Synthesis, biological activity, and evaluation of the mode of action of novel antitubercular benzofurobenzopyrans substituted on A ring.
The 8-, 9-, 10-, and 11-halo, hydroxy, and methoxy derivatives of the antimycobacterial 3,3-dimethyl-3H-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-3H-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-2H-benzofuro[2,3-g][1]benzopyran (46) exhibiting a good antimycobacterial activity and devoid of cytotoxicity appeared to be the most promising compound.
Laboratoire de Pharmacognosie, Université Paris Descartes, UMR/CNRS 8638, Faculté des Sciences Pharmaceutiques et Biologiques, 4 avenue de l'Observatoire, 75006 Paris, France.
Aikaterini
A
Termentzi
Inana
I
Khouri
Thomas
T
Gaslonde
Soizic
S
Prado
Brigitte
B
Saint-Joanis
Fabienne
F
Bardou
Elsa P
EP
Amanatiadou
Ioannis S
IS
Vizirianakis
Jana
J
Kordulakova
Mary
M
Jackson
Roland
R
Brosch
Yves L
YL
Janin
Mamadou
M
Daffé
François
F
Tillequin
Sylvie
S
Michel
D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology*; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002522:Chlorocebus aethiops; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009163:Mycobacterium bovis / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014709:Vero Cells
D000995:Antitubercular Agents; D001572:Benzofurans; D001578:Benzopyrans