Thymidylate synthase (TS, ThyA) catalyzes the reductive methylation of 2'-deoxyuridine 5'-monophosphate to 2'-deoxythymidine 5'-monophosphate, an essential precursor for DNA synthesis. A specific inhibition of this enzyme induces bacterial cell death. As a second round lead optimization design, new 1,2-naphthalein derivatives have been synthesized and tested against a TS-based biolibrary, including human thymidylate synthase (hTS). Docking studies have been performed to rationalize the experimentally observed affinity profiles of 1,2-naphthalein compounds toward Lactobacillus casei TS and hTS. The best TS inhibitors have been tested against a number of clinical isolates of Gram-positive-resistant bacterial strains. Compound 3,3-bis(3,5-dibromo-4-hydroxyphenyl)-1H, 3H-naphtho[1,2-c]furan-1-one(5) showed significant antibacterial activity, no in vitro toxicity, and dose-response effects against Staphylococcus epidermidis (MIC = 0.5-2.5 mu g/mL) clinical isolate strains, which are resistant to at least 17 of the best known antibacterial agents, including vancomycin. So far this compound can be regarded as a leading antibacterial agent.

Antibacterial agent discovery using thymidylate synthase biolibrary screening / Costi, Maria Paola; A., Gelain; D., Barlocco; S., Ghelli; Soragni, Fabrizia; F., Reniero; Rossi, Tiziana; Ruberto, Ippazio Antonio; C., Guillou; A., Cavazzuti; Casolari, Chiara; Ferrari, Stefania. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 49:20(2006), pp. 5958-5968. [10.1021/jm051187d]

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