Novel triazolo[4,3-a]quinazolinone and bis-triazolo[4,3-a:4,3'-c]quinazolines: synthesis and antitoxoplasmosis effect.

Several quinazoline derivatives containing substituted thiosemicarbazido and S-methylisothiosemicarbazido groups at the 2-position and at both the 2- and 4-positions have been synthesized. Treatment of the S-methylthiosemicarbazides with morpholine or diethylamine did not give the corresponding guanidines. Instead, they underwent cyclodesulfurization into the condensed ring systems, [1,2,4]triazolo[4,3-a]quinazolinones and bis-[1,2,4]triazolo[4,3-a:4'.3'-c]quinazolines. Evaluation of the products for antitoxoplasmosis effect by studying the ultrastructure morphology of the organisms using scanning electron microscopy (SEM) indicated their efficacy in causing structural deformity of Toxoplasma gondii. Such a deformity plays an important role in obstructing the entry of the organisms into host cells.

Synthesis, estrogen receptor binding affinity and biological evaluation of some 2-substituted estrone derivatives.

This report details the preparation of modified estrogens which are structurally designed to possess estrogenic and/or antiestrogenic activity. The prominent feature of these estrogens is the introduction of a novel side chain in the 2-position of ring A of the steroid nucleus. Their synthesis includes the use of transformations based upon Mannich base chemistry: preparation of the intermediate 2-dimethylamino-methylestrone via aminomethylation of estrone and introduction of various functionalities via reaction of this Mannich base with different reagents. When evaluated for their interaction with the estrogen receptor by competitive binding assays, the tested products were found to be relatively weak competitors at 0 degree C. The uterotrophic and post-coital antifertility assays indicated effects varying in magnitude relative to estradiol. Ethyl[(2'-acetyl-3'-(3-hydroxyestra-17-oxo-1,3,5 (10)-trien-2-yl)]propionate (15) showed uterotrophic and antiimplantation activities of 95% and 20% respectively.

Novel steroidal 1,4-diketones and pyridazine derivatives as potential antiestrogens.

A series of steroidal 1,4-diketone derivatives was synthesized by acid-catalyzed condensation of 2-acetylestradiol-17 beta-acetate with substituted phenylglyoxals. Conversion of the products into the corresponding pyridazine derivatives was achieved by reaction with hydrazine hydrate. The synthesized compounds were evaluated for their uterotrophic, antiuterotrophic, and antifertility activities in mature female albino rats. Among the compounds tested, the phenyl 2, p-bromophenyl 3, and p-methoxyphenyl 5 diketone derivatives displayed uterotrophic activity of 72%, 72%, and 91%, respectively. The gradation of antiestrogenic activity was assessed in vivo by the inhibition of the estrone-stimulated uterine growth. Compounds 2-5 showed moderate antiestrogenic activity of 53-56%. None of the tested compounds elicited antifertility activity as assessed by the post-coital antiimplantation activity test.

4',17-dioxo-5'H-estra-1(10),4-dieno[3,2-b]furan: synthesis, binding affinity to the estrogen receptor, uterotrophic and antiimplantation activities.

4',17-Dioxo-5'H-estra-1(10),4-dieno[3,2-b]furan (3) has been prepared by several routes starting from 2-bromoacetylestrone (2). Performance of the reaction with thiourea at elevated temperature provided compound 3 in good yield. When other reagents such as thiosemicarbazide, morpholine, sodium hydroxide or sodium hydride were treated with 2-bromoacetylestrone at room temperature, the furano derivative 3 was also obtained as the sole product. This new type of structural modification provided an estrogen nucleus deprived of the 3-hydroxyl function which was previously thought to be an essential requisite for binding to the estrogen receptor (ER). When evaluated in vitro for binding to the ER and in vivo for uterotrophic and antifertility activities, the furano derivative 3 was capable of inhibiting [3H]E2 binding by 16% while still eliciting high uterotrophic (99%) and postcoital antiimplantation (100%) activities relative to estradiol.

Synthesis and antimicrobial activity of some tetramethylenethieno[2,3-d]pyrimidine derivatives.

