Quinoxaline derivatives. Part II: Synthesis and antimicrobial testing of 1,2,4-triazolo[4,3-a]quinoxalines, 1,2,4-triazino[4,3-a]quinoxalines and 2-pyrazolylquinoxalines

Three main classes of quinoxaline derivatives have been synthesized. The first class comprises the synthesis of three novel series of 1,2,4-triazolo[4,3-a]quinoxalines; namely 1-substituted-1,2,4-triazolo[4,3-a]quinoxalines 3a-f, 1-substituted aminomethyl-1,2,4-triazolo[4,3-a]quinoxalines 14a-d and 1-cyano or ethoxycarbonylmethyl-1,2,4-triazolo[4,3-a]quinoxalines 6, 12. The second class involves the synthesis of 2-substituted-1 H-1,2,4-triazino[4,3-a]quinoxalines 4a-d. The third class deals with the synthesis of a variety of 2-pyrazolylquinoxalines, namely 2-(5-amino-3-arylpyrazol-1-yl)-3-phenylquinoxalines 5a-d, 2-[5-hydroxy-3-phenyl-4-(4-substituted sulfamoylphenyl)azopyrazol-1-yl]-3-phenylquinoxalines 15a, b, and 2-(5-hydroxy-4-nitroso-3-phenylpyrazol-1-yl)-3-phenylquinoxalin e (16). The prepared compounds were tested in vitro for their antimicrobial activity. Compounds 13 and 14b exhibited promising antifungal activity against C. albicans (MIC 25, 50 mu/ml respectively). Compound 13 was as active as the antibiotic nystatin.     

1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 3.1 Synthesis and biological properties of aminodeoxystatine and difluorostatone derivatives

Two series of 1,2,4-triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity have been synthesized which incorporate the transition-state mimetics (3S,4S)- and (3R,4S)-5-cyclohexyl-3,4-diaminopentanoic acid ((S)- and (R)-CDAPA), and (4S)-4-amino-5-cyclohexyl-2,2-difluoro-3-oxopentanoic acid (ACDFOPA). Several compounds in these series, for example 13a, 19c, and 19f, were highly potent inhibitors of partially purified human renin (IC50 values of 3.9, 1.6, and 1.4 nM, respectively). The ACDFOPA-based compounds 19c and 19f contain no natural amino acid fragments and have molecular weights which compare well with those of previously reported inhibitors of nanomolar in vitro potency. When administered intravenously to anesthetized, sodium-depleted marmosets at doses of 3 mg/kg, compounds 13a and 19c caused a marked reduction in mean arterial pressure, but in the same animal model at 30 mg/kg, oral activity was not seen.     

1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 2. Synthesis, biological properties and molecular modeling of hydroxyethylene isostere derivatives

A series of inhibitors of human renin have been synthesized, derived from combination of a 2-(8-propyl-6-pyridin-3-yl-1,2,4-triazolo[4,3-a]pyrazin-3-yl)- 3-pyridin- 3-ylpropionic acid moiety 6c with the hydroxyethylene isostere of the scissile amide bond (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid (ChaOH--Val). The more potent members of this series showed good inhibitory activity against partially purified human renin, 7d, for example, having an IC50 of 0.2 nM. Structure-activity relationships for these compounds were consistent with their binding to the S4-S2' sites of human renin. Analogues 7e and 7h-k with a variety of substituents at the C-terminus all had in vitro IC50S less than 1 nM. In contrast with the majority of previously reported inhibitors of similar potency, these compounds contain no natural amino acid fragments. When administered intravenously to anesthetized, sodium-depleted marmosets at doses of 0.3-3.0 mg/kg, compound 7d caused a marked reduction in mean arterial pressure. Following oral administration at 30 mg/kg in the same animal model, 7d again elicited a significant fall in mean arterial pressure, accompanied by suppression of plasma renin activity lasting up to 3 h after dosing.     

Syntheses and 5-HT2 antagonist activity of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives.

