Several 1,3,4-trisubstituted pyrazole derivatives were synthesized and screened for their cytotoxic effect in a primary 3 tumor cell line test at 10(-4) M drug concentration. Compounds 19 and 20 reduced the growth of one or more of these cell lines to less than 32% and escalated up to evaluation in the full panel of 60 human tumor cell lines at a minimum of 5 concentrations at 10 fold dilutions. Compound N'-(1-[1-[4-nitrophenyl]-3-phenyl-1H-pyrazol-4-yl]methylene)-2-chlorobenzohydrazide 19 proved to be the most active of these derivatives with full panel median growth inhibition (GI50), total growth concentration (TGI) and median lethal concentration (LC50) mean graph mid-point (MG-MID) of 3.79, 12.5 and 51.5 microM, respectively. In addition, compounds 19, 39, 40, 41, 43, 45, 47 were tested for their antiangiogenic properties by testing their ability to inhibit human umbilical vein endothelial cells (HUVECs) proliferation, cord formation and migration in response to chemoattractant. 3-Acetyl-2-(1-(4-nitrophenyl)-3-phenylpyrazol-4-yl)-5-(4-pyridyl)-1,3,4-oxadiazoline 39 showed significant antiangiogenic profile at non-cytotoxic doses, with HUVEC proliferation inhibition IC50 of 7.60 microM, chemotaxis IC50 of 0.86 microM and was superior to the reference celecoxib 2 in both tests. Furthermore, in contrary to the references TNP-470 and celecoxib, all the tested compounds interfered with the migratory function of HUVECs in response to vascular endothelium growth factor (VEGF) rather than the endothelial cells proliferation.

No abstract

Despite the optimal use of the currently available antiepileptic drugs, 30 to 40% of the epileptic population fails to experience seizure control, and others do so only at the expense of significant toxic effects that range in severity from minimal brain impairment to death from aplastic anemia or hepatic failure.1-3) These facts provoked the need for new anticonvulsant drugs with higher potency and fewer side effects. Several studies reported that chromone derivatives are promising anticonvulsant candidates that perform their activity through a g-aminobutyric acid (GABA)-mediated mechanism. [4][5][6][7][8][9][10][11][12][13][14][15][16][17] Likewise, flavones (2-phenylbenzopyrons) are with a well known positive GABA-modulating ability; their central activity was attributed to their potential to penetrate the blood-brain barrier which is strongly correlated to their lipophilicity.18) Semicarbazones and their bioisosteres thiosemicarbazones, have a documented essential role in the design of novel anticonvulsant agents that performing their anticonvulsant activity also through a GABA-mediated mechanism.19-41) Extensive structure-activity relationship studies proposed certain pharmacophoric requirements for (thio)-semicarbazones interaction at the binding site which are a hydrophobic binding area represented by aryl or heteroaryl group and a hydrogen bonding domain represented by the NH-CO(S)-NH system. [24][25][26]33,38) It was suggested that (thio)semicarbazones anticonvulsant activity is mediated through GABA-mediated mechanism. 19,22,29,32,37,41) In the present investigation the two anticonvulsant candidates, chromones or flavones and thiosemicarbazones, were amalgamated to obtain more potent anticonvulsants compounds of series 1 and 2. In the synthesized hybrid compounds the chromone or the furochromone ring acts as the hydrophobic aryl ring required for binding which itself possesses anticonvulsant tendency. On the other hand, various bicyclic heterocycles containing thiosemicarbazono group showed significant anticonvulsant activity. 33,34,[42][43][44] Herein the tricyclic furochromone moiety was simplified to the bicyclic benzofuran system, which was reported to possess anticonvulsant activity [42][43][44] to give compounds of series 3. Obviously, the compounds of this series are the bicyclic analogs of the reported phenyl congener 4 synthesized by Dimmock et al. which showed marked anticonvulsant activity. 20) Replacement of the phenyl ring in 4 by the bicyclic benzofuran structure is thought to increase the hydrophobic aryl area which binds to the binding site and thus may enhance the binding. Moreover, the effect of the hydrophobic group on the terminal amino group of the thiosemicarbazono moiety was studied in the synthesized compounds of series 1, 2 and 3.Due to certain limitations associated with the (thio)semicarbazone functionality, mainly the poor solubility and liability to metabolism 45) ; improvement of the molecule, pharmacologically and pharmaceutically, was carried out by replacement of the th...

