Nonsteroidal antiinflammatory agents. 2. [(Heteroarylamino)phenyl]alkanoic acids

A series of [(heteroarylamino)phenyl]alkanoic acids having pyridine, quinoline, or pyrimidine as the heteroaryl moiety was prepared as potential antiinflammatory agents. Among them, 2-[4-(2-pyridylamino)phenyl]propionic acid (14b) showed excellent antiinflammatory and analgesic activities with less tendency to cause gastric side effects. Structure-activity relationships are discussed.     

Synthesis of new triazolyl-N,N-Dialkyldithiocarbamates as antifungal agents

N,N-Dialkylditihiocarbamate derivatives have been well known as broad-range fungicides. In this study, the triazole derivatives of ten new N,N-disubstituted dithiocarbamates (3a-j) were synthesized and their structures were identified by spectral and elemental analysis. Results of the antifungal activity studies showed that some of the compounds tested were active against M. canis, M. gypseum, and T. rubrum at the concentration of 12.5 microg/mL when clotrimazol was used as a standard.     

Evaluation of some classical hydrazones of ketones and 1,2-diketones as antileishmanial, antibacterial and antifungal agents

The paper describes the synthesis and antimicrobial (antileishmanial, antibacterial and antifungal) activity of some classical hydrazones of benzophenones and of 1,2-diketones. N-(Diaryl) acyl derivatives of these hydrazones have also been synthesized and evaluated. 4,4,-Demthoxybenzil monohydrazone and 4,4'-dimethoxybenzophenone hydrazone showed significant antileishmanial activity. The effect of substituents on the bioactivity is discussed.     

Patent Evaluation: Tricyclic-ylidene acetic acids as anti-eosinophil agents

Summary

Novelty: Compounds potentially useful in the treatment of disorders resulting from eosinophil accumulation/activation are disclosed (e.g. obstructive and inflammatory airway diseases, allergic and non-allergic eosinophil-related conditions).

Biology: Suppression of eosinophil accumulation is measured in guinea pigs; the animals are sensitized to ovalbumin and challenged via administration of a 0.1% ovalbumin nebulized solution. Preferred compounds significantly reduce eosinophil accumulation (relative to controls) at 10–50 mg/kg/day via inhalation or sc administration. The efficacy of the compounds in pneumoconiosis/bronchitis and other eosinophil related disorders is measured in clinical studies. Preferred embodiments of the invention result in improved lung function and reduced eosinophil counts.

Chemistry: The use of the (Z)-isomer of α-[10-oxy-4H-benzo[4,5]cycloheptal[1,2-b]-thiophen-4-ylidene]-acetic acid is specifically claimed and is one of eleven compounds exemplified. Preparative details are not presented.     

Patent Evaluation: Trisubstituted tetrahydrofuran antifungal agents

Summary

Novelty: Novel tri-substituted tetrahydrofurans, stated to have potential utility as antifungal agents, are disclosed.

Biology: A range of in vivo rodent studies demonstrating pharmacological efficacy are presented. These include evaluation of antifungal activity using an Aspergillus pulmonary infection model. Oral treatment (100mg/kg/day) was initiated 24 hours post-infection and maintained for 4 days. A preferred test compound was found to have greater antifungal activity than itraconazole, fluconazole and saperconazole. Results are presented in figures.

Chemistry:(-)-[(5R)-cis]-4-[4-[4-[4-[[5-(2-4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl) tetrahydofuran-3-yl]methoxy]phenyl-1-piperazinyl]phenyl]-2,4-dihydro-2[(S)-(1-methylpropyl)]-3H-1,2,4,-triazol-3-one is one of thirty compounds specifically exemplified. Full preparative details using standard techniques are presented.     

Design, synthesis, and testing of potential antisickling agents. 10. (2,2-Dimethylchroman-6-yl)alkanoic acids

Five (2,2-dimethylchroman-6-yl)alkanoic acids were synthesized and tested for antigelling activities. It was envisioned that these agents might bind via hydrophobic bonding to nonpolar sites of the "donor-acceptor" regions of hemoglobin S. Several (2,2-dimethylchroman-6-yl)alkanoic acids containing 1-4 carbon atoms on the side-chain residue were designed to interact at the acceptor site, were synthesized, and were found to be moderately potent antigelling agents. The weak activity observed for two of the acids at low concentrations is rationalized in terms of weak binding affinities or multiple binding to active and nonactive sites. The effect of these compounds on shifting the allosteric equilibrium was small or negligible. The low toxicity of one of the (2,2-dimethylchroman-6-yl)alkanoic acids demonstrates the potential use of yet another class of compounds that can be modified in the development of antisickling agents.     

Compounds with positive inotropic activity, III: Synthesis of 4-aminoquinoline derivatives as potential positive inotropic agents

Anilinoacrylic acid derivatives 2-4 are the key intermediates from which 1-alkyl substituted 4-aminoquinoline 10-15 as well as 4-alkylaminoquinoline derivatives 16-23 are synthesized and examined for positive inotropic activity on isolated left atria and papillary muscles from guinea-pig. Structure activity relationships indicate that the effect depends on the alkyl side chain of the target compounds.     

