Imidazo[1,2-a]quinoxalines: synthesis and cyclic nucleotide phosphodiesterase inhibitory activity

A group of imidazo[1,2-a]quinoxalines have been synthesised from quinoxaline by condensation of an appropriate haloester or intramolecular cyclisation of a keto moiety on an intracyclic nitrogen atom. The reactivity of the heterocycle was explored through diverse reactions such as electrophilic substitution, lithiation and halogen-metal exchange to give access to a new series of derivatives. Confirmation of their structure was mainly performed by NMR, after careful assignment of the signals in comparison to previous attributions made on the parent imidazo[1,2-a]quinoxaline and discussion of available data in the literature. The cyclic nucleotide phosphodiesterase inhibitor activity of some of these derivatives has been assessed on isoenzymes type III and type lV. Compound 15, 4-(methylamino)imidazo[1,2-a]quinoxaline-2-carbonitrile, exhibited potent relaxant activity on smooth muscle, with a potency similar to the one measured with SCA 40, its structural analogue in the imidazo[1,2-a]pyrazine series.     

New ferrocenic pyrrolo[1,2-a]quinoxaline derivatives: synthesis, and in vitro antimalarial activity--Part II

Following our search for antimalarial compounds, novel series of ferrocenyl-substituted pyrrolo[1,2-a]quinoxalines 1-2 were synthesized from ferrocene-carboxaldehyde and tested for their in vitro activity upon the erythrocytic development of Plasmodium falciparum strains with different chloroquine-resistance status. The ferrocenic pyrrolo[1,2-a]quinoxalines 1-2 were prepared in 6 or 9 steps through a Barton-Zard reaction. Promising pharmacological results against FcB1, K1 and F32 strains were obtained with ferrocenyl pyrrolo[1,2-a]quinoxalines 1j-l linked by a bis-(3-aminopropyl)piperazine linker substituted by a nitrobenzyl moiety.     

Novel imidazo[1,2-a]naphthyridinic systems (part 1): synthesis, antiproliferative and DNA-intercalating activities

Novel imidazo[1,2-a]naphthyridinic systems 6a-15a and 6b-15b were obtained from Friedl?nder's reaction in imidazo[1,2-a]pyridine series. Most of the compounds were evaluated for their antitumor activity in the NCIs in vitro human tumor cell line screening panel. Among them, pentacyclic derivatives 13b and 14a exhibited in vitro activity comparable to anticancer agent such as amsacrine. Their mechanism of cytotoxicity action was unrelated to poisoning or inhibiting abilities against topo1. On the contrary, we highlighted a direct intercalation of the drugs into DNA by electrophoresis on agarose gel.     

Synthesis of some new 4-styryltetrazolo[1,5-a]quinoxaline and 1-substituted-4-styryl[1,2,4]triazolo[4,3-a]quinoxaline derivatives as potent anticonvulsants

4-Methyltetrazolo[1,5-a]quinoxaline (3) was prepared by the azide cyclocondensation of 2-chloro-3-methylquinoxaline (2). The reaction of 3 with aromatic aldehydes furnished 4-styryltetrazolo[1,5-a]quinoxalines (4a-f). Compound 2, on treatment with hydrazine hydrate gave 2-hydrazino-3-methylquinoxaline (5). The ring closure of 5 was achieved by the reaction of orthoesters and trifluoroacetic acid to yield 4-methyl-1-(substituted)[1,2,4]triazolo[4,3-a]quinoxalines (7a-c). Further, reaction of 7a-c with different aromatic aldehydes furnished the title compounds, 4-styryl-1-(substituted)[1,2,4]triazolo[4,3-a]quinoxalines (8a-i) in good yield. In another scheme, the hydrazino compound 5 was treated with different aromatic aldehydes to yield corresponding N-arylidenehydrazino quinoxalines (6a-d). Further, the oxidative cyclization of hydrazones by nitrobenzene yielded 1-aryl-4-methyl[1,2,4]triazolo[4,3-a]quinoxalines (7d-g), which on condensation with aromatic aldehydes gave the title compounds, 1-aryl-4-styryl[1,2,4]triazolo[4,3-a]quinoxalines (8j-u). The newly synthesized compounds have been characterized by FTIR, (1)H NMR, (13)C NMR and mass spectral data, followed by elemental analysis. Some of the compounds were screened for in vivo anticonvulsant activity. Few of them exhibited promising results.     

