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.     

Cyclic guanidines: synthesis and antiplatelet activity of 4,6,7,8-tetrahydro-1H-imidazo[1,2-a]pyrazolo[3,4-d]pyrimidin-7-ones and 1,4,6,7,8,9-hexahydropyrazolo [3',4':4,5]pyrimido[2,1-c] [1,2,4]triazin-7-ones

A series of 4,6,7,8-tetrahydro-1H-imidazo[1,2-a]pyrazolo [3,4-d]pyrimidin-7-ones (1b-n) and 1,4,6,7,8,9-hexahydropyrazolo [3',4':4,5]pyrimido [2,1-c][1,2,4]triazin-7-ones (2a-d) has been synthesized. In view of their potential anti-aggregating activity the compounds were tested in vitro for inhibitory activity towards ADP- and collagen-induced aggregation of human platelets. Among the compounds studied, 8-benzyl-1-(2,5-dichlorophenyl)-4,6,7,8-tetrahydro-1H-imidazo [1,2-a]pyrazolo[3,4-d]pyrimidin-7-one (1n) exhibited the most favorable activity. The 2,5-dichlorophenyl side chain is an important lipophilic and/or steric pharmacophore.     

Synthesis and Antimicrobial Evaluation of Some New Thiazoline and Thiazolidinone Derivatives Incorporating [1,2,4]Triazolo[1,5-a]benzimidazole

Two new series of 3-[2-(3,4-disubstituted-2,3-dihydrothiazol-2-ylidene)hydrazonopropylidenyl]-2-(methylthio)-3H-[1,2,4]triazolo[1,5-a]benzimidazole (6-29) and 3-[2-(3-substituted-4-oxothiazolidin-2-ylidene)hydrazonopropylidenyl]-2-(methylthio)-3H-[1,2,4]triazolo[1,5-a]benzimidazole (30-33) were synthesised starting from 1-[2-(methylthio)-3H-[1,2,4]triazolo[1,5-a]benzimidazol-3-yl] acetone N⁴-alkyl (aryl) thiosemicarbazones (2-5). Chemical structures of the compounds have been elucidated by different spectral data as well as elemental microanalysis. The newly synthesised compounds were tested for their in vitro antimicrobial activity using the standard agar cup diffusion method. Results revealed that most of the test compounds showed promising broad spectrum antibacterial and antifungal profiles against tested microorganisms, relative to references.     

Synthesis of new pyrido[4',3':4,5]thieno[2,3-d]-1,2,4-triazolo[3,4-c]pyrimidines and a 5,6-dihydro-1,2,4-triazolo[4",3":1',2']pyrido[4',3':4,5]thieno [2,3-d]-pyrimidine ring system

A series of substituted pyrido[4',3':4,5]thieno[2,3-d]-1,2,4-triazolo[3,4-c]pyrimidines 4-6, 8, pyrido[4',3':4,5]thieno[2,3-d]-1,2,4-triazolo[3,4-c]pyrimidines 11-13 and 5,6-dihydro-1,2,4-triazolo[4",3":1',2']pyrido[4',3':4,5]thieno[2,3-d] pyrimidines 16-19 have been synthesized from 3, 10 and 15 through the reaction with orthoesters and carbon disulphide, respectively.     

Synthesis of pyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidine derivatives for antiviral evaluation

6-Amino-3-methyl-4-(4-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1) was used as a precursor for preparation of some novel 3,7-dimethyl-4-(4-nitrophenyl)-2,4-dihydropyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidine derivatives 3-6, and some of their corresponding N(2)- and C(5)-S-acyclic nucleosides 7 and 8. Furthermore, the preparation of 5-amino-1-[3,7-dimethyl-4-(4-nitrophenyl)-2,4-dihydropyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidin-5-yl]-1H-pyrazole derivatives 10-16 were described. Some of the prepared products were selected and tested for antiviral activity against Herpes Simplex Virus type-1 (HSV-1).     