A series of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives with a 4-[bis(4-fluoro-phenyl)methylene]piperidine or 4-(4-fluorobenzoyl)piperidine group has been prepared and tested for 5-HT2 and alpha 1 receptor antagonist activity. Among the compounds prepared, 2-[2-[4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl]ethyl]- 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (7b) had the most potent 5-HT2 antagonist activity, which was greater than ritanserin (2), while 7b did not show alpha 1 antagonist activity in vivo. The central 5-HT2 receptor antagonism was approximately 1/30 that of 2 when tested for the ability to block head twitches induced by 5-hydroxytryptophan. Compound 21b, 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro- 2H- pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione also displayed potent 5-HT2 antagonist activity. The compound had moderate alpha 1 receptor antagonism, and the potency inhibiting head twitches was about one-third that of ketanserin (1). These results indicate that 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrimidin-3(2H)-one and 6,7,8,9-tetrahydro-2H-pyrido-[1,2-a]-1,3,5-triazine-2,4(3H)-dione ring systems are useful components of 5-HT2 antagonists.     

1,2,4-triazolo[4,3-a]quinoxalin-1-one moiety as an attractive scaffold to develop new potent and selective human A3 adenosine receptor antagonists: synthesis, pharmacological, and ligand-receptor modeling studies

In the past few years much effort in our laboratory has been directed toward the study of adenosine receptor antagonists, and recently we focused our attention on 2-aryl-1,2,4-triazolo[4,3-a]quinoxaline-1,4-diones and 2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-4-amino-1-ones, some of which were potent and/or selective A(3) receptor antagonists. In the present paper, a new series of triazoloquinoxaline derivatives is described. Most of the new compounds, biologically evaluated in radioligand binding assays at bovine (b) A(1) and A(2A) and at human (h) A(1) and A(3) adenosine receptors, showed high hA(3) adenosine receptor affinity and selectivity. In particular, 2-(4-nitrophenyl)-1,2,4,5-tetrahydro-1,2,4-triazolo[4,3-a]quinoxaline-1,4-dione (1), also tested at the hA(2A) ARs, shows the best binding profile with a high hA(3) affinity (K(i) = 0.60 nM) and strong selectivity vs hA(1) and vs hA(2A) receptors (both selectivity ratios greater than 16 600). To interpret our experimental results, we decided to theoretically depict the putative transmembrane binding motif of our triazoloquinoxaline analogues on hA(3) receptor. Structure-activity relationships have been explained analyzing the three-dimensional structure of the antagonist-receptor models obtained by molecular docking simulation.     

Synthesis of 6-(Ethoxymethylenimino)-1,2,4-triazolo[3′,4′:5,1]-[1,2,4]triazolo[4,3-a]quinazolin-7(6H)-one

As a progressive continuation of our study in the condensed quinazolinone series^{1, 2)}, we recently described the synthesis and antihypertensive activity of some 4-amino[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one derivatives ( 1a-c , R=H, OH, SH). Now, we wish to report the conversion of one of these derivatives, namely 4-amino-1-mercapto-[1,2,4]-triazolo[4,3-a]quinazolin-5(4H)-one (1c) into a more complicate condensed quinazolinone system.     

Synthesis of new functionalized 3-substituted [1,2,4]triazolo [4,3-a]pyrimidine derivatives: potential antihypertensive agents

A convenient synthesis of a series of thiosemicarbazide, 1,3,4-oxadiazole, 1,3,4-thiadiazole, thiazole, 1,2,4-triazole, pyrazole and dioxoisoindoline derivatives incorporating 1,2,4-triazolo[4,3-a]pyrimidine via the reaction of the readily accessible 1,5-dihydro-5-oxo-1.7-diphenyl-1,2.4-triazolo[4,3-a]pyrimidine-3-carbohydrazide (2) with the appropriate reagents is described. The newly synthesized compounds were found to possess antihypertensive and diuretic activities compared to captopril and furosemide as reference controls, respectively.     