6-Substituted imidazo[1,2-a]pyridines: synthesis and biological activity against colon cancer cell lines HT-29 and Caco-2

A range of 6-substituted imidazo[1,2-a]pyridines were synthesized using a multicomponent coupling reaction. Most of these compounds were found to exhibit excellent activity against the colon cancer cell lines HT-29 and Caco-2, whilst not showing significant toxicity against white blood cells. Our studies have shown that the proteolytic phase of apoptosis was initiated 2 h after treatment with these imidazo-[1,2-a]pyridines. The data suggests that the imidazo[1,2-a]pyridine-induced cell death in HT-29 and Caco-2 cells is mediated via pathway(s) that include the release of cytochrome c from the mitochondria to the cytosol and the activation of caspase 3 and caspase 8.     

Synthesis and anticancer and anti-HIV testing of some pyrazino[1,2-a]benzimidazole derivatives

In this study, some 1-methylene-2,3-diaryl-1,2-dihydropyrazino[1,2-a]benzimidazole and some 1-(2-arylvinyl)-3-arylpyrazino[1,2-a]benzimidazole derivatives were synthesised. The structure elucidation of the compounds was performed by IR, 1H-NMR and MASS spectroscopic data and elemental analyses results. Anticancer and anti-HIV activities of the compounds were examined, however no anti-HIV activity was seen; highly notable anticancer activity was obtained. It was also observed that the compounds were more potent against leukaemia cell lines.     

Urinary excretion levels of carcinogenic glutamic acid pyrolysis products and their N-acetyl derivatives in humans.

The carcinogenic glutamic acid pyrolysis products 2-amino-6-methyldipyrido [1, 2-a: 3', 2'-d]imidazole (Glu-P-1) and 2-amino-dipyrido [1, 2-a: 3', 2'-d] imidazole (Glu-P-2), and their N-acetyl derivatives were measured in 24-h urine of individual subjects by high-performance liquid chromatography. These compounds were detected in all urine samples analyzed, although the contents varied widely among subjects. The mean levels of Glu-P-1, N-acetyl-Glu-P-1, Glu-P-2 and N-acetyl-Glu-P-2 in 24-h urine were 0.53, 0.41, 2.12 and 4.60 pmol, respectively. In vitro experiments revealed N-acetyltransferase activity with Glu-P-1 and Glu-P-2 in the cytosolic fractions from rat kidneys and human autopsy kidney specimens as well as those from liver specimens, suggesting that extrahepatic tissues may also play significant roles in the N-acetylation of these carcinogens. These results show that Glu-P-1 and Glu-P-2, after being partially N-acetylated in metabolic organs such as liver and kidney, are excreted into urine together with their N-acetyl derivatives. It is suggested that daily excretion of carcinogenic glutamic acid pyrolysis products and their N-acetyl derivatives into urine can be a suitable biological monitor for exposure to these carcinogens. Abbreviations: Glu-P-1, 2-amino-6-methyldipyrido [1, 2-a: 3', 2'-d] imidazole; Glu-P-2, 2-aminodipyrido [1, 2-a: 3', 2'-d] imidazole; N-acetyl-Glu-P-1, 2-acetylamino-6-methyldipyrido [1, 2-a: 3', 2'-d] imidazole; N-acetyl-Glu-P-2, 2-acetylaminodipyrido[1,2- a:3', 2'-d]imidazole; HPLC, high-performance liquid chromatography.     

