New 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e]pyrimidine derivatives as diuretics

New 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e]pyrimidines 1 and 6,10-dihydro-5H-pyrido[3',2':5,6]pyrimido[2,1-c] [1,2,4]triazines 4 with 5-one, 5-thione or 5-hydrazono substituents and in some cases 1,2,3,4 or 8,9 hydrogenated are synthetized. The diuretic, natriuretic and kaliuretic activities of these compounds in Wistar rats at a dose of 24 mg/kg were estimated. A series of 24 possible derivatives of 1 and 4 possessing diuretic and saliuretic activities are investigated for structure-activity relationships in light of Fujita-Ban model. The Fujita-Ban group contributions have been calculated for different structural variations on the parent ring 1a. It is observed that the hydrogenation of pyridine, [1,3]thiazole or [1,2,4]triazine rings on 1 or 4 decrease the diuretic and saliuretic activities.     

A novel synthesis and molluscicidal activity of some functionally substituted pyridine, pyrido[3,2-c]pyridazine, and pyrido[3,2-c]pyridazino[2',3'-a]quinazoline derivatives

Ethyl benzoylacetate reacts with the malononitrile dimer to afford 4-amino-5-benzoyl-2-dicyano methyl-6-hydroxypyridine, which undergoes the coupling reaction with aromatic diazonium salts to afford azo derivatives. These azo derivatives could be cyclized into pyrido[3,2-c]pyridazine and pyrido[3,2-c]pyridazino[2',3'-a]quinazoline derivatives upon reflux in ethanolic NaOH, presumably via their hydrazo tautomers. The molluscicidal activity of these compounds was evaluated.     

Discovery of novel thieno[3,2-b]pyrrole 5-carboxamides as potent inhibitors of Chikungunya virus

Chikungunya fever(CHIKF)is an arboviral disease that typically consists of an acute illness with fever,skin rash,and incapacitating arthralgia.The causative agent of CHIKF is Chikungunya virus(CHIKV),an alphavirus that is transmitted by the Aedes mosquitoes.Despite the re-emergence of CHIKV as an epidemic threat,there is no approved effective anti-viral treatment currently available for CHIKV.In our preliminary studies,selected small molecule inhibitors of arboviruses related to CHIKV were investigated and this led us to identify compounds with thieno[3,2-b]pyrrole scaffold as hits.Building on the discovery of our best hit compounds,5-carboxylic acid thieno[3,2-b]pyrrole 1 and 5-carboxamide thieno[3,2-b]pyrrole 2,the main aim of this study is to optimize their anti-viral activities by synthesizing analogs of thieno[3,2-b]pyrroles 1 and 2 and examine their activities against CHIKV.In these two parallel optimization studies,we synthesized two series of thieno[3,2-b]pyrroles,namely the 5-carboxylic acids and 5-carboxamides that possessed a variety of substituents at N4,C2,C6 or C5positions of the thieno[3,2-b]pyrrole scaffold.These compounds were then examined for their cytotoxicity effects and anti-viral activities using a luminescence-labelled CHIKV infectious clone.The most potent compound in our studies was found in the 5-carboxamide series.The synthesis,biological activity and structure-activity relationship(SAR)will be presented and discussed in detail.     

Preparation of thieno[3,2-h]cinnolinones as matrix metalloproteinase inhibitors

A new series of thieno[3,2-h]cinnolinone analogues was synthesized which is structurally related to 2,3,4,4a,5,6-hexahydrothieno [3,2-h]cinnolin-3-one 1, a weak inhibitor of the matrix metalloproteinase MMP-8 (human neutrophil collagenase). Preliminary SAR studies have shown that while C4a-methyl, C7-acetylamino, C7 and C8-nitro substitution, and C4-C4a olefination provided no increase in activity relative to 1, C8-acetylamino substitution as in 5 and 8 was favourable. Moreover, to predict how the thieno[3,2-h]cinnolinone inhibitors might bind to MMP-8, the unsubstituted compound 9 was docked into the MMP-8 crystal structure. These studies revealed that inhibitor 9 does not seem to be able to coordinate the catalytically-active zinc ion but preferably interact with the peptide-binding region of the active site.     

