SYNTHESIS OF NOVEL 1-(3-PHENYLBENZO[C]ISOXAZOL-5-YL)-1H-1,2,3-TRIAZOLE-4-CARBOXAMIDES AND THEIR ANTIBACTERIAL AND ANTIFUNGAL ACTIVITIES

284 Journal of Chemistry and Technologies, 2024, 32(2), 284-293 Journal of Chemistry and Technologies pISSN 2663-2934 (Print), ISSN 2663-2942 (Online). journal homepage: http://chemistry.dnu.dp.ua UDC 547.791; 615.27 SYNTHESIS OF NOVEL 1-(3-PHENYLBENZO[C]ISOXAZOL-5-YL)-1H-1,2,3-TRIAZOLE-4CARBOXAMIDES AND THEIR ANTIBACTERIAL AND ANTIFUNGAL ACTIVITIES Nazariy T. Pokhodylo1,2*, Mykola A. Tupychak1, Orest O. Bonetskyi2, Nadiia M. Grynchyshyn2, Vasyl S. Matiychuk1 1Ivan 2Stepan Franko National University of Lviv, Kyryla and Mefodiya Str., 6, 79005 Lviv, Ukraine Gzhytskyi National University of Veterinary Medicine and Biotechnologies, Lviv, Pekarska St, 50, 79010 Lviv, Ukraine Received 31 January 2024; accepted 14 May 2024; available online 10 July 2024 Abstract Novel 1-(3-arylbenzo[c]isoxazol-5-yl)-1H-1,2,3-triazole-4-carboxamides were designed, synthesizing and evaluated for antimicrobial activity toward five key ESKAPE pathogenic bacteria, one Gram‐positive bacteria methicillin‐resistant Staphylococcus aureus (ATCC 43300), four Gram‐negative bacteria, Escherichia coli (ATCC 25922), Klebsiella pneumonia (ATCC 700603), Acinetobacter baumannii (ATCC 19606), and Pseudomonas aeruginosa (ATCC 27853) and antifungal activity towards two pathogenic fungal strains Candida albicans (ATCC 90028) and Cryptococcus neoformans var. Grubii (H99; ATCC 208821). The target compounds were obtained in a convenient synthetic path including consequent Dimroth cyclocondensation of 4-nitrophenyl azide with βketoesters, vicarious nucleophilic substitution in nitroaryl fragments and amidation of 1,2,3-triazole-4-carboxylic acid motif. In this way, a mini combinatorial library of 24 compounds was obtained with good overall yields. Five compounds, 7a, 7b, 7i, 7t and 7u, reduced the growth of microorganisms by approximately 20 %. Compounds 7b, 7i, and 7u demonstrated the inhibitory activity towards Staphylococcus aureus. In contrary 7a and 7t towards Cryptococcus neoformans. The data obtained will be used for further design and scaffold optimization. Keywords: azide; benzo[c]isoxazoles; 1H-1,2,3-triazole-4-carboxamides; antimicrobial. СИНТЕЗ НОВИХ 1-(3-ФЕНІЛБЕНЗО[C]ІЗОКСАЗОЛ-5-ІЛ)-1Н-1,2,3-ТРИАЗОЛ-4КАРБОКСАМІДІВ ТА ЇХ АНТИБАКТЕРІАЛЬНА ТА ПРОТИГРИБКОВА АКТИВНІСТЬ Назарій Т. Походило1,2*, Микола А. Тупичак1, Орест О. Бонецький2, Надія М. Гринчишин2, Василь С. Матійчук1 1Львівський національний університет імені Івана Франка, вул. Кирила та Мефодія, 6, 79005 Львів, Україна національний університет ветеринарної медицини та біотехнологій імені С.З. Гжицького, вул. Пекарська, 50, 79010 Львів, Україна 2Львівський Анотація Нові 1-(3-арилбензо[с]ізоксазол-5-іл)-1Н-1,2,3-триазол-4-карбоксаміди були розроблені, синтезовані та оцінені на антимікробну активність щодо п’яти ключових патогенних бактерій ESKAPE, однієї грампозитивної бактерії, стійкої до метициліну, Staphylococcus aureus (ATCC 43300), чотирьох грамнегативних бактерій, Escherichia coli (ATCC 25922), Klebsiella pneumonia (ATCC 700603), Acinetobacter baumannii (ATCC 19606) і Pseudomonas aeruginosa (ATCC 27853) та протигрибкову активність щодо двох патогенних штамів грибів Candida albicans (ATCC 90028) і Cryptococcus neoformans var. Grubii (H99; ATCC 208821). Цільові сполуки були отримані зручним синтетичним шляхом, з послідовними стадіями циклоконденсації Дімрота 4-нітрофенілазиду з β-кетоестерами, вікаріозного нуклеофільного заміщення в нітроарильних