1,8-Naphthyridines VI. Synthesis and anti-inflammatory activity of 5-(alkylamino)-N,N-diethyl[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides with a new substitution pattern on the triazole ring

On the basis of the good anti-inflammatory properties shown by the 9-alkyl-N,N-dialkyl-5-(alkylamino)[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides 1, a series of analogues of such compounds, in which the 9-alkyl substituent was replaced by an ester or amide group (compounds 3a-i), was prepared and tested (inhibition of carrageenan-induced paw edema in the rat). Also two 5-(N-alkyl,N-acylamino) derivatives (compounds 4a,b) were synthesized and evaluated for the same purpose. Even though the general trend for these new [1,2,4]triazolo[4,3-a][1,8]naphthyridine derivatives was a decrease in activity compared with compounds 1, some of the new synthesized compounds exhibited still good anti-inflammatory properties.     

4-Substituted anilino imidazo[1,2-a] and triazolo[4,3-a]quinoxalines. Synthesis and evaluation of in vitro biological activity

Fifteen imidazo[1,2-a] and [1,2,4]triazolo[4,3-a]quinoxalines were prepared. These compounds bear at position 4 various substituents related to the moieties present in classical and non-classical antifolic agents. And we evaluated in vitro antimicrobial, antiviral and antiproliferative activities. In particular, title compounds were evaluated in vitro against representative strains of Gram-positive and Gram-negative bacteria (S. aureus, Salmonella spp.), mycobacteria (M. fortuitum, M. smegmatis ATCC 19420 and M. tuberculosis ATCC 27294), yeast and moulds (C. albicans ATCC 10231 and A. fumigatus). Furthermore, their antiretroviral activity against HIV-1 was determined in MT-4 cells together with cytotoxicity. In these assays title compounds were tested for their capability to prevent MT-4 cell growth. Among the examined series, the compounds 5, 7 and 10 showed cytotoxicity against mock-infected MT-4 cells.     

Post Groebke-Blackburn multicomponent protocol: synthesis of new polyfunctional imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine derivatives as potential antimicrobial agents

New antimicrobial agents [imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine] have been synthesized. Their antimicrobial activities were conducted against various Gram-positive and Gram-negative bacteria including Staphylococcus aureus. Compounds 5d, 7a, 10a, 11a and 12a proved to efficiently inhibit the growth of all the Gram-positive and Gram-negative strains investigated. Results of this study showed that the nature of the substituents on the armed phenyl groups determined the extent of the activity of the fused imidazopyridine and/or imidazopyrimidine derivatives. Preliminary structure-activity observations revealed that groups with positive sigma and positive bi values (e.g. 5d, 6c, 12a, 12d) were significantly more active compared to other bioisosteres (e.g. 5b). Furthermore, increasing the molar refractivity of the substitution pattern (e.g. 5b, 6b and 6d) sharply decreased the antibacterial activity.     

Design and synthesis of 5-alkoxy-[1,2,4]triazolo[4,3-a]quinoline derivatives with anticonvulsant activity

A series of 5-alkoxy-[1,2,4]triazolo[4,3-a]quinoline derivatives were synthesized using 4-hydroxyquinolin-2(1H)-one as the starting material. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES) and their neurotoxicities were measured by the rotarod test. The results of these tests demonstrated that 5-hexyloxy-[1,2,4]triazolo[4,3-a]quinoline (3f) was the most potent anticonvulsant, with median effective dose (ED(50)) of 19.0mg/kg and protective index (PI=TD(50)/ED(50)) values of 5.8 in the MES test. Compound 5-benzyloxy-[1,2,4]triazolo[4,3-a]quinoline (3j), exhibited a little weaker activity than compound 3f in controlling the seizure induced by MES test at the dose of 22.8 mg/kg, but it possessed lower neurotoxicity with PI value of 12.0, which was safer than marketed drug carbamazepine. To explain the possible mechanism of anticonvulsant activity, compound 3j was tested in pentylenetetrazole test, isoniazid test, thiosemicarbazide test, 3-mercaptopropionic acid and strychnine test.     