Synthesis and Activity Evaluation of 2-(1-naphtho[2,1-b]furan-2-yl-carbonyl)-3,5-disubstituted-2,3-dihydro-1H-pyrazoles

Ethyl naphtho[2,1-b]furan-2-carboxylate (2) on reaction with hydrazine hydrate in presence of acid catalyst in ethanol medium affords naphtho[2,1-b]furan-2-carbohydrazide (3). The reaction of substituted acetophenones (4a-c) with aromatic aldehydes (5a-e) produces chalcones (6a-o) via the Claisen condensation. The reaction of naphtho[2,1-b]furan-2-carbohydrazide (3) with chalcones (6a-6o) in presence of acetic acid as catalyst in dioxane produces 1-(naphtho[2,1-b]furan-2-yl-carbonyl)-3,5-disubstituted-2,3-dihydro-1H-pyrazoles (7a-o). The structures of newly synthesized compounds have been established by elemental analysis and spectral studies. The compounds 7a-o have been evaluated for their antimicrobial activity and some selected compounds evaluated for antiinflammatory, analgesic, anthelmintic, diuretic and antipyretic activities.     

Synthesis and fungistatic activity of 3-(2-dialkylaminoethylthio)thieno [2,3-c] and [3,2-d] isothiazole derivatives

A series of 5-acyl-4-amino-3-(2-dialkylaminoethyl)thieno-[2,3-c] and [3,2-d]isothiazole derivatives was synthesized. The compounds were evaluated for antifungal activity.     

Synthesis and antimicrobial activity of new 2-[p-substituted-benzyl]-5-[substituted-carbonylamino]benzoxazoles

A series of 23 new 2-[p-substituted-benzyl]-5-[p-substituted-phenyl/benzyl-carbonylamino]benzoxazole derivatives has been synthesized by reacting 5-amino-2-[p-substituted-benzyl]benzoxazoles with the appropriate carboxylic acid chlorides. The structures of the synthesized compounds were confirmed by IR and (1)H-NMR spectral data. Antimicrobial activities of the compounds were investigated using the twofold serial dilution technique against two gram-positive and two gram-negative bacteria and three Candida species in comparison with standard drugs. Microbiological results indicated that the newly synthesized 2-[p-substituted-benzyl]-5-[p-substituted-phenyl/benzyl-carbonylamino]benzoxazole derivatives (3-25) possessed a broad spectrum of activity, showing MIC values of 6.25-200 microg/mL against the gram-positive and gram-negative microorganisms tested. Moreover, they showed significant antifungal activity with MIC values of 3.12-100 microg/mL against the Candida species tested. Especially, with a MIC value of 3.12 microg/mL, 2-benzyl-5-[p-bromobenzyl-carbonylamino]benzoxazole 9 displayed the same activity against C. glabrata as the standard drug myconazol.     

Synthesis and antimicrobial activities of novel naphtho[2,1-b]pyran, pyrano[2,3-d]pyrimidine and pyrano[3,2-e][1,2,4]triazolo[2,3-c]-pyrimidine derivatives

The synthesis of new naphtho[1',2':5,6]pyrano[2,3-d]pyrimidines and related heterocycles has been reported. The key intermediate 3-amino-8-bromo-1-(p-methoxyphenyl)-1H-naphtho[2,1-b] pyran-2-carbonitrile (3c) was obtained in one pot synthesis by treating alpha-cyanocinnamonitrile (1c) with 6-bromo-2-naphthol (2). Antimicrobial activity was shown for some of the synthesized compounds.     

A facile synthesis and anticancer activity evaluation of spiro[thiazolidinone-isatin] conjugates

The synthesis and evaluation of the anticancer activity of 3'-aryl-5'-arylidene-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-diones and spiro[3H-indole-3,2'-thi-azolidine]-2,4'(1H)-dione-3'-alkanoic acid esters were described. The structure of the compounds was determined by (1)H and (13)C NMR and their in vitro anticancer activity was tested in the National Cancer Institute. Among the tested compounds, (5'Z)-5'-(benzylidene)-3'-(4-chlorophenyl)spiro[3H-indole-3,2'-thia-zolidine]-2,4'(1H)-dione (IIa) and (5'Z)-3'-(4-chlorophenyl)-5'-[4-(1-methylethyl)-benzylidene]spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-dione (IIb) were superior to other related compounds.     

