Síntesis y evaluación biológica de compuestos con potencial utilidad anticancerígena, antifúngica y antiinflamatorianuevos derivados de pirazolina, imidazopirazol, pirazolopirazina y antraceno

Abstract

This doctoral thesis addresses the synthesis and biological properties of some nitrogen heterocycles of potential pharmacological interest. Chloral, acetophenones and 9-anthracenecarbaldehyde were the key starting materials used to accomplish the preparative work of compounds to be screened for anti-leukemia, anti-inflammatory, and antifungal activities. Chapter 1 presents the main lines of this project. Previous work carried out by our university research group on this subject is also indicated. Chapter 2 is devoted to the synthesis of 5-aryl-2-aryl(alkyl)-4,5-dihydroimidazo[1,5-b]pyrazol-6-ones 7 and (Z)-2-aryl-6-arylimino-4,6-dihydropyrazolo [1,5-c]thiazoles 9. Condensation of chloral with acetophenones followed by dehydration, electrochemical reduction and hydrazine treatment led to 3-aryl-5-dichoromethyl-2-pyrazolines 5. These reacted with isocyanates and isothiocyanates to give the respective N-aminocarbonyl and N-aminothiocarbonyl derivatives 6,8, which underwent cyclization under DBU treatment to yield the final products 7,9. Chapter 3 describes the sequential syntheses for several classes of products starting from pyrazolines 5. Reactions with phenyl chlorofomate and phenyl chlorothioformate provided the corresponding phenyl 3-aryl-5-dichloromethyl-4,5-dihydropyrazol-1-carboxylates 10 and thiocarboxylates analogues 13. These compounds reacted with hydrazine hydrate leading to the respective hydrazides and thiohydrazides 11,14, whose condensation with aromatic aldehydes gave the expected hydrazones and thiohydrazones 12,15. Compounds 12 were converted to 2-aryl-N-benzylideneamino-4,5-dihydro-6H-imidazo[1,5-b]pyrazol-6-ones 16 by treatment with DBU. Chapter 4 describes a stepwise synthesis and a one-pot preparative method for 2-aryl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazines 21. Electrogenerated 2,2-dichlorovinylacetophenones reacted with 2-hydroxyethylhydrazine to give 3-aryl-5-dichloromethyl-1-(2-hydoxyethyl)-2-pyrazolines 17, whose transformation to O-tosylates 18 followed by treatment with sodium azide and catalytic hydrogenation gave 3-aryl-1-(2-aminoethyl)-5-dichloromethyl-2-pirazoline hydrochlorides 20, which reacted with sodium hydroxide to provide products 21. Intermediates 18 could also be directly converted to compounds 21 following a one-pot process. Plausible reaction mechanisms were proposed. Chapter 5 corresponds to a convenient one-pot synthetic approach to 3-aryl-2-(2-hydroxyethyl)pyrazoles 22 involving base-catalyzed reactions of 2,2,2-trichloroethylideneacetophenones 3 with 2-hydroxyethylhydrazine. The regioselectivity of this process was proposed with the aid of theoretical DFT calculations. Chapter 6 details the most relevant activity data found in studying the biological properties of all the compounds in the above chapters. Some members of families 6,7,8,14,15,16 exhibited antileukemia activity, whereas compounds 20 were found to have antifungal and anti-inflammatory properties. Chapter 7 focuses on the synthesis of N-substituted 9-(2-nitrovinyl)-, 9-(2-cyanovinyl)-, and 9-(2-acetylvinyl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones 29,30 by Diels-Alder reactions between 9-subtituted anthracenes and maleimides. On the basis of the biological properties attributable to both the maleimide and the anthracene moieties, compounds 29 and 30 were designed to evaluate their activity against leukaemia cell lines.