Investigations on the synthesis and properties of new derivatives of pyrido[3,2-e]-1,3-thiazino[3,2-a]-s-triazine

It has been found that the condensation of esters of 3H-2-imino-7-methyl-4-oxopyrido[3,2-e]-1,3-thiazine-5- and -6-carboxylic acids (I, II) with formaldehyde and primary amines affords the corresponding derivatives of a new heterocyclic system pyrido[3,2-e]-1,3-thiazino [3,2-a]-s-triazine (IX-XXIV).     

Structure-activity relationships of N-acyl pyrroloquinolone PDE-5 inhibitors

The discovery of the potent and selective PDE-5 inhibitory activity of a pyrroloquinolone scaffold prompted us to explore the SAR of its acyl derivatives. During the course of these studies, three structural series were found with K(i) values for PDE-5 in the subnanomolar range. Systematic modification of one of these leads produced a compound with excellent selectivity for PDE-5 over other phosphodiesterases and oral bioavailability of 15% in male rats. This compound also displayed in vivo efficacy in an anesthetized canine model of erection when dosed intravenously.     

Synthesis and anticonvulsant activity of pyrano[4′,3′:4,5]pyrido[2,3-b]thieno[3,2-d] pyrimidine derivatives and pyrimido[5′,4′:2,3]-thieno[2,3-c]isoquinoline derivatives

Methods for the synthesis of condensed thieno[3,2-d]pyrimidines based on pyrano[4,3-d]thieno[2,3-b]pyridines and thieno[2,3-b]isoquinolines have been developed and a series of new derivatives have been synthesized. The anticonvulsant activity of the synthesized compounds has been studied. Several compounds possessing specific anticonvulsant activity with respect to corazole-induced convulsions are revealed. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 9, pp. 14–16, September, 2007.     

Synthesis and physicochemical properties of thiadiazolo[3,2-a]pyrimidinesulfonamides and thiadiazolo[3,2-a]triazinesulfonamides as candidates for topically effective carbonic anhydrase inhibitors

A series of bicyclic 1,3,4-thiadiazolo[3,2-a]pyrimidine- and 1,3,4-thiadiazolo[3,2-a]triazine-7-sulfonamides were synthesized from 5-amino-1,3,4-thiadiazole-2-sulfonamide and evaluated for topical efficacy as ocular hypotensive agents. The compounds were tested for the physicochemical properties of sulfonamide pKa, free acid water solubility, CHCl3/buffer partition, and transcorneal penetration (kin), as well as for activity against carbonic anhydrase (I50). A number of these compounds exhibited lower sulfonamide pKa and higher water solubility than those of acetazolamide (1) and methazolamide (2), and one, 12, brought about a small reduction in IOP in the normal rabbit eye.     

Synthesis and pharmacological activity of 3-substituted pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(3H)-ones

A series of 3-substituted pyridothienopyrimidin-4(3H)-ones has been synthesized from 2,7,9-trimethyl-4H-pyrido[3',2':4,5]thieno-[3,2-d] [ 1,3]oxazin-4-one. These compounds have been evaluated for analgesic, anti-inflammatory and antipyretic activities. The ulcerogenic effect of the compounds has been also studied.     

6-Chloro-1,2,4-triazolo[4,3-b]pyrido[2,3-d]-and [3,2-d]pyridazines - Synthesis and Structure Determination

5,8-Dichloropyrido[2,3-d]pyridazine ( 2 ) gave with hydrazine hydrate in dioxane 5-chloro-8-hydrazino- and 8-chloro-5-hydrazinopyrido[2,3-d]pyridazines 3 and 4 . When 3 and 4 were allowed to react with formic acid they gave a mixture of the 6-chloro-1,2,4-triazolo[4,3-b]pyrido[2,3-d] - and [3,2-d]pyridazines ( 5 and 6 ).     