Synthesis and biological evaluation of certain 3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-b)pyridazines related to formycin prepared via ring closure of pyridazine precursors

All three amino-substituted 3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-b]pyridazines (5, 19, and 20) structurally related to formycin A were prepared and tested for their antitumor and antiviral activity in cell culture. Dehydrative coupling of 4-amino-5-chloro-3-hydrazinopyridazine (7) with 3,4,6-tri-O-benzoyl-2,5-anhydro-D-allonic acid (6) in the presence of DCC and subsequent thermal ring closure of the reaction product (8) provided 8-amino-7-chloro-3-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)- triazolo[4,3-b]pyridazine (9). Dehalogenation of 9, followed by debenzoylation, gave the formycin congener 8-amino-3-beta-D-ribofuranosyl-1,2,4- triazolo[4,3-b]pyridazine (5). Similar condensation of 5-amino-4-chloro-3-hydrazinopyridazine (13) with 6 and dehalogenation of the cyclized product (16), followed by debenzoylation, gave the isomeric 7-amino-3-beta-D-ribofuranosyl-1,2,4- triazolo[4,3-b]pyridazine (19). DCC-mediated coupling of 6 with 6-chloro-3-hydrazinopyridazine (12), followed by ammonolysis of the cyclized product (21) with liquid NH3, provided a convenient route to 6-amino-3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-b]pyridazine (20). The structural assignment of 5 was made by single-crystal X-ray diffraction analysis. Compounds 5, 19, 20, and certain deprotected nucleoside intermediates were evaluated against L1210, WI-L2, and CCRF-CEM tumor cell lines, as well as against DNA and RNA viruses in culture. These compounds did not exhibit any significant antitumor or antiviral activity in vitro.     

Synthesis and antitumor activity of certain 3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazines related to formycin prepared via ring closure of a 1,2,4-triazine precursor

Several 3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazines related to formycin were prepared and tested for their antitumor activity in cell culture. Dehydrative coupling of 3-amino-6-hydrazino-1,2,4-triazin-5(4H)-one (5) with 3,4,6-tri-O-benzoyl-2,5-anhydro-D-allonic acid (6a) and further ring closure of the reaction product (7) provided 6-amino-3-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1,2,4-triazolo[3,4- f]-1,2,4-triazin-8(7H)-one (8). Condensation of 5 with 3,4,6-tri-O-benzoyl-2,5-anhydro-D-allonic acid chloride (6b), followed by ring annulation, also gave 8 in good yield. Debenzoylation of 8 furnished the guanosine analogue 6-amino-3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazin -8(7H)-one (4b). Thiation of 8 with P2S5, followed by debenzoylation of the thiated product (11a), afforded 6-amino-3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazin -8(7H)- thione (11b). Methylation of the sodium salt of 11a gave the 8-methylthio derivative (10), which on ammonolysis furnished 6,8-diamino-3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4-f]-1,2,4-triazine (9). Diazotization of 10 with tert-butyl nitrite (TBN) and SbCl3 in 1,2-dichloroethane gave the corresponding 6-chloro derivative (12a). Reaction of 10 with TBN in THF in the absence of a halogen source gave 8-(methylthio)-3-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1,2,4- triazolo[3,4-f]-1,2,4-triazine (12b). Ammonolysis of 12b gave the azaformycin A analogue 8-amino-3-beta-D-ribofuranosyl-1,2,4- triazolo[3,4-f]-1,2,4-triazine (3), which on deamination afforded 3-beta-D-ribofuranosyl-1,2,4-triazolo[3,4- f]-1,2,4-triazin-8(7H)-one (4a). The azaformycin A analogue (3) showed pronounced inhibitory effects against L1210, WIL2, and CCRF-CEM cell lines with ID50 values ranging from 5.0 to 7.3 microM.     

3-Hydrazinepyridazine derivatives. III. Synthesis and anti-hypertensive activity of new 3-(2-acylhydrazine)-pyridazine-6-alkylamino substitutes

The synthesis of 2-(6-dialkylamino-3-pyridazinyl)hydrazinecarboxylates (II) and hydrazides (V) from the corresponding 3-chloro-6-dialkylaminopyridazines (I) is described. The 6-substituted derivatives of 2,3-dihydro-1,2,4-triazolo[4,3-b]pyridazine-3-ones (III) and 1,2,4-triazolo[4,3-b)pyridazines (VI) were obtained by thermal cyclization of (II) and (V), respectively. The new acyl derivatives were evaluated together with todralazine and budralazine as antihypertensive agents in comparison with propildazine and hydralazine. The ethoxycarbonyl compound [(II g), ISF 2469] exhibits good antihypertensive activity particularly via oral administration. Its interesting pharmacodynamic properties, including slow onset and long-lasting action, qualify it for further pharmacological and clinical studies.     

