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  • Toxicity is the main reason

    2024-02-23

    Toxicity is the main reason for the failure at all stages of the new drug development process. The major part of safety-related attrition occurs at preclinical phases while predicting preclinical safety liabilities earlier in the drug development process. This strategy enables the design and/or selection of improved drug candidates that have more possibilities to become commercialised drugs. Therefore, we used the MTT cell viability assay to determine cytotoxicity against NIH/3T3 mouse embryonic fibroblast cell lines (ATCC CRL1658), which is recommended by ISO (10993-5, 2009). Results from the cytotoxicity evaluation of the most active compounds and are presented in . IC values of donepezil, compound , and compound against NIH/3T3 LY335979 were found to be 316μM, ⩾1000μM, and 100μM, respectively. IC values of compounds and against NIH/3T3 cells are higher than their IC values against AChE. Thus, it can be stated that these compounds are nontoxic at their effective concentrations against AChE. Furthermore, donepezil showed approximately 3-fold lower cytotoxicity than compound . Thus, cytotoxicity test findings enhanced the importance of compounds and as AChE inhibitors. Identification of mutagenic properties of new compounds is essential for safety, and thus, new drug candidates should be examined using the models of genotoxicity, such as the Ames test. In the current study, the Ames assay was performed to investigate the genotoxicity of compounds and . In Ames assay, more than 25 positive wells were observed with positive controls and negative control wells also showed less than eight positive wells in the presence and absence of S9 with TA98 and TA100, which complied with the requirements for the validation of the Ames and also as described in previous studies. Genotoxicity results are presented in . Compound showed a baseline of 3.08 and 6.13 against TA98 with and without S9, respectively. Fold inductions over baseline did not reach values more than 1.5 and statistically different results did not reveal any dose–response tendency. According to these findings, compound did not show any mutagenicity against TA98 (). Compound was found to show a baseline of 4.28 and 6.10 with and without S9 against TA100, respectively. Mentioned-fold increases over the baseline according to the criteria were not determined with compound and significant results did not reach these values and did not show any dose–response tendency. Compound was also found to be non-mutagenic against TA100 in the presence or absence of metabolic activation (). Compound showed a baseline of 6.40 with TA98 in the absence of S9 and a baseline of 3.58 in the presence of S9. Although there were significant differences observed, they did not reach the mentioned values above the baseline and did not show any dose–response tendency. Therefore, compound was classified as non-mutagenic against TA98 in the presence or absence of metabolic activation (S9) (). Compound had a baseline of 6.32 with TA100 in the absence of S9 and 4.42 in the presence of S9. Furthermore, fold inductions above the baseline were less than 1.5 in each concentration of the compound and the significantly different results obtained did not show any dose–response tendency. Therefore, compound was not genotoxic against TA100 with or without metabolic activation (). On the basis of the results of the Ames assay, the compounds were classified as negative. Further, cytotoxicity and genotoxicity findings strongly suggested compounds and to be AChE inhibitors. High pharmacological activity and low toxicological effects are not enough for a compound to become a drug candidate. A good pharmacokinetics profile is also very important for the new drug candidates that should be evaluated earlier in the process of drug development. In recent years, significant developments in combinatorial chemistry have made the estimation of absorption, distribution, metabolism and excretion (ADME) relatively easy. ADME properties of the newly synthesised compounds (–) were calculated using online Molinspiration property program. This program provides the data based on Lipinski’s rule, which assesses the ADME properties of new compounds and is important for the optimisation of a biologically active compound. The rule emphasises that an orally active drug should not possess more than one violation. Drug-likeness score (DLS) was also calculated for all the compounds (–) and donepezil based on the Molsoft’s chemical fingerprints mode consisting of 5K of marketed drugs from World Drug Index (positives) and 10K of carefully selected non-drug compounds (negatives). In the software, DLS score was found to be between 0 and 2, suggesting good pharmacokinetics for drug candidates.