Relationships Between the Chemical Structure of Antimycobacterial Substances and Their Activity Against Atypical Strains. Part 14: 3-Aryl-6,8-dihalogeno-2H-1,3-benzoxazine-2,4(3H)-diones

A set of eight derivatives of 6,8-dichloro-3-phenyl-2H-benzoxazine-2,4(3H)-dione and nine derivatives of 6,8-dibromo-3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dione, substituted on the phenyl ring, was prepared by the reaction of the corresponding salicylanilides with ethyl chloroformate. The compounds were evaluated in vitro for antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. Their activity increases with increasing hydrophobicity and electron-withdrawing ability of the substituents on the phenyl ring.     

A note on the antitubercular activities of 1-aryl-5-benzylsulfanyltetrazoles

A set of 32 1-phenyl-5-benzylsulfanyltetrazoles substituted on the phenyl ring as well as on the benzyl moiety was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis. The activity against M. tuberculosis becomes higher with increasing electron-accepting properties of the substituents on the phenyl ring. On the other hand, any substitution on the benzylic moiety decreases the activity.     

3-Tertiary amino-1-aryloxy- or aryl-propanes and -propan-2-ols and some related compounds.

The synthesis and pharmacological activity of some 3-tertiary amino-1-aryloxy- or 1-aryl-, 1-thiophenoxy and 1-anilino-propan-2-ols and -propanes, particularly those derived from N-phenylpiperazines are described. Effect of substituents (nature/position) on the phenyl ring, the phenoxy ring as well as alteration in the hydroxylic function vis-à-vis the structure-activity relationships (SAR) are discussed. In general, the 1-aryloxy compounds have hypotensive activity--this being more pronounced in those carrying an o-substituent on the phenyl ring, while m and p-substituted derivatives have their effect primarily on the CNS. Variations in the phenoxy moiety do not significantly alter the intrinsic activity. The 1-aryl compounds, on the other hand, have significant CNS activity, which is markedly affected by the substituents on the 1-aryl residue.     

Relationship between the structure and antimycobacterial activity of substituted salicylanilides

A series of 143 salicylanilides substituted in positions 4 and 5 and in positions 3' and 4' was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. To describe the structure-antimycobacterial activity relationships (QSARs), an approach based on the combination of the Free-Wilson and Hansch methods was employed (the substituent constants were used in the case of the substituents on the phenyl ring; indicator parameters were used for the substituents on the acyl moiety). The relationships between the antimycobacterial activity and physico-chemical parameters of all substituents were also explored. The quadratic representation of lipophilicity parameters did not lead to significant correlations.     

3-Benzyl-2H-1,3-benzoxazine-2,4(3H)-diones, a new group of antimycobacterial compounds against potentially pathogenic strains

A series of derivatives of 3-benzyl-2H-benzoxazine-2,4(3H)-dione substituted in positions 6, 7 or 8 on the benzoxazine, and in positions 3 or 4 on the benzyl moiety was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium avium and two strains of Mycobacterium kansasii. The disadvantage of the compounds is in their low solubility in water. The antimycobacterial activity of N-benzylsalicylamides correlates with that of 3-benzyl-2H-1,3-benzoxazin-2,4(3H)-diones and depends on the partition coefficients and electronic indexes.     

Structure-activity relationships of clonidine- and tolazoline-like compounds at histamine and alpha-adrenoceptor sites.

1 Thirty clonidine- and tolazoline-like compounds with differing phenyl ring substituents were tested for agonistic actions at histamine H1-receptors (guinea-pig ileum), histamine H2-receptors (guinea-pig driven right ventricular strips), post-junctional alpha-adrenoceptors (rat desheathed was deferens) and pre-junctional alpha-adrenoceptors (inhibition of sympathetic stimulation in guinea-pig driven left atria). 2 All compounds were inactive at histamine H1-receptors, while 21 of the 30 compounds displayed varying stimulant activity at H2-receptors. 3 At post-junctional alpha-receptors all 30 compounds produced stimulant actions, whereas at prejunctional alpha-receptors the compounds displayed either agonistic or antagonistic actions. 4 Thus structure-activity-relationships (SAR) could only be validated for histamine H2- and post-junctional alpha-receptor effects. These studies show that the most potent compounds are those with 2,6-phenyl substituents in which rotation is restricted so that the two rings are aplanar. Electronic effects of the substituents have a greater influence on activity at H2- than at alpha-receptors. 5 The major difference in SAR involves the influence of substituents in the 3, 4 or 5 positions on the phenyl ring. The presence of these substituents abolish significant activity at H2-receptors, while alpha-receptor stimulant activity is retained.     

