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In an attempt to design new inotropic drugs for congestive heart failure (CHF) with less proarrhythmic potential, three series of compounds analogous to milrinone were prepared, namely, 4-aryl-6-(4-pyridyl)-2-oxo-1,2-dihydropyridine-3-carbonitriles 2a-g, 4-aryl-6-(4-pyridyl)-2-thioxo-1,2-dihydropyridine-3-carbonitriles 3a-g and 2-amino-4-aryl-6-(4-pyridyl)-pyridine-3-carbonitriles 4a-g. The first series was prepared by reacting 4-acetyl pyridine with the appropriate aldehyde, ethyl cyanoacetate and ammonium acetate in ethanol. Reaction of 2a-g with phosphorus pentasulfide afforded the second series 3a-g. The third target compounds 4a-g were prepared applying the same procedure used to synthesize 2a-g using malononitrile instead of ethyl cyanoacetate. All the newly synthesized compounds were evaluated for their cardiotonic activity and their in vivo cardiovascular effects. In addition, their oral and parenteral acute toxicity were determined. Compounds 2a, 2b, 2c, 4c and 4f proved to exert cardiotonic activity comparable to that of milrinone using spontaneously beating atria model from reserpine-treated guinea pigs. In addition these compounds proved to be non-toxic and well tolerated by mice up to 250 mg kg(-1) orally and up to 125 mg kg(-1) through parenteral route.

A screening study was conducted to examine the effect of a series of synthesized pyrazoloquinoline derivatives on the growth of Leishmania donovani promastigotes. Sixteen compounds were tested, ten of which showed an inhibitory effect on the growth of promastigotes. Compound 1 demonstrated potent antileishmanial activity, followed by compounds 3 and 7. Some compounds showed less significant activities, while others exhibited little or no activity. Some of these compounds may be potential candidates for future treatment of leishmaniasis.

Four series of 1H-pyrazole derivatives have been synthesized. The first series was synthesized starting by condensing the hydrazine derivatives 1a-d with 4-(1-ethoxycarbonyl-2-oxopropyl)azobenzoic acid 2a in ethanol or glacial acetic acid to generate the corresponding pyrazoline derivatives 3a-d. Likewise, heating 1a-d with 4-(1-acetyl-2-oxopropyl)azobenzoic acid 2b gave rise to the pyrazole derivatives 4a-d. Similarly, reaction of 1a-d with ethyl 2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylazo)-3-oxobutanoate 2c or 3-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl azo)pentane-2,4-dione 2d in ethanol or glacial acetic acid led to the corresponding pyrazoline derivatives 5a-d or pyrazole derivatives 6a-d. The newly synthesized compounds were evaluated for their anti-inflammatory-antimicrobial activities. In addition, the ulcerogenic and acute toxicity profiles were determined. Compound 6c, proved to be the most active anti-inflammatory-antimicrobial agent in the present study with a good safety margin and no ulcerogenic effect.

Three structurally related aminopyrazoloquinoline derivatives were evaluated for their antiviral activity against Herpes Simplex virus type 1. These compounds were examined for their in vitro antiviral activity by two different bioassays, namely; crystal violet staining and tetrazolium dye (MTS) measurement. The antiviral role of these compounds was confirmed by enumerating the infectious particles with plaque assay. The acute toxicity values of the biologically active compounds were determined prior to their screening as antiviral agents.

Several new platinum(II) complexes of the general formulae cis-[PtCl(2)(DMSO)L], where L is a Schiff base or hydrazone derived from tetrazolo[1,5-a]quinoline-4-carboxaldehyde as carrier ligands, have been synthesized and characterized physicochemically and spectroscopically. These platinum complexes which are structurally analogues to what so called cisplatin [cis-[PtCl2(NH3)2]; the first generation anticancer agent] were evaluated for their cytotoxicity on HL-60 (human promyelocytic leukemia) cells. Two of the platinum complexes were almost similar in their activity to cisplatin, while the remaining three complexes have demonstrated higher efficacy than that of cisplatin. Based on our findings, these novel platinum complexes appear to be valuable leading compounds with high efficacy.