Design,synthesis, and biological evaluation of C9- and C2-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as new A2A and A3 adenosine receptors antagonists

In the past few years, our group has been involved in the development of A(2A) and A(3) adenosine receptor antagonists which led to the synthesis of SCH58261 (5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine, 61), potent and very selective at the A(2A) receptor subtype, and N(8)-substituted-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines-N(5)-urea or amide (MRE series, b), very selective at the human A(3) adenosine receptor subtype. We now describe a large series of C(9)- and C(2)-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines to represent an extension of structure-activity relationship work on this class of tricyclic compounds. The introduction of a substituent at 9 position of the tricyclic antagonistic structure led to retention of receptor affinity but a loss of selectivity in respect to the lead compounds b, N(8)-substituted-pirazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines-N(5)-urea or -amide. The substitution of the furanyl moiety of compound 61, necessary for receptor binding, with a phenyl or a substituted aromatic ring (compounds 5a-d, 6-8), caused a complete loss of the affinity at all the adenosine receptor subtypes, demonstrating that the furanyl ring is a necessary structural element to guarantee interaction with the adenosine receptor surface. The introduction of an ethoxy group at the ortho position of the aromatic ring to mimic the oxygen of the furan (compound 5c, 5-amino-7-(2-phenylethyl)-2-(2-ethoxyphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) did not enhance affinity. The introduction of the cycloaminomethyl function by Mannich reaction at the 5' position of the furanyl ring of 61 and the C(9)-substituted compound 41 (5-amino-8-methyl-9-methylsulfanyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) resulted in complete water solubility but a loss of receptor affinity. We can conclude that modifications or substitutions at the furanyl ring are not allowed and the introduction of a substituent at the 9-position of the core pyrazolo-triazolo-pyrimidine structure caused a severe loss of selectivity, probably due to an increased steric hindrance of the radical introduced.     

Synthesis and H1-antihistaminic activity of some novel 1-substituted-4-(3-methylphenyl)-1,2,4-triazolo[4,3-a]quinazolin-5(4H)-ones

A series of novel 1-substituted-4-(3-methylphenyl)-1,2,4-triazolo[4,3-a]quinazolin-5(4H)-ones were synthesized by the cyclization of 2-hydrazino-3-(3-methylphenyl) quinazolin-4(3H)-one with various one carbon donors. The starting material 2-hydrazino-3-(3-methylphenyl)quinazolin-4(3H)-one, was synthesized from 3-methylaniline by a novel innovative route. When tested for their in vivo H(1)-antihistaminic activity on conscious guinea pigs, all the test compounds protected the animals from histamine induced bronchospasm significantly, whereas the compound 1-methyl-4-(3-methylphenyl)-1,2,4-triazolo[4,3-a]quinazolin-5(4H)-one II was found to be equipotent (percent protection 70.0%) with the reference standard chlorpheniramine maleate (percent protection 71%). Compound II show negligible sedation (7%) when compared to chlorpheniramine maleate (25%). Hence it could serve as prototype molecule for further development as a new class of H(1)-antihistamines.     

Synthesis and excitatory amino acid pharmacology of a series of heterocyclic-fused quinoxalinones and quinazolinones.

As part of our program aimed at the development of potent excitatory amino acid antagonists, we synthesized and evaluated a series of substituted 1,2,4-triazolo[4,3-a]quinoxalin-4(5H)-ones, 4, tetrazolo[1,5-a]quinoxalin-4(5H)-ones, 5, and pyrazolo[1,5-c]quinazolin-5(6H)-ones, 6, and an imidazo[1,2-a]quinoxalin-4(5H)-one, 7. In general, the same heterocycles which demonstrated the best affinity for the AMPA receptor also demonstrated the best affinity for the glycine site on the NMDA receptor complex. 1-Propyl-7,8-dichloro-1,2,4-triazolo[4,3-a]quinoxalin-4(5H)-one, 4d, was found to bind with the greatest affinity to the AMPA receptor with an IC50 of 0.83 microM and antagonized 40 microM AMPA-induced depolarization in the cortical slice preparation with an IC50 of 44 microM. 7,8-Dichloro-1,2,4-triazolo[4,3-a]quinoxalin-4(5H)-one, 4a, and 7,8-dichloroimidazo[1,2-a]quinoxalin-4(5H)-one, 7, possessed the best affinity for the glycine site with IC50 values of 0.63 and 1.26 microM, respectively. It is noteworthy that the SAR for the heterocyclic compounds did not directly parallel that of known quinoxalinediones (e.g. DNQX, 2, and DCQX, 15) at the AMPA receptor nor that of the kynurenic acids at the glycine site on the NMDA receptor complex.     

