Synthesis of Novel Benzylic 1,2,3-triazole-4-carboxamides and their in vitro Activity Against Clinically Common Fungal Species

Article J. Mex. Chem. Soc. 2021, 65(2) Regular Issue ©2021, Sociedad Química de México ISSN-e 2594-0317 Synthesis of Novel Benzylic 1,2,3-triazole-4-carboxamides and their in vitro Activity Against Clinically Common Fungal Species Ricardo García-Monroy,1,2 Davir González-Calderón,1* Alejandra Ramírez-Villalva,1,2 Salvador Mastachi-Loza,1,2 José G. Aguirre-de Paz,1 Aydee Fuentes-Benítes1, Carlos González-Romero1* 1 Departamento de Química Orgánica, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón/Paseo Tollocan s/n, Toluca, Estado de México, 50120, México. 2 Departamento de Microbiología, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón/Paseo Tollocan s/n, Toluca, Estado de México, 50120, México. *Corresponding author: Davir González-Calderón, email: ; tel.: +52 722 2175 109 ext113; fax: +52 722 2173 890. Received October 6th, 2020; Accepted January 11th, 2021. DOI: http://dx.doi.org/10.29356/jmcs.v65i2.1457 Abstract. A library of novel benzylic 1,2,3-triazole-4-carboxamides (3a-m) were obtained with acceptable yields via a one-pot procedure. The series of compounds was screened for fungicidal activity and evaluated in vitro against four filamentous fungi and four Candida species. The former consisted of Aspergillus fumigatus, Trichosporon cutaneum, Rhizopus oryzae and Mucor hiemalis, and the latter C. krusei, C. albicans, C. utilis and C. glabrata. According to the in vitro assays, 3d and 3e were the most efficient fungicidal agents (of all the test compounds) against R. oryzae, even better than the reference drug (itraconazole). Thus, 3d and 3e represent important scaffolds that can be modified to increase antifungal activity. Additionally, they are candidates for complementary studies on the inhibition of clinical infections produced by Rhizopus spp. strains. Keywords: 1,2,3-Triazoles, antifungal activity, 1,3-dipolar cycloaddition, Rhizopus oryzae. Resumen. Se obtuvo una librería de nuevos bencil 1,2,3-triazoles-4-carboxamidas (3a-m) con rendimientos aceptables mediante un procedimiento one-pot. La serie de compuestos se seleccionó para determinar la actividad fungicida llevando a cabo una evaluación in vitro contra cuatro hongos filamentosos y cuatro especies de Candida. Los primeros consistieron en Aspergillus fumigatus, Trichosporon cutaneum, Rhizopus oryzae y Mucor hiemalis, mientras que para las segundas especies, esta fueron C. krusei, C. albicans, C. utilis y C. glabrata. Según los ensayos in vitro, 3d y 3e fueron los agentes fungicidas más eficaces (de todos los compuestos de prueba) contra R. oryzae, incluso mejores que el fármaco de referencia (itraconazol). Por tanto, 3d y 3e representan importantes núcleos que podrían modificarse para aumentar la actividad antifúngica, siendo excelentes candidatos para estudios complementarios sobre la inhibición de infecciones clínicas producidas por Rhizopus spp. Palabras clave: 1,2,3-triazol, actividad antifúngica, cicloadición 1,3-dipolar, Rhizopus oryzae. 202 Article J. Mex. Chem. Soc. 2021, 65(2) Regular Issue ©2021, Sociedad Química de México ISSN-e 2594-0317 Introduction Viral, bacterial, and parasitic diseases have profoundly harmed the health of millions of people at different times in history. Such diseases include Black Death (yersinia pestis), cholera (vibrio cholerae), malaria (plasmodium), and smallpox. More recently, HIV, dengue and coronavirus have appeared on the scene. However, fungal infections have rarely resulted in serious diseases, at least during the recorded history of human beings. However, there is something uniquely problematic about fungi. Unlike bacteria, they are eukaryotes and thus share many similarities with the cells of their human hosts. Whereas antibiotics only target prokaryotic cells, compounds that kill fungi also harm the eukaryotic host, which impairs the development of antifungal agents and makes these infections the most difficult to treat. Furthermore, fungal tropism is highly variable, as pathogens infect a wide range of cell types. Depending on the immunological status of the host, a single fungal pathogen may infect multiple tissues in the same patient [1]. Among the estimated 1.5–5 million fungal species on the planet, those able to cause disease in humans are only a few hundred. Of these, a small number fulfill the four basic conditions necessary to affect healthy people: high temperature tolerance, ability to invade the human host, lysis and absorption of human tissue, and resistance to the human immune system. It is unusual for fungal disease to take hold in healthy individuals because the immune system of humans (and animals) is sophisticated, having evolved in constant response to fungal challenges. In contrast, fungal diseases occur frequently in immunocompromised patients. The four major fungal phyla that infect humans are Entomophthoromycota (Conidiobolus spp. and Basidiobolus spp.), Ascomycota (e.g. Candida spp. Fusarium spp., Histoplasma spp., Aspergillus spp., Coccidioides spp., and Pneumocystis spp.), Basidiomycota (Cryptococcus spp. and Trichosporon spp.) and Mucorales (Mucor spp. and Rhizopus spp.). [2-3] Due to the increasing rate of fungal infections in hospitalized and immunocompromised patients, there is an urgent need to discover new antimycotic drugs. The biological attributes of triazole scaffolds, including those of the 1,2,3- and 1,2,4-isomers, are well recognized in the field of medicinal chemistry [4-10]. Many FDA-approved drugs contain such cores, being more common those with the 1,2,3-isomer: tazobactam and cefatrizine (broad-spectrum antibacterial agents), rufinamide (an anticonvulsant), suvorexant (a medication for insomnia), ticagrelor (a treatment to prevent stroke, heart attack and other adverse events in people with acute coronary syndrome) and bisoctrizole (a broad-spectrum chromophore added to sunscreens) (Scheme 1). Regarding conventional chemotherapy treatments for invasive, mucosal, and superficial fungal infections, the field is dominated by the 1,2,4-isomer. Itraconazole, terconazole, fluconazole and posaconazole (among others) have been conventional 1,2,4-triazole fungicidal agents for over 30 years, while efinaconazole and isavuconazole were more recently approved by the FDA (in 2014 and 2015, respectively) [11-17]. For pathogenic fungi, as with all microorganisms, there is the specter of the emergence of strains resistance to pharmaceuticals [18-21], particularly those observed for Rhizopus (mucormycosis) as 1,2,4triazole-drug resistant pathogen [22-23]. To meet this challenge, it is necessary to design and develop drugs that have well-defined and fungal-specific targets. The principal molecular target of azole antifungals is a protein, known as Erg11p or Cyp51p (according to distinct gene-based nomenclatures), in cytochrome P450. Cyp51p catalyzes the oxidative removal of the 14a-methyl group of lanosterol and/or eburicol in fungi by monooxygenase activity typical o (...truncated)