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Mutagenicity of N-oxide containing heterocycles and related compounds: experimental and theoretical studies
Martin Gabay, Mauricio Cabrera, Rossanna Di Maio
1Grupo de Quimica Medicinal, Facultad de Ciencias, Universidad de la Republica, Igua 4225, 11400 Montevideo, Uruguay. hcerecetto@cin.edu.uy.
Abstract:
In the development of new drugs, it is very important to know the effects these may bring to those who consume them. Drugs which act upon certain diseases must not cause toxic side effects on healthy organs. These toxic side effects can be quite varied, i.e. mutagenicity, clastogenicity, teratogenicity, etc., but undoubtedly the mutagenicity officiate in the selection process, during preclinical testing, to advance in clinical trials. Mutagenic compounds are removed and cannot continue its development. There are preclinical studies of mutagenicity and genotoxicity, ranging from in vitro to in vivo studies. Particularly, Ames test is recommended by ICH as the first input in these studies. Herein, we investigated the mutagenicity of an in-house chemical library of eighty five N-oxide containing heterocycles using Ames test in Salmonella thyphimurium TA 98 with and without S9 activation and the use of neural networks in order to predict this nondesired activity. N-oxide containing heterocycles are especially relevant regarding its pharmacological activities as antitrypanosoma, anti-leishmania, anti-tuberculosis, anti-cancer, chemopreventive, anti-inflammatory, anti-atherogenic, and analgesic agents. In some cases, a relationship was found between the presence of N-oxide and mutagenicity. Specifically, benzofuroxan system seems to be responsible for the mutagenicity of certain agents against Chagas disease and certain anti-inflammatory agents. However other N-oxides, such as furoxans with anti-inflammatory and anti-atherosclerosis activities, seem to lack mutagenicity. In other cases, such as quinoxaline dioxides with anti-parasitic activity, mutagenicity shows to be substituent dependent. Applying CODES neural network two models were defined, one without metabolism and other with metabolism. These models predict the mutagenicity with and without metabolism in an excellent manner.
Insights
This study evaluated mutagenicity in N-oxide heterocycles using the Ames test and neural networks. Certain N-oxides showed mutagenicity, while others did not, highlighting the need for careful drug development screening.
Area of Science:
- Medicinal Chemistry
- Toxicology
- Computational Chemistry
Background:
- Drug development requires assessing toxic side effects, with mutagenicity being a critical factor in preclinical screening.
- N-oxide containing heterocycles possess diverse pharmacological activities but their mutagenic potential needs thorough investigation.
- The Ames test is a standard in vitro assay for bacterial mutagenicity, recommended for early drug development stages.
Purpose of the Study:
- To investigate the mutagenicity of 85 N-oxide containing heterocycles using the Ames test.
- To develop and apply neural network models for predicting mutagenicity of these compounds, with and without metabolic activation.
- To establish structure-activity relationships between N-oxide presence and mutagenic potential.
Main Methods:
- Conducted Ames tests using Salmonella thyphimurium TA 98, with and without S9 metabolic activation.
- Utilized CODES neural networks to build predictive models for mutagenicity.
- Analyzed a library of 85 N-oxide containing heterocyclic compounds.
Main Results:
- Identified specific N-oxide containing heterocycles that exhibited mutagenicity, while others showed no such activity.
- The benzofuroxan system was implicated in the mutagenicity of certain anti-Chagas disease and anti-inflammatory agents.
- Neural network models demonstrated excellent predictive accuracy for mutagenicity, both with and without metabolic considerations.
Conclusions:
- Mutagenicity of N-oxide heterocycles is compound-specific and can be influenced by structural features and metabolic pathways.
- Neural networks offer a powerful tool for predicting mutagenicity, aiding in the early selection of safer drug candidates.
- This study provides valuable insights for the development of N-oxide based therapeutics, guiding the removal of potentially mutagenic compounds.
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