Substituted (aryloxy)alkanoic acids as antagonists of slow-reacting substance of anaphylaxis

A series of compounds in which the 4-acetyl-3-hydroxy-2-propylphenoxy moiety of the standard SRS-A antagonist, FPL-55712, is linked by a polymethylene or a polyether chain to substituted (aryloxy)alkanoic acids was prepared. The compounds were evaluated for their ability to antagonize SRS-A-induced contractions of guinea pig ilea and LTE-induced bronchoconstriction in the guinea pig. The results showed that the compounds were all less potent than FPL-55712 in vitro, yet surprisingly, most were more potent by the inhalation route of administration. Some of the most potent analogues were selected for further pharmacological evaluation and, by inhalation, exhibited selective antagonism of leukotrienes as compared with PAF or histamine. In comparison to FPL-55712, compounds 28 and 37 were more potent against LTE (40- and 80-fold, respectively), LTD (4- and 3-fold, respectively), and LTC (27- and 20-fold, respectively) induced bronchoconstriction when tested by inhalation.     

5-Nitroimidazole derivatives as possible antibacterial and antifungal agents

Some novel 1-[2-[[5-(2-furanyl)-4-substituted 4H-1,2,4-triazol-3-yl[thio[ethyl[-2-methyl-5-nitro-1H-imidazoles (3), 1-[3-[[5-(2-furanyl/2-thienyl)-4-substituted 4H-1,2,4-triazol-3-yl[-thio]-2-hydroxypropyl[-2-methyl-5-nitro-1H- imidazoles (5) and 1-[3-[(N,N-disubstituted thiocarbamoyl)-thio[-2-hydroxypropyl]-2-methyl-5-nitro-1H-imidazoles (7) were synthesized and evaluated for in vitro antibacterial and antifungal activity. Some of 5 were found to be effective against bacteria and fungi (minimum inhibitory concentration (MIC) 7.3-125 micrograms/ml), whereas 7 were found to be effective against fungi (MIC 3-25 micrograms/ml).     

Synthesis of new thiazolylthiazolidinylbenzothiazoles and thiazolylazetidinylbenzothiazoles as potential insecticidal, antifungal, and antibacterial agents

A series of 2-{[2'-(3'-chloro-2'-oxo-4'-substitutedaryl-1'-azetidinyl)-1',3'-thiazol-4'-yl] thio}benzothiazoles (4a-4e) and 2-{[(2'-(2'-substitutedaryl-4'-thiazolidinon-3'-yl)-1',3'-thiazol-4'-yl]thio}benzothiazoles (5a-5e) have been synthesized from 2-[(2'-substitutedarylidenylimino-1',3'-thiazol-4'-yl)thio]benzothiazoles (3a-3e). The structure of these compounds has been elucidated by elemental (C, H, N) and spectral (IR, (1)H-NMR, Mass) analysis. Furthermore, compounds 3a-3e, 4a-4e, and 5a-5e were screened for insecticidal activity against Periplaneta americana and antifungal, antibacterial activities in vitro against different strains of fungi and bacteria. Out of the fifteen compounds tested, compound 5b, 2-{[2'-(2'-p-hydroxy-m-methoxyphenyl)-4'-thiazolidinon-3'-yl)-1',3'-thiazol-4'-yl]thio}benzothiazole, was found to possess most prominent insecticidal activity.     

Effects of buffer magnesium on positive inotropic agents in guinea pig cardiac muscle

Experiments examined effects of extracellular Mg2+ concentration (Mgo2+) on dose-dependent actions of strophanthidin, norepinephrine, Bay K-8644 and extracellular Ca2+ (Cao2+) in electrically stimulated atrial and ventricular muscle isolated from guinea pig heart. Mgo2+ itself elicited a concentration-dependent negative inotropic effect. Elevation of Mgo2+ between 0.6 and 12 mM increased the concentration of strophanthidin necessary to produce its toxic effects without affecting the maximum developed tension prior to toxicity. Similarly, Mgo2+ did not alter the maximum contractile force elicited by cumulative addition of norepinephrine, Bay K-8644 or Cao2+, but increased their ED50 values. These data suggest that interactions between Mgo2+ and the four positive inotropic agents were not mediated by effects on receptor binding or Na+,K+-ATPase, but rather by alterations at one or more steps involved in excitation-contraction coupling.     

Positive inotropic agents: modelling, synthesis and SAR

Five non steroidal cardiotonics have been studied for the search of a common pharmacophore with the aid of the SYBYL computer modelling programme. On the basis of the model thus obtained a series of pyridylquinolones have been prepared and some structure activity relationships examined. The compounds were evaluated for positive inotropic and vasodilatory activities in vitro and in vivo animal models. Several substances displayed activities higher than that of classical references, and might be beneficial in patients with congestive heart failure.     

Synthesis of some novel 2-substituted benzoxazoles as anticancer, antifungal, and antimicrobial agents

Benzoxazole derivatives show various types of biological properties such as antiviral, antineoplastic, anti-HIV-1, antitubercular, anthelmintic, antimicrobial, and antifungal activities. In the last few years 2-substituted benzoxazole derivatives have been studied extensively for their antitumor, antiviral, and antimicrobial activities. In an effort to identify new candidates that may be of value in designing new, potent, selective, and less toxic anticancer, antiviral, and/or antimicrobial agents, we synthesized 2-[(arylhydrazono) cyanomethyl]-5-chloro benzoxazoles (II), 2-[(arylidene)cyanomethyl]-5-halo benzoxazoles (III), and 2-[(cycloalkylidine)cyanomethyl]-5-chlorobenzoxazoles (IV), and tested them for anticancer, antifungal, and antibacterial activities. Some of these (compounds 11, 14) were found to possess anticancer activity and remarkable antifungal as well as antibacterial activities.