Synthesis and Antiinflammatory Activity of 3-Substituted 4-(4′-Thiazolyl)-Sydnones

Sydnone derivatives with various substituents at C-4 of the phenyl ring and at C-2 of the thiazolyl ring were synthesised and tested for antiinflammatory activity. Five compounds have shown promising results.     

Synthesis and antiulcer activity of novel 5-(2-ethenyl substituted)-3(2H)-furanones.

In order to investigate new antiulcer agents, spizofurone 1 (AG-629) was fragmented and reassembled to generate 5-phenyl-2,2-dimethyl-3(2H)-furanone (bullatenone, 2). Because of the antiulcer activity of 2,5-phenyl-substituted 2,2-dimethyl-3(2H)-furanones (3-6) were made and shown to have poor activity. Insertion of an ethenyl link between the furanone and phenyl rings gave 5-(2-phenylethenyl)-2,2-dimethyl-3(2H)- furanone (7). This compound had better activity than 2. Compounds 8-41 were synthesized to evaluate the SAR in 5-(2-ethenyl substituted)-3(2H)-furanones. Electron-withdrawing substituents on the aromatic ring (8, 10, 19, and 20) gave 2-3-fold higher activity. Further increases in the activity were found when the phenyl ring was replaced by heterocyclic nuclei. Compounds that contained a thiophene (29), pyridine (24-26), or quinoline ring (32) had the best activity. Replacement of the methyl group on the furanone ring with a phenyl (34) or p-fluorophenyl (40) substituent in the 2-pyridine series gave compounds with activity that ranked with the best obtained in this study. The best compounds from the above SAR studies were evaluated in the ethanol-necrosis model for duration of cytoprotection action. Compounds 19, 24, and 29, which had the best duration of action, were tested with AG-629 in the acidified aspirin and indomethacin-induced lesion models. Only compound 24 had equivalent activity with AG-629 in both models.     

Synthesis of some 4-[3' or 4'-(4H- 4-oxo-1-benzopyran-2-yl)phenyl]-1,4-dihydropyridine derivatives as potential calcium channel antagonists

In this study, the synthesis of new flavonoid derivatives, which possess a 1,4-dihydropyridine (1,4-DHP) moiety on the phenyl ring of flavone were realized. 3' or 4'-Formyl-flavones were synthesized, then the aldehyde groups of these compounds were converted to the 1,4-DHP moiety by the Hantzsch method. A series of 23 new derivatives having different substituents at C-3 and C-5 of the 1,4-DHP ring were prepared. Two compounds (8a, 8b) were tested for their calcium channel blocker activity and 8b exhibited the best result.     

Structure-activity relationships of 6-hydroxy-7-methoxychroman-2-carboxylic acid N-(substituted)phenylamides as inhibitors of nuclear factor-kB activation

A series of 6-hydroxy-7-methoxychroman-2-carboxylic acid N-substitutedphenylamides (2a-n) were synthesized and their ability to inhibit nuclear factor-kappaB activity was evaluated in lipopolysaccharide (LPS)-stimulated macrophage RAW 264.7 cells. While compounds bearing -OH, or -OCH3 substituents were inactive, compounds with -CH3, -CF3, or -Cl substituents were potent inhibitors (IC50: 6.0-60.2 microM). The most active compound, 2n, contained a 4-Cl substituent on the phenyl ring and was four times more potent than the compound KL-1156.     

Synthesis, biological activity, and SAR of antimycobacterial 9-aryl-, 9-arylsulfonyl-, and 9-benzyl-6-(2-furyl)purines

9-Aryl-, 9-arylsulfonyl- and 9-benzyl-6-(2-furyl)purines were synthesized by N-alkylation or N-arylation of the purine followed by Stille coupling to introduce the furyl substituent in the 6-position and the compounds screened for activity against Mycobacterium tuberculosis. The 9-aryl- and 9-sulfonylarylpurines exhibited weak activity toward the bacteria, but 9-benzylpurines were good inhibitors especially those carrying electron-donating substituents on the phenyl ring. A chlorine atom in the purine 2-position further enhanced activity. The high antimycobacterial activity (MIC 0.39 microg/mL against M. tuberculosis), low toxicity against mammalian cells and activity inside macrophages found for 2-chloro-6-(2-furyl)-9-(4-methoxyphenylmethyl)-9H-purine makes this compound a highly interesting potential antituberculosis drug.     