The synthesis of novel series of structurally related 1H-pyrazolyl derivatives is described. All the newly synthesized compounds were tested for their in vivo anti-inflammatory activity by two different bioassays namely; cotton pellet-induced granuloma and sponge implantation model of inflammation in rats. In addition, COX-1 and COX-2 inhibitory activities, ulcerogenic effects and acute toxicity were determined. The same compounds were evaluated for their in vitro antimicrobial activity against Escherichia coli, as an example of Gram negative bacteria, Staphylococcus aureus as an example of Gram positive bacteria, and Candida albicans as a representative of fungi. The combined anti-inflammatory data from local and systemic in vivo animal models showed that compounds 4, 5, 8, 9, 11 and 12a exhibited anti-inflammatory activity comparable to that of indomethacin with no or minimal ulcerogenic effects and high safety margin (LD(50)>500 mg/Kg). In addition, compounds 4, 7, 10, 12a and 12b displayed appreciable antibacterial activities when compared with ampicillin, especially against S. aureus. Compounds 4 and 12a are the most distinctive derivatives identified in the present study because of their remarkable in vivo and in vitro anti-inflammatory potency and their pronounced antibacterial activities comparable to ampicillin against Gram positive. On the other hand, compound 12a exhibited good selective inhibitory activity against COX-2 enzyme. Therefore, such compound would represent a fruitful matrix for the development of anti-inflammatory-antimicrobial candidates.

Three series of tetrazolo[1,5-a]quinoline derivatives have been synthesized. The first series was synthesized starting by the condensation of tetrazolo[1,5-a]quinoline-4-carboxaldehyde 2 with substituted thiosemicarbazides, followed by cyclization of the resulting thiosemicarbazones 3 with malonic acid in the presence of acetyl chloride to give pyrimidyl derivatives 4a-c. The second series was prepared by the condensation of the latter compounds 4a-c with the selected aromatic aldehydes to afford the arylidene derivatives 5a-f. The third series 7a-c was synthesized by condensation of tetrazolo[1,5-a]quinoline-4-carboxaldehyde 2 with the appropriate acetophenone, followed by cyclocondensation of the formed alpha,beta-unsaturated ketones with thiourea. The newly synthesized compounds were evaluated for their anti-inflammatory and antimicrobial activities. Four compounds were proved to be as active as indomethacin in animal models of inflammation.

Synthesis of a novel series of structurally related pyrazoloquinoline nucleosides is described. All the newly synthesized compounds were examined for their in vitro antiviral activity against herpes simplex type-1 as shown by two different bioassays, namely; crystal violet staining or the MTS tetrazolium dye measurement. The acute toxicity (LD50) values of the biologically active compounds were determined.

This paper describes the synthesis of four series of 4(3H)-quinazolinone derivatives. The first series was prepared by cyclization of the intermediate 3-aryl-2-substituted thiocarbamoylhydrazonomethyl-4(3H)-quinazolinones 2a,b with ethyl bromoacetate to afford the corresponding thiazolidinonyl derivatives 3a,b. The second series were prepared by the cyclization of the intermediate 2a,b with phenacyl bromide or 4-substituted phenacyl bromide giving rise to thiazolinyl derivatives 4a-f. Furthermore, the thiazolidinonyl derivatives 5a,b were obtained by reaction of the intermediate 2a,b with thioglycolic acid. On the other hand, heating the intermediate 2a,b with acetic anhydride afforded the corresponding thiadiazolinyl derivatives 6a,b. Some of the synthesized compounds showed promising anti-inflammatory-antimicrobial activities.

Two novel series of 1,4-naphthoquinone derivatives have been synthesized namely; N-ethoxycarbonyl-2-ethoxycarbonyloxy-3- alkyl-1,4-naphthoquinon-1-substituted phenylhydrazones 3a-f and 2-chlorocetyloxy-3-alkyl-1,4-naphthoquinone-1-substituted phenylhydrazones 4a-d. The antimicrobial activity as well as anticancer activity of these compounds have been evaluated. The acute toxicity of the active compounds was determined.

Four series of 1 H-pyrazole derivatives have been synthesized. The first series was synthesized starting with the reaction of 3-(5-bromo-2-thienyl)-1-phenyl-1 H-pyrazole-4-carboxaldehyde 1 with L-serine, L-cysteine, or L-penicillamine, followed by N-protection using (Boc)(2)O to provide compounds 2. The latter compounds could be N-deprotected by 4N HCl/dioxane to afford the second series 3 or reacted with NH(4)OH in the presence of DCC/HOBt to give the corresponding amides 4 followed by N-deprotection giving rise to compounds 5. The newly synthesized compounds were evaluated for their anti-inflammatory-antimicrobial activities. In addition, the ulcerogenic and acute toxicity profiles were determined. Compound 5b (2RS, 4R)-2-[3-(5-bromo-2-thienyl)-1-phenyl-1H-pyrazol-4-yl]-5-methylthiazolidine-4-carboxamide, proved to be the most active anti-inflammatory-antimicrobial agent in the present study with a good safety margin and no ulcerogenic effect.

