Medicinal Chemistry

Background: Alzheimer’s disease (AD) is a neurodegenerative disease and is the most common because of late life dementia. Alteration of Secretary Phospholipase A2-IIA (sPLA2-IIA) may have an important role in membrane phospholipids metabolism and the pathogenesis of AD. The aim of our study was to determine serum levels and genetic variant of sPLA2-IIA in Alzheimer’s disease and compare to controls.

Methods: This study included 40 healthy unrelated individuals and 40 patients with AD. Serum levels and the polymorphisms of sPLA2-IIA enzyme were determined.

Results: In Alzheimer patients¸ the CC genotype and C allele frequencies of enzyme were significantly lower while the CG and GG genotypes and G allele frequencies of enzyme were significantly higher than controls. The mean concentration and mean rank of enzyme for CC genotype significantly were lower while the CG and GG genotypes of enzyme were significantly higher than controls.

Conclusion: The effect of different gene polymorphisms for the incident of AD is still unclear. We determined gene polymorphisms of sPLA2-IIA which may relate to AD. It can be suggest that a single or combination of gene polymorphisms have possible effect for development of AD. Further studies are needed to research the functional roles of sPLA2-IIA in the context of AD.

Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class, is synthesized for commercial use as a drug substance in highly pure form. During the synthetic process development studies of Sertraline hydrochloride, an impurity was detected in the final product at levels ranging from 0.05% to 0.15% in Gas Chromatography (GC) method and its molecular weight was determined by LC-MS analysis. The impurity was identified as 4-(4-chlorophenyl)-3,4-dihydronaphthalen-1(2H)-ol impurity, synthesized and characterized, the process of its formation was discussed in detail. After qualification of impurity standard, it was used as a reference standard for development of quantification by High Performance Liquid Chromatography (HPLC) method.

Chemotherapy is one of the treatment options for cancer. A major problem in cancer chemotherapy is the lack of selective toxicity of many commonly used anti-cancer agents towards tumor tissue compared to normal tissue. Studies have shown that α-naphthol is selectively toxic to cultures of human tumor tissue compared to normal tissues in vitro. Hence, this study was conducted to synthesize a series of new hydroxamate derivatives containing α-naphthol nucleus by the reaction of naphthol acetic acid with amino acid methyl ester derivatives which were directly reacted with hydroxyl amine at room temperature. Structures of these compounds were confirmed by standard studies of IR, 1H NMR, 13 CNMR, MS and elemental analysis. The cytotoxicity of the synthesized compounds were studied using the MTT assay in four human cancer cell lines, including HepG2, PC-3, HT-29 and MCF-7. Among the compounds, compound 6g and 6h exhibited a significant cytotoxicity against almost all the used cells including the normal cells (WRL-68). Further studies have shown that the cell death observed was closely associated with generation of reactive oxygen species (ROS). In this study, other naphthol derivatives have shown significant increase in the level of ROS in concentration dependent manner in treated cells. In conclusion, the study has shown that among the synthesized compounds, compounds 6g , 6k and 6h hold the potential for further research. Furthermore, a molecular docking of the tested compounds was carried out to investigate their binding pattern with the prospective target, HDAC (PDB-code: 1T69).