Synthesis and antihypertensive activity of a series of spiro[1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine-2,5'-oxazolidin-2'-one]s

The 2R*,11bS* and 2S*,11bS* diastereoisomers of the spiro[1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine-2, 5'-oxazolidin-2'-one] system were prepared by stereoselective methods. Evaluation of these compounds for antihypertensive activity by oral administration to the spontaneously hypertensive rat showed the 2S*,11bS* series was the more potent. Within that series it was found that small alkyl substituents at positions 3 and 4' enhanced antihypertensive activity and that methoxyl substitution at positions 9 and 10 was optimal. (2S,3S,11bS)-Spiro-[2-ethyl-9,10-dimethoxy-1,3,4,6,7, 11b-hexahydro-2H-benzo[a]quinolizine-2,5'-oxazolidin-2'-one] [(-)-9e] was one of the most efficacious compounds of this series, while its antipode, (+)-9e, was inactive. Selected compounds in this series were shown to be alpha-adrenoceptor antagonists.     

Synthesis and antifungal activity of new derivatives of 5-(4-halobenzoyl)-4-amino-3-(2-dialkylaminoethylthio)thieno [2,3-c] and [3,2-d] isothiazole

A new series of 5-(4-halobenzoyl)-4-amino-3-(2-dialkylamino-ethylthio)thieno [2,3-c] and [3,2-d] isothiazole derivatives has been synthetized. The compounds were evaluated for antifungal activity on yeast and dermatophytes. The compound (VI b) resulted about thirty times less potent than miconazole on dermatophytes.     

Synthesis of new thiazolylthiazolidinylbenzothiazoles and thiazolylazetidinylbenzothiazoles as potential insecticidal, antifungal, and antibacterial agents

A series of 2-{[2'-(3'-chloro-2'-oxo-4'-substitutedaryl-1'-azetidinyl)-1',3'-thiazol-4'-yl] thio}benzothiazoles (4a-4e) and 2-{[(2'-(2'-substitutedaryl-4'-thiazolidinon-3'-yl)-1',3'-thiazol-4'-yl]thio}benzothiazoles (5a-5e) have been synthesized from 2-[(2'-substitutedarylidenylimino-1',3'-thiazol-4'-yl)thio]benzothiazoles (3a-3e). The structure of these compounds has been elucidated by elemental (C, H, N) and spectral (IR, (1)H-NMR, Mass) analysis. Furthermore, compounds 3a-3e, 4a-4e, and 5a-5e were screened for insecticidal activity against Periplaneta americana and antifungal, antibacterial activities in vitro against different strains of fungi and bacteria. Out of the fifteen compounds tested, compound 5b, 2-{[2'-(2'-p-hydroxy-m-methoxyphenyl)-4'-thiazolidinon-3'-yl)-1',3'-thiazol-4'-yl]thio}benzothiazole, was found to possess most prominent insecticidal activity.     

Identification of important structural features of thiazolo[4,5-d]pyrimidines required for potent antifungal activity

Pyrimidines, either mononuclear or condensed with other heterocycles have established its importance in medicinal chemistry. Variety of biological activities have been reported by thiazolo[4,5-d]pyrimidine derivatives. The present work describes the synthesis and antifungal activity of several 3-(substituted)-5-(substituted)phenylamino-6-(substituted)phenylthiazolo[4,5-d]pyrimidine-7(6H)-one-2(3H)-thiones. The target compounds were synthesized by cyclocondensation of 4-amino-5-carbethoxy-3-(substituted)thiazolo-2(3H)-thione and S-methyl di(substituted)phenylisothiourea. All synthesized compounds were tested for minimum inhibitory concentration against different fungal strains such as, Aspergillus niger, A. clavatus and Candida albicans and compared with fluconazole and nystatin as reference drug. Some of the compounds have exhibited potent inhibitory activity on all fungal strains, and were found more potent than reference standard. Some of the important structural features required for broad spectrum activity in this series have been derived.     

Potential antitumor agents. 37. Synthesis and antitumor activity of guanylhydrazones from imidazo[2,1-b]thiazoles and from the new heterocyclic system thiazolo[2',3':2,3]imidazo[4,5-c]quinoline

This paper reports synthesis and antitumor activity of new guanylhydrazones from imidazo[2,1-b]thiazoles and from the new heterocyclic system thiazolo[2',3':2,3]imidazo[4,5-c]quinoline. The compounds were tested as potential antitumor agents at the National Cancer Institute. The effect of the guanylhydrazone of 2-chloro-6-(2,5-dimethoxy-4-nitrophenyl)imidazo[2,1-b]thiazole-5-carbaldehyde (41) was investigated, and it was found to be an inhibitor of Complex III of the mitochondrial respiratory chain and is able to induce apoptosis in the cell lines HT29 and HL60.     

