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 Cytotoxicity Evaluation of Novel Indole Derivatives as Potential Anti-Cancer Agents.

BACKGROUND: Marine sponges and tunicates have been a wealthy source of cytotoxic compounds such as indole alkaloids. Most of the indole alkaloids show in vitro cytotoxic and antineoplastic activities against a wide range of cancer cell lines. OBJECTIVE: Three series of bioisosteres of marine indole alkaloids (meridianins) were synthesized and the compounds were tested for their in vitro anti-proliferative activity against HCT-116 cellline. In the design of the targeted analogues, the 2-aminopyrimidine ring of merdianins was replaced with 5-aminopyrazole, pyrazolo[1,5-a]pyrimidine and pyrazolo[3,4-b]pyridine rings. RESULTS: The cytotoxic screening of the synthesized compounds revealed that pyrazolo[1,5- a]pyrimidines (compounds 9c and 11a) had the most potent cytotoxic activity with IC50 = 0.31 µM and 0.34 µM respectively. Compounds 9c and 11a were further investigated for their kinase inhibitory potencies toward six kinases (CDK5/p25, CK1ð/ε, GSK-3α/ß, Dyrk1A, Erk2, and CLK1). They exhibited effective inhibition of GSK-3α/ß (IC50 = 0.196 µM and 0.246 µM, respectively) and Erk2 (IC50 = 0.295 µM and 0.376 µM, respectively). CONCLUSION: Meridianins emerged as promising lead structures that need further development to obtain more selective and potent cytotoxic agents. One of these modifications involved the replacement of 2-aminopyrimidinyl ring of meridianins with other heterocyclic rings. Both pyrazolo[ 1,5-a]pyrimidine and pyrazolo[3,4-b]pyridine rings showed promising cytotoxic activity compared to the five membered 5-aminopyrazole.

Synthesis, Characterization and Cytotoxicity of Substituted [1]Benzothieno[3,2-e][1,2,4]triazolo [4,3-a]pyrimidines.

A new series of 4-benzyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidines was synthesized motivated by the widely reported anticancer activity of thieno[2,3-d]pyrimidines and triazolothienopyrimidines. The in vitro cytotoxic activity of some selected compounds was evaluated against two human cell lines: prostate cancer (PC-3) and colon cancer (HCT-116). A preliminary study of the structure-activity relationship of the target compounds was discussed. Most of the synthesized compounds showed remarkable activity on the tested cell lines, while compound 16c had the highest potency against the PC-3 cell line with an IC50 of 5.48 µM compared to Doxorubicin (IC50 = 7.7 µM), the reference standard used in this study. On the other hand, 6c and 18c were the most active against HCT-116 (IC50 = 6.12 and 6.56 µM, respectively) relative to IC50 = 15.82 µM of the standard. Thus, some of the synthesized thienopyrimidine derivatives, specially 6c, 16c and 18c, have the potential to be developed into potent anticancer agents.

Convenient synthesis, characterization, cytotoxicity and toxicity of pyrazole derivatives.

3-Methyl-1H-pyrazol-5(4H)-one (1) was used as a template to develop new anticancer compounds and investigate their SAR. The ring modification of compound 1 occurred through its reaction with aromatic aldehydes and different reagents to afford the corresponding 6-oxopyrano[2,3-c]pyrazoles4a-c and their amino analogues 6-aminopyrano[2,3-c]pyrazoles6a-c, 8; the pyrazolopyrano[2,3-b]pyridines 10a-c and the chromenopyrano[2,3-c]pyrzolones13, 14. The reaction of compound 1 with thiourea and appropriate aromatic aldehydes afforded the pyrazolo[3,4-d]pyrimidine derivatives 17a-c. On the other hand, the pyrazolo[3,4-d]thiazole derivatives 22a-d were obtained via the reaction of 1 with sulpher and aryl isothiocyanates in presence of triethylamine. The reaction of compound 1 with phenylisothiocyanate followed by treatment with the a-halocarbonyl compounds 24a-c afforded the thiazole derivatives 25a-c. The synthesized products were evaluated for their cytotoxicity against cancer and normal cell lines. Most compounds showed significant anticancer activity without affecting the normal fibroblast cells. The toxicity of the mostpontent cytotoxic compounds was measured using Brine-Shrimp Lethality Assay.

