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. Keywords: Ames test, CODES, mutagenicity, neural networks, N-oxides, preclinical tests.
Abstract Ultrasonic irradiation greatly improves the synthesis of N-arylanthranilic acids (shorter reaction times, higher purity of the final products) through the Ullmann Goldberg reaction.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
I Licenciada en Microbiologia. Hospital Clinicoquirurgico Hermanos Ameijeiras, La Habana, Cuba. II Especialista de I Grado en Medicina General Integral. Especialista de I Grado en Gastroenterologia. Instructor. Hospital Clinicoquirurgico Hermanos Ameijeiras, La Habana, Cuba. III Licenciado en Bioquimica. Hospital Clinicoquirurgico Hermanos Ameijeiras, La Habana, Cuba. IV Especialista de II Grado en Gastroenterologia. Profesor Auxiliar. Hospital Clinicoquirurgico Hermanos Ameijeiras, La Habana, Cuba.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Trypanosoma cruzi, the causative agent of Chagas' disease, affects tens of millions of South Americans. One of the most studied T. cruzi-biomolecules as a target for drug development is cruzipain, an essential cysteine proteinase of this parasite. Some of our recent studies identified amidine containing benzofuroxans as hit compounds for cruzipain inhibition with trypanosomicidal activities. Experimental and theoretical studies inspired us to modify these compounds by maintaining the amidine motif and using benzofuroxan and benzimidazole 1,3-dioxide systems as core scaffolds in order to obtain better cruzipain inhibitors. The new amidines had excellent trypanosomicidal activity, with good selectivity indexes, but without improved cruzipain-inhibitory activities compared with the parent compounds. The interaction of amidines with cruzipain has been investigated through a combined NMR -T1-differences, DOSY, and STD- and molecular docking approaches. Despite the low cruzipain-inhibition ability, our data suggest that these designed compounds have relevant structural features, i.e. aromatic groups and protonated moieties with stabilizing complex ability using stacking and electrostatic interactions, respectively, that bind reversibly to cruzipain.