazo[5,1-b]thiazol-2-yl group was prepared. Among them CP5484 showed potent anti-MRSA activity with reduced acute toxicity in mice. Further evaluaton of CP5484 is also reported.

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Keywords: Carpabapenem; MRSA; CP5484; Toxicity; Anti-MRSA activity

Article Outline

1. Introduction

2. Chemistry

3. Biological activity

4. Conclusion

5. Experimental

5.1. Chemistry

5.1.1. 4-Nitrobenzyl (1S,5R,6S)-2-[6-(2-azidoethyl)-7-methylthioimidazo[5,1-b]thiazolium-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate trifluoromethane-sulfonate (4a)

5.1.2. (1S,5R,6S)-2-[6-(2-Aminoethyl)-7-methylthioimidazo[5,1-b]thiazolium-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate hydrochloride (5a)

5.1.3. Compounds 5b–5g

5.1.4. (1S,5R,6S)-2-[6-(3-Formimidoylaminopropyl)-7-methylthioimidazo[5,1-b]thiazolium-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate hydrochloride (6a)

5.1.5. Compounds 6b and 6c

5.1.6. (1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-2-[6-(3-isothioureidopropyl)-7-methylthioimidazo[5,1-b]-thiazolium-2-yl]-1- methyl-1-carbapen-2-em-3-carboxylate hydrochloride (intramolecular salt) (8a)

5.1.7. Compounds 11a–g, 11i and 11j

5.1.8. 4-Nitrobenzyl(1S,5R,6S)-2-[6-((2R)-3-azido-2- triethylsilyloxy)propyl-7-methylthioimidazo[5,1-b]thiazolium-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate trifluoromethanesulfonate (10h)

5.1.9. (1S,5R,6S)-2-[6-((2R)-3-Amino-2-hydroxy)propyl-7-methylthioimidazo[5,1-b]thiazolium-2-yl]-6-((1R)-1-hydroxyethyl)-1- methyl-1-carbapen-2-em-3-carboxylate hydrochloride (11h, CP5484)

5.2. Antimicrobial activity in vitro

5.3. Efficacy in synthetic infection in mice

5.4. Acute toxicity test in mice

5.5. Pharmacokinetic parameters in mice

Acknowledgements

References