Synthesis of naphtho[2,3- a]phenoxazinium chlorides: Structure–activity relationships of these heterocycles and benzo[ a]phenoxazinium chlorides as new antimicrobials

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 6; pp. 3274 - 3282
• Main Authors: Frade, Vânia H.J., Sousa, Maria J., Moura, João C.V.P., Gonçalves, M. Sameiro T.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15-03-2008; Elsevier Science
• Subjects: Amino Acids - chemistry; Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal activity; Antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - pharmacology; Benzo[ a]phenoxazines; Biological and medical sciences; Cross-Linking Reagents - chemistry; Functionalised probes; Long-wavelength fluorescent dyes; Medical sciences; Microbial Sensitivity Tests; Naphtho[2,3- a]phenoxazinium salts; Oxazines - chemistry; Oxazines - pharmacology; Pharmacology. Drug treatments; Saccharomyces cerevisiae - drug effects; Spectrometry, Fluorescence; Structure-Activity Relationship; Naphtho[2,3- a]phenoxazinium salts; Functionalised probes; Antifungal activity; Benzo[ a]phenoxazines; Long-wavelength fluorescent dyes; Ascomycota; Pentacyclic compound; Benzo[a]phenoxazines: Antifungal activity; Aminoalcohol; Organic cation; Tetracyclic compound; In vitro; Fungi; Diamine; Antifungal agent; Aminoester; Structure activity relation; Carboxylic acid; Aminoacid; Aromatic compound; Naphtho[2,3-a]phenoxazinium salts; Fluorescent compound; Chemical synthesis; Saccharomyces cerevisiae; Aromatic amine; Oxygen nitrogen heterocycle
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.12.013

Synthesised functionalised naphtho[2,3-
a]phenoxazinium chlorides revealed great fluorescence with maximum emission wavelengths between 630 and 676
nm, in ethanol and water at physiological pH. Naphtho[2,3-
a]phenoxazines, as well as a series of benzo[
a]phenoxazines, were evaluated against
Saccharomyces cerevisiae, in a broth microdilution assay. This family of compounds exhibited antifungal activity depending both on the substituents of the heterocycle nucleus as well as on its size. The best activities were obtained for four-ring systems, and particularly for 5,9-diaminobenzo[
a]phenoxazines with R
=
Me, R
1
=
H and R
2
=
Et. As for R
3 substitution, the greatest efficiency was obtained for R
3
=
(CH
2)
3Cl, with a MIC of 3.75
μM. The linkage of different amino acids to the functional group of the 5-amino position of diaminobenzo[
a]phenoxazinium moiety resulted in compounds with diverse antimicrobial efficiencies, depending on the polar character of the amino acid, on its linkage position and on the size of the alkyl chain linker.