Laboratoire de Pharmacognosie, Université Paris Descartes, UMR/CNRS 8638, Faculté des Sciences Pharmaceutiques et Biologiques, 4 avenue de l'Observatoire, 75006 Paris, France.
Eur J Med Chem. 2010 Dec;45(12):5833-47. doi: 10.1016/j.ejmech.2010.09.048. Epub 2010 Oct 1.
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.
合成了抗分枝杆菌的 3,3-二甲基-3H-苯并呋喃[3,2-f][1]苯并吡喃的 8-、9-、10-和 11-卤代、羟基和甲氧基衍生物，方法是用 2-氯苯胺（13-17）的重氮盐与 1,4-苯醌（18）缩合，将中间体苯醌 19-22 还原为二羟基联苯，环化得到卤代-2-羟基二苯并呋喃 24-27，以及通过相应的二甲基炔丙基醚 35-38 的热重排构建吡喃环。钯催化的亲核芳香取代允许将卤代物转化为相应的羟基衍生物，然后将其甲基化得到甲氧基-3,3-二甲基-3H-苯并呋喃[3,2-f][1]苯并吡喃。在 A 环上取代的所有化合物都比对照化合物 1 对牛分枝杆菌 BCG 和毒力株结核分枝杆菌 H37Rv 更有效。为了证实对分枝杆菌细胞壁生物合成有影响的初步假设，研究了最活跃的衍生物对分枝菌酸合成的影响。具有良好抗分枝杆菌活性且无细胞毒性的线性 9-甲氧基-2,2-二甲基-2H-苯并呋喃[2,3-g][1]苯并吡喃（46）似乎是最有前途的化合物。