吡啶并[2,3-b]吡嗪类FGFR抑制剂的设计、合成及抗胃癌活性研究

目的设计并合成一系列吡啶并[2,3-b]吡嗪类成纤维细胞生长因子受体(FGFR)抑制剂,同时对其抗胃癌活性进行初步评价。方法以5-溴吡啶-2-胺为起始原料,经9步反应合成了13个未见报道的化合物,并通过MTT法评价其抗胃癌活性。结果与结论目标化合物的结构经NMR和HRMS确证,其中多个化合物对胃癌SNU-16细胞系具有良好的抑制活性,具有进行更深入的构效研究价值,有望成为一种潜在的新增FGFR抑制剂。     

Anellierte Thiopyrone, 5. Mitt.1): Darstellung und Reaktionen von 3-Formyl-indeno[1,2-b]-, -[1]benzofuro[3,2-b]-, -[1]-benzothieno[3,2-b]thiopyronen und 3-Formyl-thiopyrono[3,2-b]indolen

Fused Thiopyrones, V: Syntheses and Reactions of 3-Formyl-indeno[1,2-b]-, -[1]benzofuro[3,2-b]-, -[2]benzothieno[3,2-b]thiopyrones, and 3-Formyl-thiopyrono[3,2-b]indoles Alternative syntheses of the title compounds are described. The configuration of the oximes, obtained from the aldehydes, is proved. Furthermore the syntheses of the nitriles and the carboxylic acids is presented.     

Synthesis of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones as potential antimicrobial agents

Synthesis of new derivatives of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one via reaction of 7-(4-bromophenyl)-1,2-dihydro-5-(4-fluorophenyl)-2-thioxopyrido[2,3-d] pyrimidin-4(3H)-one with hydrazonoyl chlorides or reaction of 2-hydrazino-pyrido[2,3-d]pyrimidin-4(3H)-one with different aldehydes followed by cyclization of the products. All the newly synthesized compounds were evaluated for their antimicrobial activities and also their minimum inhibitory concentration against most of test organisms was performed. Amongst the tested compounds displayed excellent activity against all the tested microorganisms except SR and PA.     

Synthesis and antimicrobial study of novel 1-aryl-2-oxo-indano[3,2-d]pyrido/pyrimido[1,2-b]pyrimidines

A series of 2-(arylidene)-indan-1, 3-diones 1 were prepared by Knoevenagel reaction between indane-1,3-dione and the appropriate araldehydes. The alpha,beta-enones 1 have been used as a component of Michael addition with equimolar amounts of 2-aminopyridine/2-aminopyrimidine to give novel heterocyclic systems 4 and 5, respectively. They are reported here for the first time. The structures of the newly synthesized compounds were confirmed by IR, (1)H-NMR, (13)C-NMR, and elemental analysis. All compounds were screened for their antibacterial and antifungal activities. Some of them showed promising activities.     

3D-QSAR studies of some tetrasubstituted pyrazoles as COX-II inhibitors

Pharmacophore mapping studies were undertaken for a series of molecules belonging to tetrasubstituted pyrazoles as canine COX-II inhibitors. A six point pharmacophore with 3 hydrogen bond acceptors (A), one hydrophobic group (H) and two aromatic rings (R) as pharmacophoric feature was developed. The pharmacophoric hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of r2 = 0.958. The developed pharmacophore model was externally validated by predicting the activity of test set molecules. The squared predictive correlation coefficient of 0.852 was observed between experimental and predicted activity values of test set molecules. The geometry and features of pharmacophore model describe the key structure-activity relationship of COX-II inhibitors, can predict their activities, and can thus be used to design novel inhibitors.     

Synthesis and analgesic activity of 3-substituted derivatives of pyrido [3',2':4,5]thieno[3,2-d]pyrimidin-4(3H)-ones

A series of Schiff bases of 3-amino-2,7,9-trimethylpyrido-[3',2',:4,5]thieno[3,2-d]pyrimidin- 4(3H)-one with aromatic aldehydes was synthesized. The compounds showed interesting analgesic activity without effects on the stomach even with oral doses of 200 mg/kg.