In Vivo Toxicity, Redox-Modulating Capacity and Intestinal Permeability of Novel Aroylhydrazone Derivatives as Anti-Tuberculosis Agents
The emergence and spread of <i>Mycobacterium tuberculosis</i> strains resistant to many or all anti-tuberculosis (TB) drugs require the development of new compounds both efficient and with minimal side effects. Structure-activity-toxicity relationships of such novel, structurally diverse...
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MDPI AG
2022-12-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/1/79 |
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| author | Violeta Valcheva Rumyana Simeonova Milka Mileva Stanislav Philipov Reneta Petrova Simeon Dimitrov Almira Georgieva Elina Tsvetanova Yoana Teneva Violina T. Angelova |
| author_facet | Violeta Valcheva Rumyana Simeonova Milka Mileva Stanislav Philipov Reneta Petrova Simeon Dimitrov Almira Georgieva Elina Tsvetanova Yoana Teneva Violina T. Angelova |
| author_sort | Violeta Valcheva |
| collection | DOAJ |
| description | The emergence and spread of <i>Mycobacterium tuberculosis</i> strains resistant to many or all anti-tuberculosis (TB) drugs require the development of new compounds both efficient and with minimal side effects. Structure-activity-toxicity relationships of such novel, structurally diverse compounds must be thoroughly elucidated before further development. Here, we present the aroylhydrazone compounds (<b>3a</b> and <b>3b</b>) regarding their: (i) acute and subacute toxicity in mice; (ii) redox-modulating in vivo and in vitro capacity; (iii) pathomorphology in the liver, kidney, and small intestine tissue specimens; and (iv) intestinal permeability. The acute toxicity test showed that the two investigated compounds exhibited low toxicity by oral and intraperitoneal administration. Changes in behavior, food amount, and water intake were not observed during 14 days of the oral administration at two doses of 1/10 and 1/20 of the LD<sub>50</sub>. The histological examination of the different tissue specimens did not show toxic changes. The in vitro antioxidant assays confirmed the ex vivo results. High gastrointestinal tract permeability at all tested pH values were demonstrated for both compounds. To conclude, both compounds <b>3a</b> and <b>3b</b> are highly permeable with low toxicity and can be considered for further evaluation and/or lead optimization. |
| first_indexed | 2024-03-09T11:28:15Z |
| format | Article |
| id | doaj.art-29615c1dbe9c4d12afec9b90c194a3e4 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T11:28:15Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-29615c1dbe9c4d12afec9b90c194a3e42023-11-30T23:57:22ZengMDPI AGPharmaceutics1999-49232022-12-011517910.3390/pharmaceutics15010079In Vivo Toxicity, Redox-Modulating Capacity and Intestinal Permeability of Novel Aroylhydrazone Derivatives as Anti-Tuberculosis AgentsVioleta Valcheva0Rumyana Simeonova1Milka Mileva2Stanislav Philipov3Reneta Petrova4Simeon Dimitrov5Almira Georgieva6Elina Tsvetanova7Yoana Teneva8Violina T. Angelova9The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 1113 Sofia, BulgariaDepartment of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, BulgariaThe Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 1113 Sofia, BulgariaDepartment of Human Anatomy, Histology, General and Clinical Pathology and Forensic Medicine, Faculty of Medicine, Sofia University “St. Kliment Ohridski”, 1407 Sofia, BulgariaNational Diagnostic and Research Veterinary Medical Institute, 1000 Sofia, BulgariaThe Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 1113 Sofia, BulgariaThe Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 1113 Sofia, BulgariaThe Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 1113 Sofia, BulgariaDepartment of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, BulgariaDepartment of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, BulgariaThe emergence and spread of <i>Mycobacterium tuberculosis</i> strains resistant to many or all anti-tuberculosis (TB) drugs require the development of new compounds both efficient and with minimal side effects. Structure-activity-toxicity relationships of such novel, structurally diverse compounds must be thoroughly elucidated before further development. Here, we present the aroylhydrazone compounds (<b>3a</b> and <b>3b</b>) regarding their: (i) acute and subacute toxicity in mice; (ii) redox-modulating in vivo and in vitro capacity; (iii) pathomorphology in the liver, kidney, and small intestine tissue specimens; and (iv) intestinal permeability. The acute toxicity test showed that the two investigated compounds exhibited low toxicity by oral and intraperitoneal administration. Changes in behavior, food amount, and water intake were not observed during 14 days of the oral administration at two doses of 1/10 and 1/20 of the LD<sub>50</sub>. The histological examination of the different tissue specimens did not show toxic changes. The in vitro antioxidant assays confirmed the ex vivo results. High gastrointestinal tract permeability at all tested pH values were demonstrated for both compounds. To conclude, both compounds <b>3a</b> and <b>3b</b> are highly permeable with low toxicity and can be considered for further evaluation and/or lead optimization.https://www.mdpi.com/1999-4923/15/1/79aroylhydrazone derivativesacute and sub-acute toxicityredox-modulating capacityGIT permeabilitypathomorphological evaluation |
| spellingShingle | Violeta Valcheva Rumyana Simeonova Milka Mileva Stanislav Philipov Reneta Petrova Simeon Dimitrov Almira Georgieva Elina Tsvetanova Yoana Teneva Violina T. Angelova In Vivo Toxicity, Redox-Modulating Capacity and Intestinal Permeability of Novel Aroylhydrazone Derivatives as Anti-Tuberculosis Agents Pharmaceutics aroylhydrazone derivatives acute and sub-acute toxicity redox-modulating capacity GIT permeability pathomorphological evaluation |
| title | In Vivo Toxicity, Redox-Modulating Capacity and Intestinal Permeability of Novel Aroylhydrazone Derivatives as Anti-Tuberculosis Agents |
| title_full | In Vivo Toxicity, Redox-Modulating Capacity and Intestinal Permeability of Novel Aroylhydrazone Derivatives as Anti-Tuberculosis Agents |
| title_fullStr | In Vivo Toxicity, Redox-Modulating Capacity and Intestinal Permeability of Novel Aroylhydrazone Derivatives as Anti-Tuberculosis Agents |
| title_full_unstemmed | In Vivo Toxicity, Redox-Modulating Capacity and Intestinal Permeability of Novel Aroylhydrazone Derivatives as Anti-Tuberculosis Agents |
| title_short | In Vivo Toxicity, Redox-Modulating Capacity and Intestinal Permeability of Novel Aroylhydrazone Derivatives as Anti-Tuberculosis Agents |
| title_sort | in vivo toxicity redox modulating capacity and intestinal permeability of novel aroylhydrazone derivatives as anti tuberculosis agents |
| topic | aroylhydrazone derivatives acute and sub-acute toxicity redox-modulating capacity GIT permeability pathomorphological evaluation |
| url | https://www.mdpi.com/1999-4923/15/1/79 |
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