Synthesis and studies on the anticonvulsant activity of 5-alkoxy-[1,2,4]triazolo[4,3-a]pyridine derivatives

In this study, a series of new 5-alkoxy-[1,2,4]triazolo[4,3-a]pyridine derivatives was synthesized and their anticonvulsant activity and neurotoxicity was evaluated with the maximal electroshock and rotarod tests, respectively. The most promising compounds, 3p (5-(4-chlorophenoxy)-[1,2,4]triazolo[4,3-a]pyridine) and 3r (5-(4-bromophenoxy)-[1,2,4]triazolo[4,3-a]pyridine), showed a median effective dose of 13.2 and 15.8 mg/kg and had a protective index value of 4.8 and 6.9, respectively. For exploring the putative mechanism of action, compounds 3n, 3p and 3r were tested in chemically induced models.     

4-Amino[1,2,4]triazolo[4,3-a]quinoxalines. A novel class of potent adenosine receptor antagonists and potential rapid-onset antidepressants

A series of 4-amino[1,2,4]triazolo[4,3-a]quinoxalines has been prepared. Many compounds from this class reduce immobility in Porsolt's behavioral despair model in rats upon acute administration and may therefore have therapeutic potential as novel and rapid acting antidepressant agents. Optimal activity in this test is associated with hydrogen, CF3, or small alkyl groups in the 1-position, with NH2, NH-acetyl, or amines substituted with small alkyl groups in the 4-position, and with hydrogen or 8-halogen substituents in the aromatic ring. Furthermore, many of these 4-amino[1,2,4]triazolo[4,3-a]quinoxalines bind avidly, and in some cases very selectively, to adenosine A1 and A2 receptors. A1 affinity of these compounds was measured by their inhibition of tritiated CHA (N6-cyclohexyladenosine) binding in rat cerebral cortex membranes and A2 affinity by their inhibition of tritiated NECA (5'-(N-ethylcarbamoyl)adenosine) binding to rat striatal homogenate in the presence of cold N6-cyclopentyladenosine. Structure-activity relationship (SAR) studies show that best A1 affinity is associated with ethyl, CF3, or C2F5 in the 1-position, NH-iPr or NH-cycloalkyl in the 4-position, and with an 8-chloro substituent. Affinity at the A2 receptor is mostly dependent on the presence of an NH2 group in the 4-position and is enhanced by phenyl, CF3, or ethyl in the 1-position. The most selective A1 ligand by a factor of greater than 3000 is 121 (CP-68,247; 8-chloro-4-(cyclohexyl-amino)-1- (trifluoromethyl)[1,2,4]triazolo[4,3-a]quinoxaline) with an IC50 of 28 nM at the A1 receptor. The most potent A2 ligand is 128 (CP-66,713; 4-amino-8-chloro-1- phenyl[1,2,4]triazolo[4,3-a]quinoxaline) with an IC50 of 21 nM at the A2 receptor and a 13-fold selectivity for this receptor. Representatives from this series appear to act as antagonists at both A1 and A2 receptors since they antagonize the inhibiting action of CHA on norepinephrine-stimulated cAMP formation in fat cells and they decrease cAMP accumulation induced by adenosine in limbic forebrain slices. Thus certain members of this 4-amino[1,2,4]triazolo[4,3-a]quinoxaline series are among the most potent and A1 or A2 selective non-xanthine adenosine antagonists known.     

