RESUMEN
A synthetic method to prepare bicyclo[6.3.0]undeca-2,4,9,trienyl esters efficiently from gold(I)-catalyzed Rautenstrauch rearrangement/1,5-hydride shift/8-endo-dig cyclization of 1-ene-4,10-diynyl esters is described. The suggested double cycloisomerization mechanism delineates the first example of an unactivated all-carbon tethered 1,7-enyne, either preformed or formed in situ, which undergoes an 8-endo-dig cyclization pathway to give a cyclooctane motif. It also offers an extremely rare synthetic method in organic chemistry that can sequentially assemble both ring components of the bicyclic motif from an acyclic precursor in one step.
RESUMEN
A synthetic method for the efficient assembly of benzo[c]carbazole derivatives that relies on silica gel-activated benzoic acid-mediated cycloaromatization of 1H-indol-2-yl propargyl benzoates under atmospheric conditions is described. Robust with a variety of substitution patterns tolerated, the reaction provides a one-step strategy to construct a member of the N-heterocycles family in good to excellent yields. A tentative mechanism is proposed in which the cycloaromatization process is thought to involve a Brønsted acid-mediated formal 1,3-acyloxy migration/6π-electrocyclization pathway.
RESUMEN
Tuberculosis (TB) remains a deadly disease and infects one-third of the world's population. Given the low success rates encountered in clinical development, there is an urgent need to identify structurally novel antimicrobials for tuberculosis. The present report details the anti-mycobacterial activities, structure-activity relationships (SARs) and mechanism of action of amphiphilic xanthone derivatives. The xanthones exhibited potent MIC, rapid time-kill and no cross-resistance with the current anti-TB drugs. Evidence is presented that these compounds disrupted the inner membrane and led to ATP depletion. Amphiphilic xanthone derivatives exhibited superior metabolic stability, low cytotoxicity and low activity against the common cytochrome P450. Compound 5 was selected for an in vivo pharmacokinetic study. Its bioavailability at an oral dose of 2 mg/kg was 15%. The xanthones thuse provide valuable insight for the development of a new class of membrane targeting antimycobacterial agents that may assist in overcoming the limitations of the current TB medications.
