Thienopyrimidine Derivatives Research Articles

QSAR Studies on Thienopyrimidines as Potential Antimicrobial Agents

Background: Recent research has revealed promising antibacterial action for thienopyrimidines. To comprehend the underlying molecular features underlying their antibacterial potency, a thorough quantitative structure-activity relationship (QSAR) investigation is required. Objective: In order to clarify the structural parameters for effective antibacterial activity, we conducted QSAR analyses on a variety of thienopyrimidines in this work. Methods: Through the analysis of physicochemical properties and molecular descriptors, we aimed to develop predictive models that can guide the design of novel thienopyrimidine derivatives with enhanced antimicrobial potential. Results: It was discovered through the descriptor importance analysis that specific physicochemical characteristics, including lipophilicity, electronic distribution, and steric effects, significantly influenced the antibacterial efficacy of these drugs. Conclusion: The identified molecular characteristics and descriptors can be used to guide the development of new thienopyrimidine derivatives with higher antibacterial activity.

Synthesis and in vitro antitumor evaluation of new thieno[2,3-d]pyrimidine derivatives as EGFR and DHFR inhibitors

New thienopyrimidine derivatives 2–16 have been synthesized and their in vitro cytotoxicity was evaluated against five different human cancer cell lines HCT-116, Hela, MDA-MB-231, MCF7 and PC3. Compounds 6e, 7a, 7b, 7d, 10c and 10e displayed the highest antitumor activity against all tested cell lines compared to Doxorubicin. Enzyme inhibition assay revealed that compounds 6e and 10e showed high inhibitory activity against EGFR-TK, with IC50 values of 0.133 and 0.151 µM, compared to Olmutinib (IC50 = 0.028 µM); while the highest DHFR inhibitory activity was shown by compounds 7d and 10e with IC50 values of 0.462 and 0.541 µM, compared to Methotrexate (IC50 = 0.117 µM). Cell cycle analysis following a flow cytometric study using colorectal HCT-116 cancer cell line proved that compound 6e induced cell cycle arrest in G0-G1 phase, while compound 10e arrested the cell cycle at both G0-G1 and S phases. Additionally, both compounds (6e and 10e) were potently able to induce apoptosis in HCT-116 cell line. Docking results of compounds 6e and 10e into the pocket of EGFR active site showed their similar main binding features with Olmutinib, while compounds 7d and 10e showed only moderate fitting into DHFR compared to methotrexate. In silico studies revealed that most of the tested compounds obeyed Lipinski’s RO5 and showed positive drug likeness scores.

Auxin-like and Cytokinin-like Effects of New Synthetic Thienopyrimidine Derivatives on the Growth and Photosynthesis of Wheat

The regulatory effect of new synthetic thienopyrimidine derivatives on the growth and photosynthesis of wheat (Triticum aestivum L.) variety Svitlana in the vegetative phase was studied. The regulatory effect of new synthetic thienopyrimidine derivatives was compared with the regulatory effect of auxin IAA (1H-indol-3-yl)acetic acid) or synthetic plant growth regulators Methyur (sodium salt of 6-methyl-2-mercapto-4-hydroxypyrimidine) and Kamethur (potassium salt of 6-methyl-2-mercapto-4-hydroxypyrimidine). After 2 weeks, morphometric parameters (such as average length of shoots and roots (mm), average biomass of 10 plants (g)) and biochemical parameters (such as content of photosynthetic pigments (µg/ml)) of wheat plants grown from seeds treated with synthetic thienopyrimidine derivatives, or auxin IAA, or synthetic plant growth regulators Methyur and Kamethur at a concentration of 10-6M, were measured and compared with similar parameters of control wheat plants grown from seeds treated with distilled water. The regulatory effect of new synthetic thienopyrimidine derivatives on the morphometric and biochemical parameters of wheat plants was similar or higher compared to the regulatory effect of auxin IAA, or synthetic plant growth regulators Methyur and Kamethur. The relationship between the chemical structure of new synthetic thienopyrimidine derivatives and their regulatory effect on the growth and photosynthesis of wheat plants was revealed. The most biologically active thienopyrimidine derivatives are proposed to be used as new synthetic physiological analogues of auxins and cytokinins to improve growth and increase photosynthesis of wheat (Triticum aestivum L.) variety Svitlana in the vegetative phase.