Synthesis and antidepressant activity of 4-aryltetrahydrothieno[2,3-c]pyridine derivatives

A series of substituted 4-aryltetrahydrothieno[2,3-c]pyridines was prepared by acid-catalyzed cyclization of 1-aryl-2-[(2-thienylmethyl)amino]ethanol derivatives. The compounds were examined for their antidepressant activity, as demonstrated by their ability to inhibit the uptake of norepinephrine (NE) and serotonin (5-HT) and to prevent tetrabenazine-induced ptosis (TBZ) in mice. Significant inhibition of both neurotransmitters is observed for several of the tested compounds, while some of them are selective inhibitors of either NE or 5-HT uptake. Optimal activity is associated with the introduction of lipophilic substituents into the 4-position of the phenyl ring and less lipophilic substituents into the 2-position of the thiophene ring (11, 23). Compound 33 bearing substituents in positions 2 and 6 of the phenyl ring is inactive. This might be a consequence of an out of plane conformation of this compound.     

Stereochemical requirement at 4-position of 4-phenyl-1-arylsulfonylimidazolidinones for their cytotoxicities

In order to investigate the stereochemical requirements of planar structure at 4-position of 4-phenyl-1-arylsulfonylimidazolidinones (1) for their cytoxicities against human cancer cell lines, the size, the distance from imidazolidinone ring, and the conformation of this moiety were variegated. Replacement of phenyl moiety with naphthyl in compounds 2 and 3 or benzyl moiety in compound 4 sharply reduced activity of 1. Conformational restriction on phenyl ring in compound 5 also resulted in the loss of activity of 1. Therefore, phenyl moiety without any substituents directly attached to imidazolidinone ring of 1 should be considered as an essential pharmacophore for this analog.     

Methylenedioxy-benzopyran analogs of podophyllotoxin, a new synthetic class of antimitotic agents that inhibit tubulin polymerization

A new class of compounds was synthesized and, based on structural analogy to podophyllotoxin, examined as potential microtubule inhibitors and evaluated for in vivo antineoplastic activity. These agents are derivatives of methylenedioxy-benzopyran bearing a phenyl substituent at position 8. The hydrogen atoms at positions 7 and 8 are in a trans configuration, in contrast to the cis configuration of analogous hydrogen atoms at positions 1 and 2 in podophyllotoxin. Compounds with a variety of substituents at positions 6 and 7 were examined, as well as compounds with varying methoxy substituent patterns on the phenyl ring attached at position 8. The most active compounds inhibited tubulin polymerization at concentrations approximately stoichiometric with tubulin, competitively inhibited the binding of colchicine to tubulin, and caused mitotic arrest at cytotoxic drug concentrations. No structure-activity correlations were obvious for the substituents at positions 6 and 7, but optimal activity was only observed when the phenyl substituent at position 8 was a trimethoxybenzene ring identical to the analogous ring in podophyllotoxin (i.e. methoxy groups at positions 3', 4' and 5'). Despite their structural and functional similarities to podophyllotoxin, however, the methylenedioxy-benzopyran derivatives subtly differ from the natural product in their interaction with tubulin, for they stimulated rather than inhibited tubulin-dependent GTP hydrolysis.     

Photochemical study of hexahydroquinoline derivatives--a new group of calcium antagonists

The photochemical stability of 2,6,6-trimethyl-3-carbmethoxy-4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline (HHQ) derivatives with different substituents on the phenyl ring (-Cl, -NO2, -CF3, -CH3, -OCH3) has been studied. The process of photodegradation was studied by UV spectrophotometry. The rate of photodegradation was found to depend on the type and position of the substituent in the phenyl ring. The compounds most susceptible to the damaging effect of light proved to be those containing the nitro group, in particular with the substituent in the ortho position of the aromatic ring. Derivatives with alkyl (-CH3) and halo-alkyl (-CF3) substituents showed the greatest photochemical stability. The compounds with substituents in the ortho position were found to be much less photostable than the meta isomers. The quantum yield values obtained ranged from 10(-4) to 10(-3), indicating the occurrence of secondary photochemical processes initiated by the primary products of decomposition.     

