Sinteza i cAMP-ovisna inhibicija fosfodiesteraze novih derivata tiazolokinazolina

The series of 6,7,8,9-tetrahydro-5H-5-(2\u27-hydroxyphenyl)-2-(4\u27-substituted benzylidine) thiazolo(2,3-b)quinazolin-3(2H)-ones (4a-j) and 6,7,8,9-tetrahydro-5H-5-(2\u27-hydroxyphenyl)-2-(4\u27-substituted benzylidine)-3-(4-nitrophenylamino)thiazoloquinazolines (5a-j) were synthesized by the reported method and evaluated for their phosphodiesterase inhibitory activity. All test compounds exhibited good activity. The structure-activity relationships were also studied. In both series of compounds, electron-withdrawing substitutions showed higher activity. Among the tested compounds, 6,7,8,9-tetrahydro-5H-5-(2\u27-hydroxyphenyl)-2-(4\u27-fluorobenzylidine)-3-(4-nitrophenylamino)thiazoloquinazoline (5e), 6,7,8,9-tetrahydro-5H-5-(2\u27-hydroxyphenyl)-2-(4\u27-nitrobenzylidine)-3-(4-nitrophenylamino)thiazoloquinazoline (5j) and 6,7,8,9-tetrahydro-5H-5-(2\u27-hydroxyphenyl)-2-(4\u27-chlorobenzylidine)-3-(4-nitrophenylamino)thiazoloquinazoline (5f) were found to be more potent than theophylline (IC50 in mmol L–1 of 1.34 ± 0.09 for 5f, 1.44 ± 0.02 for 5e, 1.52 ± 0.05 for 5j vs. 1.72 ± 0.09 for theophylline).U radu je opisana sinteza serije 6,7,8,9-tetrahidro-5H-5-(2\u27-hidroksifenil)-2-(4\u27-supstituiranih benzilidin)tiazolo(2,3-b)kinazolin-3(2H)-ona (4a-j) i 6,7,8,9-tetrahidro-5H-5-(2\u27-hidroksifenil)-2-(4\u27-supstituiranih benzilidin)-3-(4-nitrofenilamino)tiazolokinazolina (5a-j) prema objavljenoj metodi te ispitano njihovo inhibitorno djelovanje na fosfodiesterazu. Svi testirani spojevi pokazuju dobro djelovanje. Proučavan je i odnos strukture i djelovanja. U obje serije spojeva, elektron-odvlačeći supstituenti doprinose jačem djelovanju. Među ispitivanim spojevima pronađeno je da 6,7,8,9-tetrahidro-5H-5-(2\u27-hidroksifenil)-2-(4\u27-fluorobenzilidine)-3-(4-nitrofenilamino)tiazolokinazolin (5e), 6,7,8,9-tetrahidro-5H-5-(2\u27-hidroksifenil)-2-(4\u27-nitrobenzilidine)-3-(4-nitrofenilamino)tiazolokinazolin (5j) i 6,7,8,9-tetrahidro-5H-5-(2\u27-hidroksifenil)-2-(4\u27-klorobenzilidin)-3-(4-nitrofenilamino)tiazolokinazolin (5f) imaju jače djelovanje od teofilina (IC50 u mmol L–1 1,34 ± 0,09 za 5f, 1,44 ± 0,02 za 5e, 1,52 ± 0,05 za 5j nasuprot 1,72 ± 0,09 za teofilin)

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (<b>1</b>) for VL

Enantioselective BINOL-phosphoric acid catalyzed Pictet-Spengler reactions of N-benzyltryptamine

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