Synthesis, antifungal activity and CoMFA analysis of novel 1,2,4-triazolo[1,5-a]pyrimidine derivatives

In order to search novel agrochemicals with higher antifungal activity, a series of new 1,2,4-triazolo[1,5-a]pyrimidine derivatives bearing 1,3,4-oxadiazole moieties were designed and synthesized. Their antifungal activities against Rhizoctonia solani were evaluated in vitro. By determining the EC(50) values of all the newly synthesized compounds and 10 formerly synthesized compounds, compound 8r, 2-((5-(sec-butylthio)-1,3,4-oxadiazol-2-yl)-methylthio)-5-dimethyl-1,2,4-triazolo-[1,5-a]pyrimidine, was found to display the highest antifungal activity (EC(50)=6.57 microg mL(-1)). Based on the quantitative structure-activity relationships analyses, 2-(1-(5-(sec-butylthio)-1,3,4-oxadiazol-2-yl)ethylthio)-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (9j) was designed and synthesized, which was found to display much higher activity (EC(50)=3.34 microg mL(-1)) than compound 8r and the control. To further explore the comprehensive structure-activity relationships, a 3D-QSAR analysis using the method of comparative molecular field analysis (CoMFA) was performed and a statistically reliable model with good predictive power (r(2)=0.929, q(2)=0.588) was achieved on the basis of the common substructure-based alignment. According to the CoMFA model, the structure-antifungal activity relationship was explained reasonably.     

Design, synthesis of 8-alkoxy-5,6-dihydro-[1,2,4]triazino[4,3-a]quinolin-1-ones with anticonvulsant activity

A new series of 8-alkoxy-5,6-dihydro-[1,2,4]triazino[4,3-a]quinolin-1-one derivatives were synthesized. Their anticonvulsant activities were evaluated by the maximal electroshock (MES) test, and their neurotoxicities were evaluated by the rotarod neurotoxicity test. The results showed that 8-heptyloxy-5,6-dihydro-[1,2,4]triazino[4,3-a]quinolin-1-one 5t was the most potent with median effective dose (ED(50)) value of 11.4 mg/kg, median toxicity dose (TD(50)) of 114.1 mg/kg, providing a protective index (PI=TD(50)/ED(50)) value of 10.0, which is much greater than the PI of the prototype drug carbamazepine (PI=6.4). To explain the possible mechanism of anticonvulsant activity, the compound 5t was tested in chemically induced seizures.     

1,5-benzodiazepines. Part XIII. Substituted 4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amines and 4H-imidazo[1,2-a][1,5]benzodiazepin-5-amines as analgesic,anti-inflammatory and/or antipyretic agents with low acute toxicity

The reaction of proper N,N-dialkyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amines (1) with N-chlorosuccinimide afforded their 4-chloroderivatives 3 which in turn were treated with cyclic amines to give the corresponding 4,5-diaminoderivatives 4. The N,N-dialkyl-4H-imidazo[1,2-a][1,5]benzodiazepin-5-amines (5) were prepared starting from suitable 4-(dialkylamino)-1,3-dihydro-2H-1,5-benzodiazepin-2-ones (8), through multistep synthetic routes. At the 200 mg kg(-1) os dose, some compounds 3 and 4 showed notable analgesic or anti-inflammatory activity but no antipyretic properties, whereas the 5-(dibutylamino) derivatives 5b and 5f proved to be significantly endowed with all these activities. Almost all the compounds 3, 4 and 5 did not show acute toxicity in mice up to 800 mg kg(-1) os dose.     

Evaluation of the anti-inflammatory and anti-nociceptive activities of novel synthesized melatonin analogues

This study aimed at evaluation of the reactivity of melatonin (1) towards various chemical reagents to produce new melatonin analogues containing heterocyclic moieties which would provide basic pharmacological activities. The pyrrolo[1,2-a]indole derivatives 3, 5, 12, 14 and pyrido[1,2-a]indole derivatives 9a, b were synthesized via straightforward and efficient methods and their structures were established based on the analytical and spectral data. Also, this work was extended to study the potential role of the novel synthesized melatonin analogues 3, 5, 9a and 12 as anti-inflammatory and anti-nociceptive agents in comparison with melatonin. After s.c. administration all compounds induced significant anti-inflammatory activity, inhibiting the paw oedema response compared with the control group at all time points in the test. Compound 5 has the strongest anti-inflammatory activity which exceeds that of the parent reference, melatonin, followed by compounds 9a and 12, at the first 2h of administration. Effect of melatonin analogues on thermal pain, acetic acid-induced writhing and gastric lesions caused by indomethacin was also investigated. Compounds 5 and 12 were more potent as anti-nociceptive drugs; they are more potent in this respect than melatonin.     

