Design, synthesis, and biological evaluation of thienopyrimidine derivatives as multifunctional agents against Alzheimer's disease.

A series of 12 S-substituted tetrahydrobenzothienopyrimidines were designed and synthesized based on the donepezil scaffold. All the newly synthesized compounds were evaluated for their acetylcholinesterase (AChE) inhibitory activity and the most active compounds were tested for their butyrylcholinesterase (BuChE) inhibitory activity. Moreover, all the synthesized compounds were evaluated for their inhibitory effects against Aß aggregation and antioxidant activity using the oxygen radical absorbance capacity method. Compounds 4b, 6b, and 8b displayed the most prominent AChE inhibitory action comparable to donepezil. Compound 6b showed the greatest AChE inhibitory action (IC50 = 0.07 ± 0.003 µM) and the most potent BuChE inhibitory action (IC50 = 0.059 ± 0.004 µM). Furthermore, the three compounds exhibited significant antioxidant activity. Compounds 6b and 8b exerted more inhibitory action on Aß aggregation than donepezil. The cytotoxic activity of compounds 4b, 6b, and 8b against the WI-38 cell line in comparison with donepezil was examined using 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay. The results revealed that compounds 6b and 8b were less cytotixic than donepezil, while compound 4b showed nonsignificant cytotoxicity compared to donepezil. For more insights about the binding patterns of the most promising compounds (4b, 6b, and 8b) with the AChE at molecular levels; molecular docking and molecular dynamics simulations were performed. The density functional theory calculations and absorption, distribution, metabolism, excretion and toxicity properties were described as well. The results highlighted compound 6b, which incorporates a phenylpiperazine moiety coupled to a thienopyrimidone scaffold via two-atom spacer, to be a promising multifunctional therapeutic agent for the treatment of Alzheimer's disease. It is a potent dual AChE and BuChE inhibitor. Furthermore, it had stronger Aß aggregation inhibitory action than donepezil. Additionally, compound 6b exerted significant antioxidant activity.

Development of new Alzheimer's disease drug candidates using donepezil as a key model.

Alzheimer's disease (AD) is one of the most prevalent geriatric diseases and a significant cause of high mortality. This crippling disorder is becoming more prevalent at an unprecedented rate, which has led to an increase in the financial cost of caring. It is a pathologically complicated, multifactorial disease characterized by ß-amyloid precipitation, ß-amyloid oligomer production, decrease in cholinergic function, and dysregulation of other neurotransmitter systems. Due to the pathogenic complexity of AD, multitarget drugs that can simultaneously alternate multiple biological targets may enhance the therapeutic efficacy. Donepezil (DNP) is the most potent approved drug for the treatment of AD. It has a remarkable effect on a number of AD-related processes, including cholinesterase activity, anti-Aß aggregation, oxidative stress, and more. DNP resembles an excellent scaffold to be hybridized with other pharmacophoric moieties having biological activity against AD pathological factors. There have been significant attempts made to modify the structure of DNP to create new bioactive chemical entities with novel structural patterns. In this review, we highlight recent advances in the development of multiple-target DNP-hybridized models for the treatment of AD that can be used in the future in the rational design of new potential AD therapeutics. The design and development of new drug candidates for the treatment of AD using DNP as a molecular scaffold have also been reviewed and summarized.

Design, synthesis, and biological evaluation of thienopyrimidine and thienotriazine derivatives as multitarget anti-Alzheimer agents.

A series of tetrahydrobenzothienopyrimidines and tetrahydrobenzothienotriazines incorporating a pharmacophore from donepezil molecule were designed and synthesized. The 12 newly synthesized compounds were screened for their inhibition activity against acetylcholinesterase enzyme (AChE). Compounds that exerted the most potent AChE inhibitory action were further evaluated for their BChE inhibitory activity. In addition, the inhibitory effects of all newly synthesized compounds on Aß and reactive oxygen species were assessed. Compounds 4d, 10b, and 10c showed potent inhibitory activity on AChE comparable to donepezil. Compound 10b (IC50 = 0.124 ± 0.006 nM) showed the greatest AChE inhibitory action and the most potent BChE inhibitory action (IC50 = 0.379 ± 0.02 nM). These three compounds showed more inhibitory action on Aß accumulation than donepezil. Moreover, they showed potent antioxidant activity. The binding pattern of compounds 4d and 10b into AChE active site rationalized their remarkable AChE inhibitory activity. Taken together, these results indicated that these derivatives could be promising multifunctional agents for Alzheimer's disease management.

Synthesis and anti-inflammatory activity of novel pyridazine and pyridazinone derivatives as non-ulcerogenic agents.

Herein, we report the synthesis and pharmacological properties of several series of pyridazine and pyridazinone derivatives. All the synthesized compounds were tested, in vivo, for their anti-inflammatory and ulcerogenic properties against indomethacin, as a reference compound. Compounds 4a and 9d have shown a potent anti-inflammatory activity more than indomethacin with rapid onset of action and safe gastric profile. The latter compounds were then selected for further investigation. In the MTT assay in vitro, both compounds were identified as potent and selective COX-2 inhibitors.