Synthesis of imidazo[1,2-a]pyridines as antiviral agents

The synthesis of original imidazo[1,2-a]pyridines bearing a thioether side chain at the 3 position and their antiviral activity are reported. From the synthesized compounds, 4, 15, and 21 were highly active against human cytomegalovirus with a therapeutic index superior to 150. These compounds also showed pronounced activity against varicella-zoster virus. Their structure-activity relationship is discussed.     

Bis-cationic heteroaromatics as macrofilaricides: synthesis of bis-amidine and bis-guanylhydrazone derivatives of substituted imidazo[1,2-a]pyridines

A series of guanylhydrazone, amidine, and hydrazone derivatives of 2-phenylimidazo[1,2-a]pyridine have been prepared and evaluated for macrofilarial activity against Acanthocheilonema viteae and Brugia pahangi in jirds. Compounds with 4',6-bis-substitution by cyclic guanylhydrazone groups show activity. 4',6-Bis-amidines show some activity but are more toxic; 4'- or 6-monosubstituted compounds are inactive. 2,6-Bis-substituted compounds lacking the phenyl ring are inactive. 4',6-Bis-substituted compounds having additional double bonds inserted between the heterocyclic ring and the phenyl ring or between the substituent and the ring system show reduced activity.     

Synthesis, properties and biological evaluation of substituted furo[3,2-e] and pyrano[3,2-e]pyrido[4,3-b]indoles

Furo[3,2-e]- and pyrano[3,2-e]pyrido[4,3-b] indoles were synthesized from 1,4,5-trisubstituted 8-hydroxy-5H-pyrido[4,3-b]indoles. The intermediates, 10-chloro-6H-furo[3,2-e]pyrido[4,3-b]indole (11), 10-chloro-2,6-dihydro-1H-furo[3,2-e]pyrido-[4,3-b]indole (10) and 11-chloro-2,3-dihydro-3H,7H-pyrano[3,2-e]pyrido[4,3-b]indole (15), were substituted by diamines under thermal conditions (180 degrees C). In contrast, 11-chloro-3H,7H-pyrano[3,2-e]pyrido[4,3-b]indole (14), 9-allyl-1-chloro-4,5-dimethyl-5H-pyrido[4,3-b]indole (9a) and 8-propargyloxy-4,5-dimethyl-5H-pyrido[4,3-b]indole (8) led mainly to 1-aminosubstituted 8-hydroxy-5H-pyrido[4,3-b]indole derivatives resulting from an unexpected C3 unit elimination. When examined in three tumour cell lines (L1210 leukaemia, the B16 melanoma and the MCF7 breast adenocarcinoma) the new amino substituted furo[3,2-e]-, dihydrofuro[3,2-e]- and dihydropyrano[3,2-e]-pyrido[4,3-b]indole derivatives revealed cytotoxic properties, especially important for the 2,6-dihydro-1H-furo[3,2-e]pyrido[4,3-b]indole series. The most active compound (12b) significantly inhibits both DNA topoisomerases I and II, and is as potent as Adriamycin at inhibiting cell proliferation and inducing a massive accumulation of L1210 cells in the G2 + M phase of the cell cycle. However, 12b was less active than Adriamycin when tested in vivo against P388 leukaemia or the B16 melanoma tumour models.     

Regioselective synthesis of pyrazolo[4,5-g]pyrido[1,2-a]benzimidazoles: cytotoxic derivatives of pyrido[1,2-a]benzimidazolic ring system

N-1 and N-2 substituted pyrazolo[4,5-g]pyrido[1,2-a]benzimidazoles were prepared regioselectively, and cytotoxicities evaluated in vitro against K562 and HL60 cells. All compounds displayed weaker activity than doxorubicin against sensitive lines, but showed the same activity against resistant cell lines (multidrug resistance+, (MDR+); K562R and HL60R) indicating no resistance phenomena.     