Spectroscopic study of hexahydroquinoline derivatives--a potential group of calcium antagonists

Spectral properties of 2, 6, 6-trimethyl-3-carbmethoxy-4-phenyl-5-oxo -1,4,5,6,7,8-hexahydroquinoline derivatives (HHQ) with different substituents in the phenyl ring (-Cl, -NO2, -CF3, -CH3, -OCH3) have been studied. Their emission and absorption spectra have been analyzed and quantum yields of emission were determined. The quantum yield of emission was found to depend on the kind, number, and position of substituents in the phenyl ring: it was the highest for the chlorine derivatives of HHQ, and the lowest for the compounds containing -NO2 group.     

DDPH 衍生物α1-受体拮抗活性三维定量构效关系的研究

目的和方法应用计算机模拟Apex3D软件研究DDPH及其衍生物拮抗α1受体活性的三维定量构效关系。结果结果表明芳氧烷胺结构中芳环邻、对位取代对生物活性有重要影响。结论我们所构建的药效团和三维定量构效关系方程不仅能帮助理解药物与受体的相互作用,而且为设计活性更好的新化合物提供参考。     

Photochemical Study of Hexahydroquinoline Derivatives - A New Group of Calcium Antagonists

The photochemical stability of 2, 6, 6-trimethyl-3-carbmethoxy-4-phenyl-5-oxo-1, 4, 5, 6, 7, 8-hexahydroquinoline (HHQ) derivatives with different substituents on the phenyl ring (-Cl, -NO(2), -CF(3), -CH(3), -OCH(3)) has been studied.The process of photodegradation was studied by UV spectrophotometry. The rate of photodegradation was found to depend on the type and position of the substituent in the phenyl ring. The compounds most susceptible to the damaging effect of light proved to be those containing the nitro group, in particular with the substituent in the ortho position of the aromatic ring. Derivatives with alkyl (-CH(3)) and halo-alkyl (-CF(3)) substituents showed the greatest photochemical stability. The compounds with substituents in the ortho position were found to be much less photostable than the meta isomers. The quantum yield values obtained ranged from 10(-4) to 10(-3), indicating the occurrence of secondary photochemical processes initiated by the primary products of decomposition.     

Synthesis and biological evaluation of 2-amino-3-(4-chlorobenzoyl)-4-[N-(substituted) piperazin-1-yl]thiophenes as potent allosteric enhancers of the A1 adenosine receptor

The synthesis and evaluation of a series of 2-amino-3-(4-chlorobenzoyl)-4-[4-(alkyl/aryl)piperazin-yl]thiophene derivatives as allosteric enhancers of the A 1-adenosine receptor are described. The nature of substituents on the phenyl ring tethered to the piperazine seem to exert a fundamental influence on the allosteric enhancer activity, with the 4-chlorophenyl 8f and 4-trifluoromethyl 8j derivatives being the most active compounds in binding (saturation and displacement experiments) and functional cAMP studies.     

3-Phenyl-5-acyloxymethyl-2H,5H-furan-2-ones: synthesis and biological activity of a novel group of potential antifungal drugs

3-(Substituted phenyl)-5-acyloxymethyl-2H,5H-furan-2-ones related to the natural product (-)incrustoporine were synthesized and their in vitro antifungal activity evaluated. The compounds with halogen substituents on the phenyl ring displayed much higher antifungal effect against Aspergillus fumigatus than selected representatives of azole antifungal drugs. In particular, the activity (1.34 microg/mL) of the most promising derivative, 3-(3,4-dichlorophenyl)-5-pivaloyloxymethyl-2H,5H-furan-2-one, was comparable to that of amphotericin B (0.5 microg/mL). Preliminary evaluation of the toxicity of the compound was carried out as well. Considering the size and properties of these molecules in comparison with those of amphotericin B, further development of this novel group of antifungals may lead to substances with better pharmacological profiles than that of the standard anti-Aspergillus drug.