The synthesis of two novel series of structurally related 1H-pyrazolyl derivatives of thiazolo[4,5-d]pyrimidines is described. All the newly synthesised compounds were examined for their in vivo anti-inflammatory activity in two different bioassays namely; cotton pellet-induced granuloma and carrageenan-induced paw edema in rats. The in vitro inhibitory activity of the most active compounds towards human COX-1 and COX-2 enzymes was also estimated. In addition, the ulcerogenic effects and acute toxicity (LD(50)) values of these compounds were determined. The same compounds were evaluated for their in vitro antimicrobial activity against Escherichia coli, as an example of Gram negative bacteria, Staphylococcus aureus as an example of Gram positive bacteria, and Candida albicans as a representative of fungi. The results revealed that compounds 5a, 9a, 9b, 10b and 12a exhibited anti-inflammatory activity comparable to that of indomethacin in both local and systemic in vivo animal models with no or minimal ulcerogenic effects (0-10%) and high safety margin (LD(50) > 500 mg kg(-1)). In addition, most of them displayed appreciable antibacterial activities when compared with ampicillin, especially against S. aureus. Compounds 9a and 12a are the most distinctive derivatives identified in the present study because of their remarkable in vivo and in vitro anti-inflammatory activity in addition to their pronounced antibacterial activities comparable to ampicillin against Gram positive and -negative bacteria. Therefore, they are considered as successful dual anti-inflammatory-antimicrobial candidates., (Copyright 2002 Editions scienctifiques et médicales Elsevier SAS)

Several new 5-(2,3-dihydrothiazol-2-yledinyl)rhodanines 3a-c and 5-(4-oxothiazolidinon-2-ylidenyl)rhodanine 4 were synthesized through the reaction of 5-thiocarbamoyl rhodanines 2 with phenacyl bromides or chloroacetic acid, respectively. The synthesis of the arylidene derivatives 5a-c were also described. The 5-(4-amino-5-cyano-2,3-dihydrothiazol-2-yledinyl)rhodanines 10a, b were obtained through reaction of rhodanines 1a, b with thiazolium salt 9. All the prepared compounds were screened for their anticancer activity using the NCI in vitro anticancer screening program. Three compounds showed promising anticancer activity against particular human cell lines used in the assay.

New derivatives of 4(3H)-quinazolinone were synthesized and evaluated for their antibacterial and antifungal activity. The derivatives are: 3-Aryl-2-[3-aryl-1-(carboxymethylthio)-3-oxopropyl)]-4(3H)-quinazolinones 2a-f; 3-Aryl-2-(3-aryl-1H-pyrazol-5-yl)-4(3H)-quinazolinones 3a-f; 3-Aryl-2-(1,3-diaryl-1H-pyrazol-5-yl)-4(3H)-quinazolinones 4a-f; 3-Aryl-2-(3-aryl-1-thiocarbamoyl-1H-pyrazol-5-yl)-4(3H)-quinazolinones 5a-f; 3-Aryl-2-[3-aryl-1-(carboxymethylthio)-3-hydroxyiminopropyl)]-4(3H)- quinazolinones 6a-f; and 3-Aryl-2-[3-aryl-1-(carboxymethy- lthio)-3-thiocarbamoyliminopropyl)]-4(3H)-quinazolinones 7a-f. Some of the tested compounds showed activity comparable to that of the standard references used.

The synthesis of three categories of compounds containing the 1H-pyrazole ring linked to some dihydrothiazoles, thiazolidinones, and thiazolo[4, 5-d]pyrimidines through different linkages is described. Nine of the newly synthesized target compounds were selected by the NCI for in-vitro antitumor screening. Four compounds, namely 4a, 4b, 13, and 14, exhibited a broad spectrum of antitumor activity against most of the tested tumor cell lines. Compound 4a, 3-phenyl-4-amino-5-(3, 5-dimethyl-1-phenyl-1H-pyrazole-4-methylidenehydrazinocarbonyl)thiazole-2(3H)-thione proved to be the most active antitumor agent in the present study with GI(50), TGI, and LC(50) MG-MID values of 3.93, 41.7, and 91.2 microM, respectively. The same compound also exhibited high selectivity towards CNS SNB-75 and Ovarian IGROV1 cancer cell lines at both the GI(50) and TGI levels. Compound 4b, 3-(4-chlorophenyl)-4-amino-5-(3, 5-dimethyl-1-phenyl-1H-pyrazole-4-methylidenehydra-zinocarbonyl) thiazole-2(3H)-thione showed nearly the same pattern of activity as 4a but to a lesser extent. Compounds 13 and 14 displayed moderate antitumor activity against most of the tested tumor cell lines with GI(50) MG-MID values range of 20.4-80.6 microM and TGI MG-MID values of 55.5-95.5 microM.

The increasing clinical importance of drug-resistant bacterial pathogens has encouraged additional microbiological and antibacterial research. New chalcone and sydnone derivatives of 4(3H)-quinazolinone were synthesized and evaluated for their antibacterial and antifungal activity. The microorganisms used were Escherichia coli ATCC 25922 as Gram-negative bacteria, Staphylococcus aureus ATCC 19433 as Gram-Positive bacteria and Candida albicans as yeast like fungi. The most potent compound was the nitroso derivative 6b, which exhibits interesting antibacterial and antifungal activities.