Synthesis of acyclo C-nucleosides of phenanthro[9,10-e][1,2, 4]triazino[3,4-c]-[1,2,4]triazoles, and their precursors

Reaction of 3-hydrazinophenanthro [9, 10-e] [1, 2, 4] triazine (1) with aliphatic and aromatic aldehydes as well as monosaccharides gave the corresponding hydrazones 2a-g. The D-glucose analogue exists in the cyclic pyranosyl structure 5. Acetylation and partial acetylation of the sugar hydrazones were carried out. Cyclization of a number of hydrazones including the partially acetylated sugar hydrazones by thionyl chloride gave regioselectively the respective angular isomer 1-substituted phenanthro [9, 10-e] [1, 2, 4] triazino [3, 4- and not the linear isomer. The cyclization of 1 with acetic acid, however, gave regioselectively the linear isomer 19. The structural assignments were based on a model study whereby the angular 16a was found to be different from the linear isomer 19a obtained by the condensation of 4, 5-diamino-3-methyl-1, 2, 4-triazole with 9, 10-phenanthraquinone. Periodate oxidation of 2d gave 20 whose reaction with 1 gave 21.     

Synthesis and biological evaluation of a series of substituted pyrazolo[3,4-d]-1,2,3-triazoles and pyrazolo[3,4-d]oxazoles

In view of the biological relevance of triazole-based heterocyclic structures as antifungal, antiviral, and antitumor agents, we have synthesized a series of substituted pyrazolo[3,4-d]-1,2,3-triazoles (2e-h, 2j, 4b) which we evaluated for their cytostatic and antiviral (HIV-1 included) activity and for their capability to inhibit the multiplication of various human pathogenic fungi and bacteria. Moreover, the biological activities of a few compounds, namely pyrazolo[3,4-d]oxazoles (3a-e) and pyrazolo[3,4-d]-1,2,3-triazoles (2a-d, 4a, 5), previously obtained by us but not investigated for their biological activity, were also studied. Only compounds 3a-e were endowed with a significative antiproliferative activity on the human lymphoblastoid cell line MT-4 cells. All pyrazole derivatives proved ineffective in protecting cell cultures against the HIV-1-induced cytopathogenicity, and none of the compounds was active against the bacteria and fungi tested.     

Synthesis of isomeric 3-piperidinyl and 3-pyrrolidinyl benzo[5,6]cyclohepta[1,2-b]pyridines: sulfonamido derivatives as inhibitors of Ras prenylation

Blocking farnesylation of oncogenic Ras proteins is a mechanism based therapeutic approach that is of current interest for the development of antitumor agents to treat ras associated tumors. As part of a SAR study on the lead farnesyl protein transferase (FPT) inhibitor I, we report here the synthesis of novel geometric isomers II and III and the FPT inhibition activity of their N-acyl and N-sulfonamido derivatives 15-65. The N-acyl derivatives are markedly less active than the lead inhibitor I thereby demonstrating that the spatial location of the N-acyl group in I is critical for binding of the compound to FPT. In contrast to I, the N-sulfonamido-II series is a novel lead of non-sulfhydryl, nonpeptidic compounds that are dual FPT/GGPT inhibitors. In light of recent reports on the alternative prenylation of N- and K-Ras, dual FPT/GGPT inhibitors may be required to control cell proliferation in tumors containing activated Ras.     

Synthesis of novel C7-aryl substituted pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) via pro-N10-Troc protection and Suzuki coupling

Novel C7-aryl pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) have been synthesized via Suzuki coupling between a 7-Iodo N10-Troc-protected PBD carbinolamine and commercially available boronic acids.     

Fullerene lipids: synthesis of dialkyl 1,2-[6,6]-methano-[60]-fullerene dicarboxylate derivatives

OBJECTIVE: To determine the prevalence of chronic arthritis with special reference to rheumatoid arthritis. METHOD: A cross-sectional study was performed during the years 1990 and 1991 in a randomly selected sample of the urban population of Belgrade. RESULTS: Out of 2184 participants, > or = 20 yr old, surveyed by questionnaire, 756 (34.6%) reported peripheral joint complaints. Of those with complaints, 621 (82.1%) agreed to undergo detailed examination. Arthritis was diagnosed in four men (one had rheumatoid arthritis and three had spondylarthropathy with peripheral arthritis) and 11 women (three had rheumatoid arthritis, one had B27-positive polyarthritis and seven had undifferentiated chronic arthritis). The prevalence of chronic arthritis in the adult population was 0.69% (0.35% for men and 1.05% for women). The prevalence for rheumatoid arthritis was 0.18% (0.09% for men and 0.29% for women). Re-examination of 15 individuals with chronic arthritis 3 yr later showed changes in diagnosis only in those patients who at baseline examination had undifferentiated chronic arthritis. CONCLUSION: According to the results obtained, the urban population of Belgrade is among populations with a low prevalence of rheumatoid arthritis.     

