Chromenol Derivatives as Novel Antifungal Agents: Synthesis, In Silico and In Vitro Evaluation
Marina Zveaghintseva,
Eugenia Stingaci,
Serghei Pogrebnoi,
Anastasia Smetanscaia,
Vladimir Valica,
Livia Uncu,
Victor Ch. Kravtsov,
Elena Melnic,
Anthi Petrou,
Jasmina Glamočlija,
Marina Soković,
Alejandro Carazo,
Přemysl Mladěnka,
Vladimir Poroikov,
Athina Geronikaki,
Fliur Z. Macaev
Affiliations
Marina Zveaghintseva
Laboratory of Organic Synthesis, Institute of Chemistry, 3 Str. Academiei 3, MD-2028 Chișinău, Moldova
Eugenia Stingaci
Laboratory of Organic Synthesis, Institute of Chemistry, 3 Str. Academiei 3, MD-2028 Chișinău, Moldova
Serghei Pogrebnoi
Laboratory of Organic Synthesis, Institute of Chemistry, 3 Str. Academiei 3, MD-2028 Chișinău, Moldova
Anastasia Smetanscaia
Scientific Center for Drug Research, “Nicolae Testemițanu” State University of Medicine and Pharmacy, Bd. Stefan Cel Mare și Sfant 165, MD-2004 Chișinău, Moldova
Vladimir Valica
Scientific Center for Drug Research, “Nicolae Testemițanu” State University of Medicine and Pharmacy, Bd. Stefan Cel Mare și Sfant 165, MD-2004 Chișinău, Moldova
Livia Uncu
Scientific Center for Drug Research, “Nicolae Testemițanu” State University of Medicine and Pharmacy, Bd. Stefan Cel Mare și Sfant 165, MD-2004 Chișinău, Moldova
Victor Ch. Kravtsov
Laboratory of Physical Methods of Solid State Investigation “Tadeusz Malinowski”, Institute of Applied Physics, Str. Academiei 5, MD-2028 Chișinău, Moldova
Elena Melnic
Laboratory of Physical Methods of Solid State Investigation “Tadeusz Malinowski”, Institute of Applied Physics, Str. Academiei 5, MD-2028 Chișinău, Moldova
Anthi Petrou
Department of Pharmacy, School of Health, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Jasmina Glamočlija
Mycological Laboratory, Department of Plant Physiology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, 11060 Beograd, Serbia
Marina Soković
Mycological Laboratory, Department of Plant Physiology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, 11060 Beograd, Serbia
Alejandro Carazo
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, 500 05 Hradec Králové, Czech Republic
Přemysl Mladěnka
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, 500 05 Hradec Králové, Czech Republic
Vladimir Poroikov
Laboratory of Structure-Function Based Drug Design, Institute of Biomedical Chemistry, Pogodinskaya Str. 10, Bldg. 8, 119121 Moscow, Russia
Athina Geronikaki
Department of Pharmacy, School of Health, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Fliur Z. Macaev
Laboratory of Organic Synthesis, Institute of Chemistry, 3 Str. Academiei 3, MD-2028 Chișinău, Moldova
Herein we report the synthesis of some new 1H-1,2,4-triazole functionalized chromenols (3a–3n) via tandem reactions of 1-(alkyl/aryl)-2-(1H-1,2,4-triazole-1-yl) with salicylic aldehydes and the evaluation of their antifungal activity. In silico prediction of biological activity with computer program PASS indicate that the compounds have a high novelty compared to the known antifungal agents. We did not find any close analog among the over 580,000 pharmaceutical agents in the Cortellis Drug Discovery Intelligence database at the similarity cutoff of 70%. The evaluation of antifungal activity in vitro revealed that the highest activity was exhibited by compound 3k, followed by 3n. Their MIC values for different fungi were 22.1–184.2 and 71.3–199.8 µM, respectively. Twelve from fourteen tested compounds were more active than the reference drugs ketoconazole and bifonazole. The most sensitive fungus appeared to be Trichoderma viride, while Aspergillus fumigatus was the most resistant one. It was found that the presence of the 2-(tert-butyl)-2H-chromen-2-ol substituent on the 4th position of the triazole ring is very beneficial for antifungal activity. Molecular docking studies on C. albicans sterol 14α-demethylase (CYP51) and DNA topoisomerase IV were used to predict the mechanism of antifungal activities. According to the docking results, the inhibition of CYP51 is a putative mechanism of antifungal activity of the novel chromenol derivatives. We also showed that most active compounds have a low cytotoxicity, which allows us to consider them promising antifungal agents for the subsequent testing activity in in vivo assays.