Evaluation of Fifteen 5,6-Dihydrotetrazolo[1,5-<i>c</i>]quinazolines Against <i>Nakaseomyces glabrata</i>: Integrating In Vitro Studies, Molecular Docking, QSAR, and In Silico Toxicity Assessments
<i>Nakaseomyces glabrata</i> (<i>Candida glabrata</i>), the second most prevalent Candida pathogen globally, has emerged as a major clinical threat due to its ability to develop high-level azole resistance. In this study, two new 5,6-dihydrotetrazolo[1,5-<i>c</i>]...
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2024-11-01
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| author | Lyudmyla Antypenko Oleksii Antypenko Alina Fominichenko Iryna Karnaukh Serhii Kovalenko Mieko Arisawa |
| author_facet | Lyudmyla Antypenko Oleksii Antypenko Alina Fominichenko Iryna Karnaukh Serhii Kovalenko Mieko Arisawa |
| author_sort | Lyudmyla Antypenko |
| collection | DOAJ |
| description | <i>Nakaseomyces glabrata</i> (<i>Candida glabrata</i>), the second most prevalent Candida pathogen globally, has emerged as a major clinical threat due to its ability to develop high-level azole resistance. In this study, two new 5,6-dihydrotetrazolo[1,5-<i>c</i>]quinazoline derivatives (<b>c11</b> and <b>c12</b>) were synthesized and characterized using IR, LC-MS, <sup>1</sup>H, and <sup>13</sup>C NMR spectra. Along with 13 previously reported analogues, these compounds underwent in vitro antifungal testing against clinical <i>N. glabrata</i> isolates using a serial dilution method (0.125–64 mg/L). Remarkably, compounds <b>c5</b> and <b>c1</b> exhibited potent antifungal activity, with minimum inhibitory concentrations of 0.37 μM and 0.47 μM, respectively—about a 20-fold improvement in μM concentration over standard drugs like amphotericin B, caspofungin, and micafungin. A detailed structure–activity relationship analysis revealed crucial molecular features enhancing antifungal potency. Extensive molecular docking studies across 18 protein targets explored potential binding pockets and affinities of the lead compounds. A robust 3D-QSAR model, incorporating molecular descriptors Mor26m and Mor29e, displayed good predictive ability for antifungal activity. In silico predictions indicated an absence of herbicidal effect, negligible environmental toxicity (to honeybees, avian species, and aquatic organisms), and mild human toxicity concerns for these compounds. This comprehensive approach aims to develop novel and effective antifungal compounds against the clinically relevant pathogen <i>N. glabrata</i>. |
| format | Article |
| id | doaj-art-8e8dead77c6643419a8ee36c9934528a |
| institution | OA Journals |
| issn | 2309-608X |
| language | English |
| publishDate | 2024-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Fungi |
| spelling | doaj-art-8e8dead77c6643419a8ee36c9934528a2025-08-20T02:00:42ZengMDPI AGJournal of Fungi2309-608X2024-11-01101281610.3390/jof10120816Evaluation of Fifteen 5,6-Dihydrotetrazolo[1,5-<i>c</i>]quinazolines Against <i>Nakaseomyces glabrata</i>: Integrating In Vitro Studies, Molecular Docking, QSAR, and In Silico Toxicity AssessmentsLyudmyla Antypenko0Oleksii Antypenko1Alina Fominichenko2Iryna Karnaukh3Serhii Kovalenko4Mieko Arisawa5Independent Researcher, Lamana 11, 69063 Zaporizhzhia, UkraineDepartment of Pharmaceutical, Organic, and Bioorganic Chemistry, Zaporizhzhia State Medical and Pharmaceutical University, M. Prymachenko Ave. 26, 69035 Zaporizhzhia, UkraineBacteriological Laboratory, Zaporizhzhia Regional Clinical Hospital of Zaporizhzhia Regional Council, Orikhivs’ke Hwy. 10, 69600 Zaporizhzhia, UkraineBacteriological Laboratory, Zaporizhzhia Regional Clinical Hospital of Zaporizhzhia Regional Council, Orikhivs’ke Hwy. 10, 69600 Zaporizhzhia, UkraineResearch Institute of Chemistry and Geology, Oles Honchar Dnipro National University, Nauky Ave. 72, 49010 Dnipro, UkraineDepartment of Biosciences and Biotechnologies, Graduate