Synthesis, biological activity, and evaluation of the mode of action of novel antitubercular benzofurobenzopyrans substituted on A ring

• Published in: European journal of medicinal chemistry Vol. 45; no. 12; pp. 5833 - 5847
• Main Authors: Termentzi, Aikaterini, Khouri, Inana, Gaslonde, Thomas, Prado, Soizic, Saint-Joanis, Brigitte, Bardou, Fabienne, Amanatiadou, Elsa P., Vizirianakis, Ioannis S., Kordulakova, Jana, Jackson, Mary, Brosch, Roland, Janin, Yves L., Daffé, Mamadou, Tillequin, François, Michel, Sylvie
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.12.2010; Elsevier
• Subjects: 3,3-Dimethyl-3 H-benzofuro[3,2- f]benzopyran; Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimycobacterials; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Benzofurans - chemical synthesis; Benzofurans - pharmacology; Benzopyrans - chemical synthesis; Benzopyrans - pharmacology; Biological and medical sciences; Cell Death - drug effects; Cercopithecus aethiops; Chemistry, Medicinal; Life Sciences & Biomedicine; Medical sciences; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium bovis - drug effects; Mycobacterium tuberculosis - drug effects; Mycolates; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Vero Cells; Antimycobacterials; Mycolates; Structure-activity relationship; 3,3-Dimethyl-3 H-benzofuro[3,2- f]benzopyran; MYCOBACTERIUM-TUBERCULOSIS; ANTIMYCOBACTERIAL; MECHANISM; 3,3-Dimethyl-3H-benzofuro[3,2-f]benzopyran; ANTITUMOR-ACTIVITY; MYCOLIC ACID SYNTHESIS; SYNTHASE; INHIBITION; COUPLING REACTIONS; BIOSYNTHESIS; FATTY-ACID; 3,3-Dimethyl-3H-benzofuro[3,2-f] benzopyran; Mycobacterium bovis; Tetracyclic compound; Oxygen heterocycle; In vitro; Mycobacterium tuberculosis; Structure activity relation; Mycobacteriales; Mycobacteriaceae; Bacteria; Actinomycetes; Antituberculous agent; Aromatic compound; Antibacterial agent; Mechanism of action; Chemical synthesis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2010.09.048

The 8-, 9-, 10-, and 11-halo, hydroxy, and methoxy derivatives of the antimycobacterial 3,3-dimethyl-3 H-benzofuro[3,2- f][1]benzopyran were synthesized by condensation of the diazonium salts of 2-chloroanilines ( 13– 17) with 1,4-benzoquinone ( 18), reduction of the intermediate phenylbenzoquinones 19– 22 to dihydroxybiphenyls, cyclisation to halo-2-hydroxydibenzofurans 24– 27, and construction of the pyran ring by thermal rearrangement of the corresponding dimethylpropargyl ethers 35– 38. Palladium catalyzed nucleophilic aromatic substitution permitted conversion of the halo to the corresponding hydroxy derivatives which were methylated to methoxy-3,3-dimethyl-3 H-benzofuro[3,2- f][1]benzopyran. All compounds substituted on the A ring were found more potent than the reference compound 1 against Mycobacterium bovis BCG and the virulent strain Mycobacterium tuberculosis H37Rv. The effect of the most active derivatives on mycolate synthesis was explored in order to confirm the preliminary hypothesis of an effect on mycobacterial cell wall biosynthesis. The linear 9-methoxy-2,2-dimethyl-2 H-benzofuro[2,3- g][1]benzopyran ( 46) exhibiting a good antimycobacterial activity and devoid of cytotoxicity appeared to be the most promising compound. Halo, hydroxy, and methoxy derivatives of 3,3-dimethyl-3 H-benzofuro[3,2- f][1]benzopyran were synthesized and tested against Mycobacterium bovis and Mycobacterium tuberculosis. Effect of the most active derivatives on mycolate synthesis was explored. [Display omitted]