Matiichuk Y. Synthesis and biological activity of furancarboxylic acid derivatives

The dissertation work is devoted to the urgent task of today – the design of biologically active substances with antitumor, antimicrobial and anti-inflammatory activities in order to create potential medicines. 2,4-Dimethyl-N-arylfuran-3-carboxamides and 2,5-dimethyl-N-arylfuran-3-carboxamides were synthesized by the interaction of 2,4-dimethyl- and 2,5-dimethylfuran-3-carboxylic acid chlorides and aromatic amines. For them, anti-inflammatory activity was investigated on the carrageenan model of inflammatory swelling of the paws of white rats. The most active compounds were methyl 2-[(2,4-dimethyl-3-furoyl)amino]-4,5-dimethoxybenzoate and 2,5-dimethyl-N-[5-(4-chlorobenzyl)-1,3-thiazol- 2-yl]furan-3-carboxamide, with activity of 112.9% and 114.2%, respectively, compared to ibuprofen. For 2,5-dimethyl-N-[5-(R-benzyl)-1,3-thiazol-2-yl]furan-3-carboxamides, antitumor activity was studied in accordance with the international scientific program of the Developmental Therapeutic Program of the National Cancer Institute (USA). 2,5-Dimethyl-N-[5-(4-chlorobenzyl)-1,3-thiazol-2-yl]furan-3-carboxamide was identified as a hit compound with an MG-MID GI50 value of 4.22μM, which is lower in compared to known anticancer drugs. This compound is also an effective anti-inflammatory agent. We synthesized 2-benzofurancarboxamide derivatives and screened their antitumor activity. N-[5-(3-methylbenzyl)-1,3-thiazol-2-yl]-1-benzofuran-2-carboxamide showed the best inhibitory activity (GI50<10µM) against all 58 human tumor cell lines tested with MG-MID GI50 2.03µM. A number of corresponding amides were synthesized on the basis of 5-aryl-2-furan-3-carboxylic acids and 5-aryl-2-methylfuran-3-carboxylic acids. In collaboration with CO-ADD (The Community for Antimicrobial Drug Discovery), funded by the Wellcome Trust (Great Britain) and The University of Queensland (Australia), antimicrobial activity screening was performed. Highly active derivatives of 5-[2-(trifluoromethyl)phenyl]-N-(aryl)-2-furamides against the fungus strain C. neoformans ATCC 208821 were identified. Derivatives based on morpholine also showed significant antifungal activity against this strain: 4-[5-(4-nitrophenyl)-2-furoyl]morpholine, 4-{[5-(4-isopropylphenyl)-2-furyl]carbonothioyl}morpholine and 4-{[5-(4-bromophenyl)-2-furyl]carbonothioyl}morpholine. The synthesis of 2-azolyl-3-furan-2-yl acrylonitrile and 3-furan-2-yl-2-(4-oxo-3,4-dihydroquinazolin-2-yl)acrylonitrile was developed. The interaction of furfural and its 5-aryl substituted with benzimidazolacetonitrile, benzthiazolylacetonitrile, 4-arylthiazolylacetonitrile and their furan and thiophene bioisosteres ((4-furan-2-yl-thiazol-2-yl)-acetonitrile, (4-thiophen-2-yl-thiazol-2-yl)-acetonitrile), and (4-oxo-3,4-dihydro-quinazolin-2-yl)-acetonitrile. A combinatorial library of 3-furan-2-yl-2-(thiazol-2-yl)acrylonitrile, 3-furan-2-yl-2-(1H-benzimidazol-2-yl)acrylonitrile and 3-[5-arylfuran derivatives was obtained -2-yl]-2-(4-oxo-3,4-dihydroquinazolin-2-yl)acrylonitrile and investigated their antitumor activity, identified 2-(1H-benzimidazol-2-yl)-3-[5-(4 -chlorophenyl)furan-2-yl]-acrylonitrile with activity of the same order as cisplatin, curcumin and gefitinib. The interaction of 5-benzothiazol-2-ylfuran-2-carbaldehyde with compounds with an active methylene group, in particular with thiazolyl acetonitrile and cyanacetamide, was studied. A number of new derivatives of 3-(5-benzothiazol-2-ylfuran-2-yl)-2-cyano-N-R-acrylamides and 3-(5-benzothiazol-2-ylfuran-2-yl)-2-(4-arylthiazole)-2-yl)acrylonitrile were synthesized. By the interaction of the same aldehyde with acetoacetic ester and ammonia under the conditions of the Hanch reaction diethyl-4-[5-(1,3-benzothiazol-2-yl)-2-furyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained.3-(5-Benzothiazol-2-ylfuran-2-yl)-2-(4-phenylthiazol-2-yl)acrylonitrile showed an antitumor effect at a concentration (MG-MID = 0.69 μM), which is an order of magnitude lower than in comparison of drugs. The structure, composition and purity of the synthesized compounds were confirmed by elemental analysis and 1H NMR spectroscopy methods. Calculations of ADME-Toh parameters were carried out using pkCSM and SwissADME internet resources, which indicate the future prospects of furancarboxylic acid derivative research. Directed synthesis of 96 compounds was carried out. As a result of biological screening, 17 hit compounds with antitumor, antimicrobial and anti-inflammatory activities were identified. 27 scientific works have been published based on the materials of the dissertation.