Synthesis and biological activity of thienobenzo-triazoles

Cilj rada bio je sintetizirati nove tienobenzo-triazole te ispitati njihovu inhibicijsku potenciju prema kolinesterazama. Također je procijenjena selektivnost njihove inhibicije, a rezultati su interpretirani molekularnim modeliranjem. Uspješno je sintetizirano 15 novih spojeva koji se razlikuju po supstituentu pričvršćenom na triazolni prsten ili po aromatičnosti središnjeg prstena. Fotociklizacijskim putem sintetiziran je jedan spoj 1, dok je alternativni put dao širok spektar molekula dihidro-tienobenzo-triazola i aromatiziranih tienobenzo-triazola 2-15. Većina novih molekula pokazala je bolju inhibicijsku potenciju prema butirilkolinesterazi (BChE – eng. butyrylcholinesterase). Računalne studije ukazuju na povezivanje tienobenzo-triazola s kolinesterazama preko vodikovih veza koje uključuju jedan od dušika triazola, smještenih između aromatskih ostataka liganda i aromatskih ostataka aktivnih mjesta kolinesteraza. Također su prisutne i alkilne interakcije. Molekularno pristajanje omogućuje uvid u strukturu dobivenih kompleksa i identifikaciju stabilizirajućih interakcija između enzima i potencijalnog inhibitora kolinesteraze. Novosintetizirani tienobenzo-triazoli pokazali su dobre karakteristike za budući dizajn inhibitora kolinesteraza i traženje terapeutika za liječenje neuroloških poremećaja.The aim of this study was to synthesize new thienobenzo-triazoles and to examine their inhibitory potency towards cholinesterases. The selectivity of their inhibition was also assessed, and the results were interpreted by molecular modeling. 15 new compounds have been successfully synthesized, differing in the substituent attached to the triazole ring or by the aromaticity of the central ring. A single compound 1 was synthesized by photocyclization route, while the alternative pathway gave a wide range of molecules of dihydro-thienobenzo-triazole and aromatized thienobenzo-triazole 2-15. Most of the new molecules showed better inhibitory potency towards butyrylcholinesterase (BChE). Computational studies suggest that thienobenzo-triazole and cholinesterases are linked via hydrogen bonds involving one of the triazole nitrogen, located between aromatic ligand residues and aromatic residues of the active cholinesterase sited. Alkyl interactions are also present. Molecular docking gives insight into the structure of the obtained complexes and the identification of stabilizing interactions between enzymes and a potential cholinesterase inhibitor. The newly synthesized thienobenzo-triazoles showed good characteristics for the future design of cholinesterase inhibitors and the search for therapeutics for the treatment of neurological disorders