Amidinoquinoxaline N-oxides: synthesis and activity against anaerobic bacteria

Abstract

We present herein an in-depth study on the activity of amidinoquinoxaline N-oxides 1 against Gram-positive and Gram-negative anaerobic bacteria. Based on 5-phenyl-2,3-dihydropyrimidoquinoxaline N-oxide 1a, the selected structural variations included in our study comprise the substituents α- to the N-oxide function, the benzofused ring, substitution and quaternization of the amidine moiety, and the amidine ring size. Compounds 1 showed good to excellent antianaerobic activity, evaluated as the corresponding CIM₅₀ and CIM₉₀ values, and an antimicrobial spectrum similar to metronidazole. Six out of 13 compounds 1 had CIM₉₀ values significantly lower than the reference drug. Among them, imidazoline derivatives 1i-l were the most active structures. Such compounds were synthesized by base-promoted ring closure of the corresponding amidines. The N-oxides under study showed no significant cytotoxicity against RAW 264.7 cells, with high selectivity indexes. Their calculated ADME properties indicate that the compounds are potentially good oral drug candidates. The antianaerobic activity correlated satisfactorily with the electron affinity of the compounds, suggesting that they may undergo bioreductive activation before exerting their antibacterial activity.

Fig. 1. Amidinoquinoxaline N-oxides 1 and their quaternary salts 2.

Scheme 1. Synthesis of amidinoquinoxaline N-oxides 1.

Scheme 2. Synthesis of amidinium salts 2a–c.

Scheme 3. Probable base-promoted cyclodehydration mechanism.

Fig. 2. Relationship between calculated electron affinity and log CIM₉₀ for C. difficile. Six-membered ring amidines are shown in blue, five-membered analogues in orange and the 7-membered ring nitrone in violet; quaternary salts are in green.