Synthesis and pharmacological investigation of novel 1-alkyl-4-(4-substituted aryl/heteroaryl)-1,2,4-triazolo [4,3- a] quinazolin-5 (4H)-ones as a new class of H1-antihistaminic agents

A series of novel 1-alkyl-4-(4-substituted aryl/heteroaryl)- 1,2,4-triazolo [4,3-a] quinazolin-5(4H)-ones were synthesized by the cyclization of 2-hydrazino-3-(4-subst. aryl/heteroaryl) quinazolin-4(3H)-one with various carbon donors. The starting material, 2-hydrazino-3-(4-subst. aryl/heteroaryl) quinazolin-4(3H)-one, was synthesized from 4-subst. arylamine/ heteroarylamine by a novel innovative route. When tested for their in vivo Hi-antihistaminic activity on conscious guinea pigs, all the test compounds protected the animals from histamine induced bronchospasm significantly, whereby the compound 1-methyl-4-(2-py-ridyl)-1,2,4-triazolo[4,3-a] quinazolin-5(4H)-one (II) was found to be more potent (percent protection 71.43 %) when compared to the reference standard, chlorpheniramine maleate (percent protection 71 %). Compound II showed negligible sedation (8 %) when compared to chlorpheniramine maleate (25 %). Hence it could serve as prototype molecule for further development as a new class of H1-antihistamines.     

Synthesis and anti-inflammatory activity evaluation of novel 7-alkoxy-1-amino-4,5-dihydro[1,2,4]triazole[4,3-a]quinolines

In this study, a novel series of 7-alkoxy-1-amino-4,5-dihydro[1,2,4]triazole[4,3-a]quinolines were synthesized by using 6-hydroxy-3,4-dihydro-2(1H)-quinolone as the starting material. These compounds were evaluated for anti-inflammatory activity through monitoring their ability to inhibit xylene-induced ear edema in mice. Some of the tested compounds exhibited significant activity, and the compounds 5f (7-(benzyloxy)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolin-1-amine) and 5i (7-(p-chlorobenzyloxy)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolin-1-amine) showed the highest anti-inflammatory activity (52% and 58% inhibition, respectively, at 2 h pre-administration) which were comparable to or even slightly more potent than the reference drug ibuprofen (55%). Furthermore, the structure-activity relationship of these 1,2,4-triazole quinolines was demonstrated.     

Synthesis of certain substituted quinoxalines as antimicrobial agents (part II)

Several fused triazolo and ditriazoloquinoxaline derivatives such as 1-aryl-4-chloro-[1,2,4]triazolo[4,3-a]quinoxalines (3a-d), 4-alkoxy[1,2,4]triazolo[4,3-a]quinoxalines (4a,b), 4-substituted-amino-[1,2,4] triazolo[4,3-a]quinoxalines (5a-h), 1-(aryl)-[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-thione (6), 4-(arylidenehydrazino)1-phenyl-[1,2,4]triazolo[4,3-a]quinoxalines (10a-e) and [1,2,4]ditriazolo[4,3-a:3',4'-c]quinoxaline derivatives (11-13) have been synthesized and some of these derivatives were evaluated for antimicrobial and antifungal activity in vitro. It was found that compounds 3a and 9b possess potent antibacterial activity compared to the standard tetracycline.     

Pharmacological activities of a novel thienodiazepine derivative as a platelet-activating factor antagonist. Effects on microvascular permeability, hypotension and nephrosis.

The effects of a newly synthesized platelet-activating factor (PAF) antagonist, (S)-(+)-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8,11- dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepine (E-6123, CAS 131614-02-3) on microvascular permeability, systemic hypotension and nephrosis were investigated. E-6123 inhibited PAF injection-induced microvascular permeability (edema) in guinea pigs after oral administration at 3 micrograms/kg. The inhibitory effects of E-6123 were very potent compared to those of other PAF antagonists. E-6123 reversed PAF and/or endotoxin injection-induced hypotension in rats after intravenous administration at 3 micrograms/kg. The increase in urinary protein excretion of rats in which nephrosis had been induced by intraperitoneal injection of aminonucleoside was not inhibited by oral administration of E-6123 at 10 mg/kg/d.     

SAR of a series of 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridines as potent inhibitors of human eosinophil phosphodiesterase

The potency and physical properties of a previously reported 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine series of human eosinophil phosphodiesterase inhibitors were improved by tying the lactam moiety into a triazolo ring. The resulting 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine series provided nonionizable analogs with melting point properties suitable for micronization. Substitution at the 3-position of the 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine tricycle led to a 2-thienyl analog, 19 (tofimilast), a potent PDE4 inhibitor with low oral bioavailability and no emesis-associated behaviors in ferrets at plasma concentrations up to 152 ng/mL.