Pyrido[3',2':4,5]thieno[3,2-d]-N-triazines: a new series of orally active antiallergic agents

A new series of orally active mediator release inhibitors, pyrido[3',2':4,5]thieno[3,2-d]-N-triazines, was synthesized and evaluated for antiallergic activity. Several products showed high activity as inhibitors or wheal information in the rat passive cutaneous anaphylaxis screen and as inhibitors of histamine release from passively sensitized rat mast cells. Many compounds were orally active in the PCA test. The most potent compound, 7-phenylpyrido-[3',2':4,5]thieno[3,2-d]-1,2,3-triazin-4(3H)- one (10) with an I50 value of 0.05 microM, was 60 times more potent than disodium cromoglycate (DSCG) in the RMC assay.     

Synthesis and antiviral activity of methyl derivatives of 9-[2-(phosphonomethoxy)ethyl]guanine.

A number of methyl derivatives of 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG, 1) have been synthesized and tested in vitro for anti-herpes and anti-human immunodeficiency virus (HIV) activity. Among these analogues, (R)-2'-methyl-PMEG [(R)-3] and 2',2'-dimethyl-PMEG (7) demonstrated potent anti-HIV activity in the XTT assay with EC50 values of 1.0 and 2.6 microM, respectively. The corresponding (S)-2'-methyl-PMEG [(S)-3] was found to be less potent against HIV. In addition, the (R) and (S) enantiomers of 9-[3-hydroxy-2-(phosphonomethoxy)propyl]guanine (HPMPG, 8) were prepared for comparison of biological activity, and shown to be active and equipotent against herpesviruses, but inactive against HIV.     

1,5-Benzodiazepines XIV. Synthesis of new substituted 9H-bis-[1,2,4]triazolo[4,3-a:3',4'-d] [1,5]benzodiazepines and relate compounds endowed with in vitro cytotoxic properties

A series of 11 new 9H-bis-[1,2,4]triazolo[4,3-a:3',4'-d] [1,5]benzodiazepine derivatives 8e-o was synthesized. Ten of these compounds (8e-m,o), along with four analogues (8a-d) (previously synthesized by us) were tested in vitro in order to evaluate their cytotoxic and anti-HIV-1 properties. In this connection other six original compounds, i.e., five 9-substituted compounds prepared starting from the 6,12-diphenylderivative 8c (compounds 10, 11, 12, 13a,b) and the bis-triazolone derivative 14, were synthesized and tested for the same purpose. While none of the 20 compounds tested exhibited any appreciable anti-HIV-1 activity, some of them exhibited interesting cytotoxic properties, the best results being shown by compounds 8c,d,k and 11 (CC(50) range=3-12 microM). Therefore, these four compounds were further evaluated for their antiproliferative activity against a panel of human tumor cell lines; actually, compounds 8d, 8k and 11 showed antiproliferative properties against either or both leukemia- and lymphoma-derived cell lines in the low micromolar range.     

Synthesis and antiproliferative activity in vitro of new derivatives of 3-aminopyrazolo[3,4-b]pyridine. Part 1. Reaction of 3-aminopyrazolo[3,4-b]pyridine with 1,3-, 1,4-diketones and alpha,beta-unsaturated ketones

The synthesis of several new pyrazolo[3,4-b]pyridine, pyrido[2',3':3,4]-pyrazolo[1,5-a]pyrimidine and imidazo[1',2':1,5]pyrazolo[3,4-b]pyridine derivatives is described. The obtained compounds were tested for their antiproliferative activity in vitro. One of them, 4-phenyl-2-(3,4,5-trimethoxy-beta-styrylo)pyrido- [2',3':3,4]pyrazolo[1,5-a]pyrimidine (9), revealed cytotoxic properties against the cells of all three human cancer cell lines applied. Another one, 2,4-dimethyl-pyrido[2',3':3,4]pyrazolo[1,5-a]-pyrimidine (2), revealed weak cytotoxic activity only against the cells of human bladder cancer cell line HCV29T. All other compounds tested did not reveal any cytotoxic activity.