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

A series of novel 1-substituted-4-(2-methylphenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones were synthesized by the cyclization of 2-hydrazino-3-(2-methylphenyl)-3H-quinazolin-4-one with various one carbon donors. The starting material 2-hydrazino-3-(2-methylphenyl)-3H-quinazolin-4-one was synthesized from 2-methyl aniline by a novel innovative route. The title compounds were tested for their in vivo H(1)-antihistaminic activity on guinea pigs; all the tested compounds protected the animals from histamine-induced bronchospasm significantly. Compound 1-methyl-4-(2-methylphenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (II) emerged as the most active compound of the series and it is more potent (72.45%) when compared to the reference standard chlorpheniramine maleate (71%). Compound II showed negligible sedation (11%) when compared to chlorpheniramine maleate (30%). Hence it could serve as the prototype molecule for further development as a new class of H(1)-antihistaminic agents.     

Suppression of genotoxicity of carcinogens by (-)-epigallocatechin gallate.

Epidemiological evidence shows that green tea may be a factor in lowering cancer risk. We have investigated the possibility that (-)-epigallocatechin gallate (EGCG), a major polyphenol in green tea, might be an antimutagenic substance. In the Ames Salmonella test, EGCG suppressed the direct-acting mutagenicity of 3-hydroxyamino-1-methyl-5H-pyrido-[4,3-b]indole (Trp-P-2(NHOH)) and 2-hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1(NHOH)), the activated forms of food-derived carcinogens 3-amino-1-methyl-5H-pyrido[4,3-b]indole and 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole. EGCG was also effective in reducing the mutagenicity of Trp-P-2(NHOH) in mouse FM3A cells in culture. Furthermore, EGCG demonstrated a suppressive effect in the in vivo Drosophila mutation assays, i.e., the wing spot test, and the DNA repair test, on several carcinogens. EGCG was also effective in inhibiting DNA single-strand breaks in vitro caused by Glu-P-1(NHOH). We conclude that the mechanism of inhibition may not have resulted from direct interaction between EGCG and the mutagens, but rather from indirect interception of mutagen action by EGCG.     

Synthesis and biological activity of imidazopyridine anticoccidial agents: Part II

Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Recently, we reported the synthesis and biological activity of potent imidazo[1,2-a]pyridine anticoccidial agents. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we report the synthesis and anticoccidial activity of a second set of such compounds, focusing on derivatization of the amine side chain at the imidazopyridine 7-position. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.     

Synthesis and biological activity of imidazopyridine anticoccidial agents: part I

Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we present the synthesis and biological activity of imidazo[1,2-a]pyridine anticoccidial agents. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.     

Organoiodine (III) mediated synthesis of 3-aryl/hetryl-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidines as antibacterial agents

Synthesis of some new 3-aryl/hetryl-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidines (3a-k) has been accomplished by the oxidation of 4,6-dimethyl-2-pyrimidinylhydrazones of various aldehydes with iodobenzene diacetate in dichloromethane. Nine new compounds (3b-g and 3i-k) were tested in vitro for their antibacterial activity. Two compounds, namely 3-(4'-pyridyl)-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidine (3k) and 3-(3',4'-dimethoxyphenyl)-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidine (3f), were associated with substantially higher antibacterial activity than some commercial antibiotics against Bacillus subtilis, Escherichia coli, Staphylococcus aureus and Salmonella typhi at MIC (minimum inhibitory concentration) i.e. 10 microg/ml.