Synthesis of novel 1,2,4-triazoles, triazolothiadiazines and triazolothiadiazoles as potential anticancer agents.

A series of new N-substituted-3-mercapto-1,2,4-triazoles (3a,b and 7a-d), triazolo[1,3,4]thiadiazines (5a,b) and triazolo[1,3,4]thiadiazoles (4a-d, 6 and 8a-d) have been synthesized starting from isonicotinic acid hydrazide. The structure of the newly synthesized compounds was confirmed on the basis of their spectral data and elemental analyses. All the compounds were screened for their in vitro anticancer activity against 6 human cancer cell lines and normal fibroblasts. Seven of the tested compounds (3a,b, 4c, 5a and 8b-d) exhibited significant cytotoxicity against most cell lines. Among these derivatives compound 4c exhibited equivalent cytotoxic effect to the standard CHS 828 against gastric cancer cell line (IC50 = 25 nM). Normal fibroblast cells (WI38) were affected to a much lesser extent (IC50 > 10,000 nM).

Synthesis and biological evaluation of thiophene derivatives as acetylcholinesterase inhibitors.

A series of new thiophene derivatives has been synthesized using the Gewald protocol. The acetylcholinesterase inhibition activity was assayed according to Ellman's method using donepezil as reference. Some of the compounds were found to be more potent inhibitors than the reference. 2-(2-(4-(4-Methoxyphenyl)piperazin-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (IIId) showed 60% inhibition, compared to only 40% inhibition by donepezil.

Synthesis of new indole derivatives structurally related to donepezil and their biological evaluation as acetylcholinesterase inhibitors.

New series of indole derivatives analogous to donepezil, a well known anti-Alzheimer and acetylcholinesterase inhibitor drug, was synthesized. A full chemical characterization of the new compounds is provided. Biological evaluation of the new compounds as acetylcholinesterase inhibitors was performed. Most of the compounds were found to have potent acetylcholinesterase inhibitor activity compared to donepezil as standard. The compound 1-(2-(4-(2-fluorobenzyl) piperazin-1-yl)acetyl)indoline-2,3-dione (IIId) was found to be the most potent.

Synthesis and antitumor activity of novel 6-aryl and 6-alkylpyrazolo[3,4-d]pyrimidin-4-one derivatives.

A series of new 6-arylpyrazolo[3,4-d]pyrimidin-4-ones and 6-alkylpyrazolo[3,4-d]pyrimidin-4-ones were synthesized. Some of the newly synthesized compounds were tested in vitro on human colon tumor cell line (HCT116). Most of the test compounds exploited potent antitumor activity, especially compound 10a which displayed the highest activity among the test compounds with IC(50) equal to 0.47 µg/mL.

Novel thiophenes, thienopyrimidines, and triazolothienopyrimidines for the evaluation of anticancer and augmentation effects of gamma-radiation.

New derivatives of thiophenes 2, 12, iminoaminothieno[2,3-d]pyrimidines 3, 5, and 6, triazolothieno[2,3-d]pyrimidines 8-11, pyrazolo- and triazinothieno[2,3-d]pyrimidines 4, 7, respectively, have been prepared by different synthetic procedures. Structure elucidation of the newly synthesized compounds was carried out via elemental analyses and spectral data. The antitumor activity of compounds 2, 3, and 9-12 was evaluated against in-vitro cell lines (HEPG-2 and MCF-7). Compounds 2, 3, 10, 11, and 12 showed significant in-vitro cytotoxic activity against hepatocellular carcinoma (HEPG-2) compared to the reference drug Doxorubicin. Compound 2 showed significant in-vitro cytotoxic activity against breast cancer (MCF-7) cells compared to the reference drug Doxorubicin. The augmenting effect of gamma-radiation was assessed; here, compounds 2, 3, 10, and 11 showed the most potent in-vitro anticancer activity.