Kaliendina S., Brynzei M., Kut M., Sukharev S.M., Ostapchuk Е., Onysko M. REGIOSELECTIVITY OF ALKYLATION OF 2-(THIOPHENE-2-IL)THIENO[2,3 d]PYRIMIDINE-4(3H)-ONE

Thieno[2,3-d]pyrimidines are an important class of heterocyclic compounds with a wide range of biological activities. The thieno[2,3-d]pyrimidin-4-one system is of the greatest interest to scientists, as it is one of a large number of possible thienopyrimidine derivatives. The presence of an amide fragment in these molecules allows for the introduction of various substituents via alkylation reactions. On the other hand, the presence of N- and O-nucleophilic centres makes it possible to form different types of alkylation products.
 In the present work, the alkylation reaction of 5,6-dimethyl-2-(thiophen-2-yl)thieno[2,3-d]pyrimidin-4(3H)-one, which contains N(3)- and O-nucleophilic centres for attacking alkylating reagents, was investigated. Allyl bromide was used as an alkylating reagent. It was found that the alkylation of 5,6-dimethyl-2-(thiophen-2-yl)thieno[2,3-d]pyrimidin-4(3H)-one with allyl bromide in DMF resulted in the regioselective preparation of 4-(allyloxy)-5,6-dimethyl-2-(thiophen-2-yl)thieno[2,3-d]pyrimidine, which can be used in the future to study the process of electrophilic intramolecular cyclisation. An increase in the reaction time of the starting reagents leads to an increase in the yield of the target ester.
 Keywords: 5,6-dimethyl-2-(thiophen-2-yl)thieno[2,3-d]pyrimidin-4(3H)-one; alkylation; regioselectivity; ether; 4-allyloxypyrimidine.

Identification of thienopyrimidine derivatives tethered with sulfonamide and other moieties as carbonic anhydrase inhibitors: Design, synthesis and anti-proliferative activity

Eighteen novel compounds harboring the privileged thienopyrimidine scaffold (5a-q, and 6a),were designed based on molecular hybridization strategy. These compounds were synthesized and tested for their inhibitory activity against four different carbonic anhydrase isoforms: CA I, II, IX, and XII. Microwave and conventional techniques were applied for their synthesis. Compounds 5b, 5g, 5l, and 5p showed the highest inhibition activity against the four CA isoforms. Compound 5p exhibited promising inhibitory activity against CA II, CA IX and CA XII with KI values of8.6, 13.8, and 19 nM, respectively, relative to AAZ, where KIs = 12, 25, and 5.7 nM, respectively. Also, compound 5 l showed significant activity against the tumor-associated isoform CA IX with KI = 16.1 nM. All the newly synthesized compounds were also screened for their anticancer activity against NCI 60 cancer cell lines at a 10 µM concentration. Compound 5n showed 80.38, 83.95, and 87.39 % growth inhibition against the leukemic cell lines CCRF-CEM, HL-60 (TB), and RPMI-8226, respectively. Also, 5 h showed 87.57 % growth inhibition against breast cancer cell line MDA-MB-468; and 66.58 and 60.95 % inhibitionagainst renal cancer cell lines UO-31, and ACHN, respectively. A molecular docking studywas carried out to predict binding modes of our synthesized compounds in the binding pockets of the four carbonic anhydrase isoforms, and results revealed that compounds 5b, 5g, 5l, and 5p succeeded in mimicking the binding mode of AAZ through metal coordination with Zn+2 ion and binding to the amino acids Thr199, His94, and His96 that are critical for activity.