Cinnolines, in general, have been reviewed in details over the last decades. Fused cinnolines have shown remarkable biological activities. Some fused cinnolines received approval as bioactive drug or still in advanced clinical trials. This is prompted the need to review fused cinnolines from the synthetic and biological points of view.

Four series of 1H-pyrazole derivatives have been synthesized. The first series was prepared by cyclization of the intermediate 3-(5-bromo-2-thienyl)-1-phenyl-1H-pyrazole-4-carbaldehyde aroyl-hydrazone 4a-c with acetic anhydride to afford the corresponding oxadiazoline derivatives 5a-c. The other series were prepared by the cyclization of the intermediate 3-(5-bromo-2-thienyl)-1-phenyl-4-substituted thiocarbamoylhydrazonomethyl-1H-pyrazole 6a-c with acetic anhydride, ethyl bromoacetate or phenacyl bromide giving rise to 3-(5-bromo-2-thienyl)-1-phenyl-4-[3-acetyl-5-(N-substituted acetamido)-2,3-dihydro-1,3,4-thiadiazol-2-yl]-1H-pyrazoles 7a-c, 3-(5-bromo-2-thienyl)-1-phenyl-4-(3-substituted- 4-oxothiazolidin-2-ylidenehydrazonomethyl)-1H-pyrazoles 8a-c, or 3-(5-bromo-2-thienyl)-1-phenyl-4-(3-substituted-4- phenyl-2,3-dihydrothiazol-2-ylidenehydrazonomethyl)-1H-pyraz oles 9a-c respectively. Some of these compounds showed anti-inflammatory, antibacterial or antifungal activities comparable to that of Proquazone, Ampicillin, or Clotrimazole respectively.

Four novel series of 4(3 H)-quinazolinone derivatives have been synthesized by cyclization of the intermediate 3-aryl-2-(6-aryl-2-cyclohexen-1-on-5-yl)-4(3 H)-quinazolinones 3a-f with hydrazine, phenylhydrazine, hydroxylamine and thiourea. The products are 3-aryl-2-(6-aryl-3-methyl-1 H-4,5-dihydrobenzo[d]pyrazol-4-yl)-4(3 H)-quinazolinones 4a-f; 3-aryl-2-(6-aryl-3-methyl-1-phenyl-1 H-4,5-dihydrobenzo[d]pyrazol-4-yl)-4(3 H)-quinazolinones 4g-1; 3-aryl-2-(6-aryl-3-methyl-4,5-dihydrobenzo[d]-1,2-oxazol-4-yl)-4(3 H)-quinazolinones 5a-f, and 3-aryl-2-(7-aryl-4-methyl-5,6-dihydro-2(1 H)thioxoquinazolin-5-yl)-4(3 H)-quinazolinones 6a-f. Some of these compounds showed anti-inflammatory activity comparable to or higher than that of the reference compound proquazone.

Four novel series of 4(3H)-quinazolinone derivatives have been prepared by cyclization of the key intermediates 3-aryl-2-(3-aryl-3-oxopropenyl)-4-(3H)-quinazolinones with different reagents: 3-aryl-1-iminocarbamoyl-1H-pyrazol-5-yl)-4(3H)-quinazolines, 3-aryl-2-(3-aryl-1-thiocarbamoyl-1H-pyrazol-5-yl)-4(3H)-quinazolines, 3-aryl-2-(3-aryl-4,5-dihydro-1,2-oxazol-5-yl)-4(3H)-quinazolinones , and 3-aryl-2-(4-aryl-2-thioxo-1,2,5,6-tetrahydro-1,3-diazin-6-yl )-4(3H)- quinazolinones. The antiinflammatory activity of representatives of these compounds is comparable to or higher than that of proquazone.

Four novel series of pyrazolyl-4(3H)-quinazolinones have been prepared through the reaction of 3-aryl-2-hydrazino-4(3H)-quinazolinones with antipyrylazo-derivatives of ethyl acetoacetate, acetylacetone or diethyl malonate. These series of compounds are 3-aryl-2-[1-ethoxycarbonyl-1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H - pyrazol-4-yl)hydrazono-2-propylidene]hydrazino-4(3H)-quinazo linones; 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) hydrazono-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]-4(3H)-quinaz olinones; 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)azo -3,5- dimethyl-1H-pyrazol-1-yl]-4(3H)-quinazolinones and 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) hydrazono-3,5-dioxo-pyrazolidin-2-yl]-4(3H)-quinazolinones. The antiinflammatory activity of some representatives of the prepared compounds was studied.