1-[2,3,5-三氮唑偶氮]-5-甲基-2-苯酚的合成及其与钴的显色反应

合成了 1 [2 ,3 ,5 三氮唑偶氮 ] 5 甲基 2 苯酚 (简称TZAMP) ,并研究了其与钴的显色反应。结果表明 :在 pH5～ 6的邻苯二甲酸氢钾 氢氧化钠缓冲介质中 ,该试剂与钴形成络合比为 1∶1的红色络合物 ,λmax=5 90 6nm ,表观摩尔吸光系数ε=2 5 8× 10 4 ,钴量在 0～ 1 6mg/L范围内遵守比尔定律。     

Pyrrolo[1',2':1,2]imidazo[4,5-b]pyridines, pyrrolo- [2',1':2,3]imidazo[4,5-c]pyridines and pyrrolo[2,1-f]purines as potential benzodiazepine ligands

The synthesis of some 7,8,8a,9-tetrahydro-6H-pyrrolo[1',2':1,2]imidazo[4,5-b]pyridin-6-ones, 5,5a,6,7-tetrahydro-8H-pyrrolo[2',1':2,3]imidazo[4,5-c]pyridin-8-ones and 7,8,8a,9-tetrahydro-6H-pyrrolo[2,1-f]purin-6-ones is reported. The structure of the obtained compounds has been assigned by means of 1H-NMR spectra assisted by NOESY measurements. In addition, the ability to displace [3H]-flunitrazepam binding from rat brain membranes is determined. Only the pyrrolopurine derivative 5d binds to the benzodiazepine receptor (BZR) with appreciable potency.     

Synthesis and pharmacological activities of some 2,3,4,5-tetrahydro[1,5]benzo[f]thiazepines

For the purpose of prophylactic treatment of splenic aneurysms, both examinations and treatments should be minimally invasive. Here, we report a case of a patient who underwent three-dimensional arterial computed tomography (CT) and laparoscope-assisted splenectomy with aneurysm resection as a combination of minimally invasive examination and treatment.     

Synthesis and pharmacological activity of some N,N-disubstituted 1-amino-2-phenyl-3H,12H-naphtho[1,2-b]pyrano[2,3-d]pyran-3-ones

The synthesis of some N,N-disubstituted 1-amino-2-phenyl-3H,12H-naphtho[1,2-b]pyrano[2,3-d]pyran-3-ones 4, by reaction of phenylchloroketene with a series of N,N-disubstituted 3-aminomethylene-2,3-dihydro-4H-naphtho[1,2-b]pyran-4-ones, followed by dehydrochlorination in situ of the primary adducts with DBN, is described. Some compounds 4 showed antiarrhythmic and analgesic activities.     

Synthesis and antimicrobial activity of pyrazolo[3',4':4,3]pyrido[6,5-c]pyridazine and thieno[2,3-c]pyridazine derivatives

4-Acetyl-5,6-diphenyl-2(H)pyridazine-3-one (1) was allowed to react with phenyl hydrazine to afford the corresponding hydrazone 2. Hydrazone 2 upon treatment with Vilsmeier's reagent gave pyrazolylpyridazine derivative 3, which was allowed to react with thiosemicarbazide and hydroxyl amine to give the corresponding thiosemicarbazone and oxime 4 and 5, respectively. Treatment of oxime 5 with Ac2O gave the pyrazolylpyridazine carbonitrile derivative 6. Compound 5 reacts with POCl3 to give the corresponding chloro compound 7. The chloro compound 7 was reacted with hydrazine hydrate or aniline to afford pyrazolopyridazodiazepine 9 or pyrazolopyridazopyridazine 10. When compound 1 was allowed to react with POCl3 the chloro derivative 11 resulted. This compound reacts with thiourea, piperidine or hydrazine hydrate to give compounds 12, 14 and 15, respectively. Compound 12 reacted with alpha-haloester or alpha-haloketone to give the thienopyridazines 13a and b, respectively. Most of the newly synthesized compounds were screened for fungicidal and bactericidal activity.     

Synthesis and pharmacological activity of some 3-amino-11H-indolo[3,2-c] [1,8]naphthyridines

The preparation of some 3-amino-11H-indolo [3,2-c]-[1,8] naphthyridines using the Fischer indole synthesis on the appropriate phenylhydrazones is described. Some compounds (IV b, c, d) were effective in inhibiting the reactions of delayed hypersensitivity, but the testing has been discontinued because of toxicity observed.