A series of tetramethylenethieno[2,3-d]pyrimidine derivatives has been synthesized and tested for its antimicrobial properties. All the synthesized compounds were found to exhibit in vitro antibacterial and/or antifungal activity. The highest activity was elicited by 4-benzolhydrazino-5,6-tetramethylenethieno[2,3-d]pyrimidine (9) showing MIC value of 7.81 micrograms/ml against E. Coli and C. albicans, while its MBC value was half that of nystatin. Compound 16 was almost as potent as nystatin exhibiting a minimum bactericidal concentration (MBC) value of 15.62 micrograms/ml.

Benzo[b]thiophenes, II: Novel benzo[b]thienylhydrazine and 1,3,4-oxadiazole derivatives as potential antidepressant agents.

Three novel series of benzo[b]thiophene derivatives bearing various hydrazone, hydrazine and 1,3,4-oxadiazole moieties were synthesized as potential antidepressant agents. 22 Compounds were evaluated for their in vitro inhibitory effect on monoamine oxidase enzyme (MAO) type A. Several compounds inhibited MAO stronger than pargyline hydrochloride. Maximum inhibitions of 83% and 90% were observed with 1-benzyl-2-(3-chlorobenzo[b]thienyl-2-carbonyl)hydrazine (24) and 1-[2-(4-chlorophenyl)ethyl]-2-(3-chlorobenzo[b]thienyl-2- carbonyl)hydrazine (35), respectively.

Synthesis and antimicrobial activity of some thiazolinyl tetrahydrobenzo[b]thiophenes and thiazolinyl tetrahydrobenzothieno[2,3-d]pyrimidin-4-ones.

Two series of novel 3-carbethoxy-2-(3',4'-disubstituted-2',3'- dihydrothiazol-2'-ylidenamino)-4,5,6,7-tetrahydrobenzo[b] thiophenes (3a-o) and 2-methyl-3-(3',4'-disubstituted-2',3'-dihydrothiazol-2'-ylidena mino-5,6,7,8- tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H) ones (8a-o) have been synthesized and tested for antimicrobial activity. All members of the series have been found to exhibit in vitro antibacterial and/or antifungal activities. Activity was optimized by cyclization to the thienopyrimidin-4-ones. In particular, compounds 8e and 8fd were the most active against the 3 tested microorganisms. Their antifungal activity was higher than that exhibited by nystatin while their MIC was found to be nearly equal to that of nystatin.

Synthesis and evaluation for uterotrophic and antiimplantation activities of 2-substituted estradiol derivatives.

Two novel series of 2-substituted estradiol derivatives have been synthesized and evaluated for uterotrophic and antiimplantation activities. Among the compounds tested in the rat, 2-acetylestradiol 17 beta-acetate (1), 2-(3'-dimethylamino-1'-propionyl)estradiol 3,17 beta-diacetate (7), 2-(3'-diethylamino-1'-propionyl)estradiol 3,17 beta-diacetate (8), 2-(3'-piperidino-1'-propionyl)estradiol 3,17 beta-diacetate (9), 1'-(2-estradiol 3,17 beta-diacetate-3'-diethylaminopropionyl thiosemicarbazone (12), and 1'-(2-estradiol 3,17 beta-diacetate)-3'-morpholinopropionyl thiosemicarbazone (14) displayed estrogenic activity. At dosages of 4 microliters/rat/day, none of the tested compounds elicited antiimplantation activity. All compounds shared a similar characteristic: nuclear substitution at the C-2 position of the steroid nucleus, a property previously thought to be markedly inhibitory for estrogenic activity.

Synthesis and evaluation of novel N-substituted N'-(3-hydroxy-17-oxoestra-1,3,5(10)-trien-2- and -4-yl)thiourea derivatives for binding to the estrogen receptor and cytotoxic activity on MCF-7 cells.

A novel series of estrone derivatives having a free 3-phenolic group with the 2- or 4-position substituted with a thiourea function was synthesized. None of the products showed significant binding to the estrogen receptor, and the cytotoxic activity on MCF-7 cells for VII and X was weak.

Steroidal thiourea and thiazoline derivatives: synthesis and in vitro effects on bovine pancreatic ribonuclease activity.

Two novel series of steroidal derivatives containing various thiourea and substituted thiazoline moieties attached to the 2- or 4-position of estrone were synthesized and examined for in vitro effect on bovine pancreatic ribonuclease activity. All compounds studied exhibited a catabolic activity. The steroidal thiazoline derivatives were more potent activators of ribonuclease than the steroidal thioureas.