A new class of inhibitors of the two-component regulatory systems (TCS) of bacteria was discovered based on the salicylanilide screening hits, closantel (1) and tetrachlorosalicylanilide (9). A systematic SAR study versus a model TCS, KinA/Spo0F, demonstrated the importance of electron-attracting substituents in the salicyloyl ring and hydrophobic groups in the anilide moiety for optimal activity. In addition, derivatives 8 and 16, containing the 2, 3-dihydroxybenzanilide structural motif, were potent inhibitors of the autophosphorylation of the KinA kinase, with IC50s of 2.8 and 6. 3 µM, respectively. Compound 8 also inhibited the TCS mediating vancomycin resistance (VanS/VanR) in a genetically engineered Enterococcus faecalis cell line at concentrations subinhibitory for growth. Closantel (1), tetrachlorosalicylanilide (9), and several related derivatives (2, 7, 10, 11, 20) had antibacterial activity against the drug-resistant organisms, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF).
As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were significantly improved compared to those of the phase 2 development compound 9-(R).
A novel SERM (selective estrogen receptor modulators), 1-(R), a chromene-derived bisbenzopyran, was discovered to alleviate hot flushes and effectively increase vaginal fluidity in rats. Moreover, 1-(R) was found to have beneficial effects on plasma cholesterol and bone metabolism while maintaining antiestrogenic activity in the uterus. The biological profile of its enantiomer 1-(S) was also evaluated.
The photolysis of iodo aromatic compounds has been employed as the key step in new synthetic routes to aporphines. Photocyclization of l-(2'-iodobenzyl)-l,2,3,4-tetrahydroisoquinoline hydrochlorides (18, 19, 10, 11) yielded noraporphines 29 and 30 and aporphines 33 and 34 directly. Photocyclization of N-acyl-l-(2'-iodobenxyl)-1,2,3,4-tetrahydroisoquinolines (14-17) followed by hydrolysis gave noraporphines 25-28. Photolysis of urethanes 12 and 13 afforded substituted dehydronoraporphines 23 and 24, and two-step reduction gave (=I=)aporphine (33) and (&)-nuciferine (34). Photolysis of iV-carbophe1ioxy-l-(2'-iodobcnzyl)-1,2,3,4-tetrahydroisoquinolines 20 and 21 followed by one-step reduction afforded good yields of (A=)-aporphine (33) and (*)-nuciferine (34). The routes via photocyclimtion of N-acyl iodo aromatic compounds have yielded oxygenated aporphines and noraporphines in the best yields reported to date.
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