Design and synthesis of some new carboxamide and propanamide derivatives bearing phenylpyridazine as a core ring and the investigation of their inhibitory potential on in-vitro acetylcholinesterase and butyrylcholinesterase.

A series of new carboxamide and propanamide derivatives bearing phenylpyridazine as a core ring were designed, synthesized and evaluated for their ability to inhibit both cholinesterase enzymes. In addition, a series of carboxamide and propanamide derivatives bearing biphenyl instead of phenylpyridazine were also synthesized to examine the inhibitory effect of pyridazine moiety on both cholinesterase enzymes. The inhibitory activity results revealed that compounds 5b, 5f, 5h, 5j, 5l pyridazine-3-carboxamide derivative, exhibited selective acetylcholinesterase (AChE) inhibition with IC50 values ranging from 0.11 to 2.69 µM. Among them, compound 5h was the most active one (IC50 = 0.11 µM) without cytotoxic effect at its effective concentration against AChE. Additionally, pyridazine-3-carboxamide derivative 5d (IC50 for AChE = 0.16 µM and IC50 for BChE = 9.80 µM) and biphenyl-4-carboxamide derivative 6d (IC50 for AChE = 0.59 µM and IC50 for BChE = 1.48 µM) displayed dual cholinesterase inhibitory activity. Besides, active compounds were also tested for their ability to inhibit Aß aggregation. Theoretical physicochemical properties of the compounds were calculated by using Molinspiration Program as well. The Lineweaver-Burk plot and docking study showed that compound 5 h targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.

Clinical and prognostic importance of XIAP and USP8 in advanced stages of non-small cell lung cancer.

PURPOSE: To investigate the relationship of the apoptosis regulators X-linked inhibitor of apoptosis (XIAP) and ubiquitin specific protease 8 (USP8) with clinical parameters, survival and response to chemotherapy in patients with advanced stages of non-small cell lung cancer (NSCLC). METHODS: The study included 34 NSCLC patients (28 females, 6 males) and 44 healthy individuals (17 males, 27 females) as a control group. XIAP and USP8 levels were determined by ELISA. RESULTS: The median serum XIAP level of the patients and the control group showed no significant difference. USP8 level was higher in patients than in controls (p<0.0001). In univariate analysis, there was no significant relationship between XIAP and USP8 serum levels and age, sex, performance status, weight loss, stage of disease, histopatological type and response to chemotherapy. Response to chemotherapy did not differ between the high and low XIAP and USP8 groups . There was no significant difference in progression- free survival (PFS) (p=0.432 and p=0.50, respectively) and overall survival (OS) (p=0.989 and p=0.90, respectively) between the low and high XIAP and USP8 groups. CONCLUSION: No relationship was found in serum XIAP and USP8 levels with clinical parameters, response to chemotherapy, PFS and OS in patients with advanced stages of NSCLC.