School of Bioresources and Bioenvironment Sciences, Kyushu University, 744 W5-674, Motooka Nishi-ku, Fukuoka 819-0395, Japan<i>Nakaseomyces glabrata</i> (<i>Candida glabrata</i>), the second most prevalent Candida pathogen globally, has emerged as a major clinical threat due to its ability to develop high-level azole resistance. In this study, two new 5,6-dihydrotetrazolo[1,5-<i>c</i>]quinazoline derivatives (<b>c11</b> and <b>c12</b>) were synthesized and characterized using IR, LC-MS, <sup>1</sup>H, and <sup>13</sup>C NMR spectra. Along with 13 previously reported analogues, these compounds underwent in vitro antifungal testing against clinical <i>N. glabrata</i> isolates using a serial dilution method (0.125–64 mg/L). Remarkably, compounds <b>c5</b> and <b>c1</b> exhibited potent antifungal activity, with minimum inhibitory concentrations of 0.37 μM and 0.47 μM, respectively—about a 20-fold improvement in μM concentration over standard drugs like amphotericin B, caspofungin, and micafungin. A detailed structure–activity relationship analysis revealed crucial molecular features enhancing antifungal potency. Extensive molecular docking studies across 18 protein targets explored potential binding pockets and affinities of the lead compounds. A robust 3D-QSAR model, incorporating molecular descriptors Mor26m and Mor29e, displayed good predictive ability for antifungal activity. In silico predictions indicated an absence of herbicidal effect, negligible environmental toxicity (to honeybees, avian species, and aquatic organisms), and mild human toxicity concerns for these compounds. This comprehensive approach aims to develop novel and effective antifungal compounds against the clinically relevant pathogen <i>N. glabrata</i>.https://www.mdpi.com/2309-608X/10/12/816antifungal activity<i>Nakaseomyces glabrata</i>5,6-dihydrotetrazolo[1,5-<i>c</i>]quinazolinesmolecular dockingtoxicityQSAR |
| spellingShingle | Lyudmyla Antypenko Oleksii Antypenko Alina Fominichenko Iryna Karnaukh Serhii Kovalenko Mieko Arisawa Evaluation of Fifteen 5,6-Dihydrotetrazolo[1,5-<i>c</i>]quinazolines Against <i>Nakaseomyces glabrata</i>: Integrating In Vitro Studies, Molecular Docking, QSAR, and In Silico Toxicity Assessments Journal of Fungi antifungal activity <i>Nakaseomyces glabrata</i> 5,6-dihydrotetrazolo[1,5-<i>c</i>]quinazolines molecular docking toxicity QSAR |
| title | Evaluation of Fifteen 5,6-Dihydrotetrazolo[1,5-<i>c</i>]quinazolines Against <i>Nakaseomyces glabrata</i>: Integrating In Vitro Studies, Molecular Docking, QSAR, and In Silico Toxicity Assessments |
| title_full | Evaluation of Fifteen 5,6-Dihydrotetrazolo[1,5-<i>c</i>]quinazolines Against <i>Nakaseomyces glabrata</i>: Integrating In Vitro Studies, Molecular Docking, QSAR, and In Silico Toxicity Assessments |
| title_fullStr | Evaluation of Fifteen 5,6-Dihydrotetrazolo[1,5-<i>c</i>]quinazolines Against <i>Nakaseomyces glabrata</i>: Integrating In Vitro Studies, Molecular Docking, QSAR, and In Silico Toxicity Assessments |
| title_full_unstemmed | Evaluation of Fifteen 5,6-Dihydrotetrazolo[1,5-<i>c</i>]quinazolines Against <i>Nakaseomyces glabrata</i>: Integrating In Vitro Studies, Molecular Docking, QSAR, and In Silico Toxicity Assessments |
| title_short | Evaluation of Fifteen 5,6-Dihydrotetrazolo[1,5-<i>c</i>]quinazolines Against <i>Nakaseomyces glabrata</i>: Integrating In Vitro Studies, Molecular Docking, QSAR, and In Silico Toxicity Assessments |
| title_sort | evaluation of fifteen 5 6 dihydrotetrazolo 1 5 i c i quinazolines against i nakaseomyces glabrata i integrating in vitro studies molecular docking qsar and in silico toxicity assessments |
| topic | antifungal activity <i>Nakaseomyces glabrata</i> 5,6-dihydrotetrazolo[1,5-<i>c</i>]quinazolines molecular docking toxicity QSAR |
| url | https://www.mdpi.com/2309-608X/10/12/816 |
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