Due to the rapidly growing number of resistant strains of bacteria, the search for antibacterial agents with new modes of action will always remain an important and challenging task. Thus, the reaction of 2-substituted or unsubstituted-4-(4-acetylanilino)-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidine derivatives 1-3 with the hydrazine derivatives, semi and/or thiosemicarbazides, provided the corresponding hydrazones 4-6 and semi and/or thiosemicarbazones 7-9. Claisen-Schmidt condensation of compounds 1 or 2 with the appropriate aldehyde yielded the chalcones 10, 11 which, when treated with hydroxylamine hydrochloride gave rise to the isoxazoline-containing compounds 12, 13. Furthermore, reacting the respective chalcones 10, 11 with different hydrazines, urea and/or thiourea, furnished compounds 14, 15, 16, and 17 respectively. Representative compounds were tested for their antimicrobial activity against Candida albicans and certain gram-positive and gram-negative bacteria. Their MICs were then determined. Compound 15e, showed a broad spectrum of activity while most of the other compounds showed varying antimicrobial activity.

Simple, three classes of new anthranilic acid derivatives were aimed at, synthesized and tested for their toxicity, anti-inflammatory, analgesic, antipyretic activity. Also, their potential protective role against ulcerative colitis in rats was performed. Furthermore, their effect on liver and kidney functions was detected through measurement of the serum level of alanine transaminase (ALT), aspartate aminotransferase (AST), urea, creatinine and other parameters. Compounds 4, 5, 6b, 6c, 7c and 7e showed significant anti-inflammatory activity. From those 6b and 7e best improved the inflammatory indices even producing better reduction in the intensity of lesion score, ulcer area and wet weight/length ratio and showed good analgesic activity. Fortunately, none of the tested compounds showed any hepatotoxicity or nephrotoxicity. None of the tested compounds showed any antipyretic activity. Conclusively, presence of a phenyl ring in the substituent added is a must, since any alteration in its nature led to decrease in activity. Also, the presence of an extra halogen in addition to the one already embedded in the main structure was detrimental to activity.

Analogues with the scaffolds of 3-cyano-4-alkoxyphenyl-6-bromoaryl-2-pyridone and 2-amino-3-cyano-4-alkoxyphenyl-6-bromoarylpyridine were synthesized. Cyclization of the 2-amino derivatives with formic acid and formamide gave the corresponding pyrido[2,3-d]pyrimidin-4(3H)-one and the pyrido[2,3-d]pyrimidin-4-amine derivatives, respectively. Active phosphodiesterase 3 (PDE3) inhibitors were identified from each of the four aforementioned scaffolds. This is the first report that pyrido[2,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4-amine derivatives can inhibit PDE3. The analogues with the pyridone and pyrido[2,3-d]pyrimidin-4(3H)-one scaffolds inhibited both cAMP and cyclic guanosine monophosphate (cGMP) hydrolysis by PDE3, while the amine containing scaffolds were more selective for cGMP hydrolysis. This observation may set the base for substrate-selective pharmacological modulation of this important class of drug targets and with less side effects, particularly tachcardia. The dual inhibitors of PDE3 were more potent inhibitor towards the growth of HT-29 cancer cell lines.

Pyrazole derivatives Pyrazole derivatives R 0180Synthesis of Novel 1,3,4-Trisubstituted Pyrazole Derivatives and Their Evaluation as Antitumor and Antiangiogenic Agents. -The title compounds of type (V) and (IX) are non-cytotoxic but of apparently true antiangiogenic profile mainly through inhibiting the motility of endothelial cells rather than its proliferation. -(ABADI*, A. H.; EISSA, A. A. H.; HASSAN, G. S.; Chem. Pharm. Bull. 51 (2003) 7, 838-844; Dep. Pharm. Chem., Fac. Pharm., Cairo Univ., Cairo, Egypt; Eng.) -M. Paetzel 50-118

All newly synthesized benzofurans (I), furochromones (II), and flavones (III) as well as selected intermediates are evaluated for their anticonvulsant activity using both scPTZ and MES tests.