фрагментах та амідування мотиву 1,2,3-триазол-4-карбонової кислоти. Таким чином була отримана міні-комбінаторна бібліотека з 24 сполук із хорошими загальними виходами. П’ять сполук, 7a, 7b, 7i, 7t та 7u, зменшили зростання мікроорганізмів приблизно на 20 %. Сполуки 7b, 7i та 7u продемонстрували інгібіторну активність щодо Staphylococcus aureus, на противагу 7a і 7t до Cryptococcus neoformans. Отримані дані будуть використані для подальшого дизайну та оптимізації скафолдів. Ключові слова: азид; бензо[с]ізоксазоли; 1Н-1,2,3-триазол-4-карбоксаміди; протимікробна дія. *Corresponding author: e-mail address: © 2024 Oles Honchar Dnipro National University; doi:10.15421/jchemtech.v32i2.297699 285 Journal of Chemistry and Technologies, 2024, 32(2), 284-293 Introduction Infectious diseases have become a significant challenge to the global health system, especially in the conditions of the pandemic and the growing number of military conflicts, which have led to the deaths of a large number of people. Deterioration of socio-economic conditions, accompanied by the growth of the disease’s causes, unavailability and high cost of medicines, also lead to psychological disorders and a reduction of the standard of living as a whole [1– 3]. A wide variety of pathogens and the emergence of new multidrug-resistant pathogenic strains complicate the treatment and prevention of infectious diseases. Invasive fungal infections represent a global problem, resulting in 1.7 million deaths every year. They are common to immunocompromised patients, as reflected in their chemotherapy, acquired immune deficiency syndrome, and organ transplantation [4–6]. The recent annual incidence of invasive aspergillosis, candidiasis, and mucormycosis is over 300,000, 750,000, and 10,000 cases, respectively [7]. Therefore, to address the above problems, there is an urgent need to develop new anti-bacterial and antifungal drugs. One of the mechanisms responsible for the formation of acquired antibiotic resistance is the bacterial DNA damage response mechanism known as the SOS response induced by many antibiotics [8; 9]. Scaffolds containing 1,2,3triazole-4-carboxamide motif, for example 5amino-N-(3,4-dimethylphenyl)-1-(2-((4-ethoxyphenyl)amino)-2-oxoethyl)-1H-1,2,3-triazole-4carboxamide A (GSK1010702A) (Fig. 1), have demonstrated good efficiency in inhibiting SOSdependent response [10]. In this regard, studies of 1H-1,2,3-triazole-4-carboxamides appear to be promising for screening their antimicrobial activity (Fig. 1). Recently, a series of novel 1-(2,6difluorobenzyl)-1H-1,2,3-triazole-4carboxamides bearing the piperazine motif (Fig. 1, B) were evaluated for their antimicrobial activity and found to be efficient against Grampositive, Gram-negative bacterial strains (Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Streptococcus pyogenes, Klebsiella pneumonia, Streptococcus aureus, Klebsiella terrigena), as well as fungal strains (Candida albicans, Trichoderma viride, Aspergillus flavus, and Aspergillus) [11]. Triazole-4-carboxamide C analogue of N-coumaroyl-tyramine (Fig. 1) was a potent inhibitor of biofilm formation by Gramnegative strain (Pseudoalteromonas ulvae TC14) [12]. The 1,2,3-triazole-4-carboxyl amide D (Fig. 1), acting as an inhibitor of succinate dehydrogenase enzyme, possessed good fungicidal activity, especially towards Sclerotinia sclerotiorum. Potentially, it can be used to develop novel pesticides [13]. In our previous work [14] A series of N-substituted 1-aryl-5substituted-1H-1,2,3-triazole-4-carboxamides wer (...truncated)