Fragment merging approach for design, synthesis, and biological assessment of urea/acetyl hydrazide clubbed thienopyrimidine derivatives as GSK-3β inhibitors

New thienopyrimidine derivatives were designed and synthesized as GSK-3β inhibitors based on the structure of active binding site of GSK-3β enzyme. In this study, compounds 6b and 6a were found to be moderate GSK-3β inhibitors with IC50s 10.2 and 17.3 μM, respectively. Molecular docking study was carried out by docking the targeted compounds in the binding site of the GSK-3β enzyme using the MOE program. Moreover, ADME study was performed to predict certain pharmacokinetic properties. The results showed that all synthesized compounds may not be able to penetrate the blood brain barrier; so, the chances of CNS side effects are predicted to be low. CYP1D6 is predicted to be inhibited by compounds (5a, 5d, 6a, 9a and 9b), So drug-drug interactions are expected upon administration of these compounds.Graphical

Design, synthesis, biological evaluation, and bio-computational modeling of imidazo, thieno, pyrimidopyrimidine, pyrimidodiazepene, and motifs as antimicrobial agents

Abstract In the drug chemistry industry, synthesizing a talented exclusive series of aza-polyheterocyclic compounds was crucial. Aminopyrimidine nucleus reacted with two equivalents of benzaldehyde in the presence of KOH as a starting material to bring about imidazopyrimidine derivative, which experienced intermolecular cyclization using carbon disulfide, Br2/AcOH, and/or HNO2 to produce thiazole, thieno, and/or nitro pyrimidine derivative, respectively. Accordingly, the nucleus of Aminopyrimidine was prepared and used to develop the novel polyheterocyclic systems acylated with two moles of succinic anhydride to furnish the imidazolopyrimidine derivative. Benzylidene ethyl cyanoacetate and aminopyrimidine undergo (3 + 4) intermolecular cycloaddition 1,3 H shift followed by hydrolysis and after CO2 evolution provided diazepine derivative. The diazepine derivative was attained due to the cyclo-condensation of the starting material and acetylacetone. Moreover, the structure of the novel synthesized compound series was exploited and verified via spectroscopic approaches. The synthesized series were tested for antimicrobial activity against gram-positive and gram-negative bacterial strains and antifungal activity. The thienopyrimidine derivatives and diazepine exhibited unusual antimicrobial activity. Furthermore, the molecular docking studies confirmed the biological studies with Molecular Operating Environment and petro orisis molinspiration studies, which proved the activity of compounds 4, 5, 7, 10, 13, and 16.

Novel 4-(2-arylidenehydrazineyl)thienopyrimidine derivatives as anticancer EGFR inhibitors: Design, synthesis, biological evaluation, kinome selectivity and in silico insights

The current study discovered fifteen new thieno[2,3-d]pyrimidine derivatives with potential anticancer action, including 5a-l, 6, and 7a-b. Results from the NCI screening revealed that compounds 5f-i and 7a significantly inhibited the proliferation of MDA-MB-468 cells at mean GI% and GI50 levels. Compared to staurosporine, these compounds (5f-i and 7a) demonstrated better safety towards typical WI-38 cells. Compounds 5g and 7a demonstrated the highest inhibition (two-digit nanomolar) when compared to erlotinib when their potency was tested on EGFR kinase. Considering the outcomes above, 5g was examined for its ability to disrupt the cell cycle with trigger apoptosis in breast cancer MDA-MB-468 cell lines. The apoptosis markers Bax, Bcl-2, Caspase-8, and Caspase-9, were detected. In silico molecular docking and dynamic simulation were used to explainthe biological activities of the most potent compound.

Synthesis of Thieno[3,2-d]pyrimidine Derivatives through Sequential SN Ar and Suzuki Reactions as Selective h-NTPDase Inhibitors.

In this study various of thieno[3,2-d]pyrimidine derivatives have been synthesized by treating different secondary amines through aromatic nucleophilic substitution reaction (SN Ar) followed by Suzuki reaction with aryl and heteroaryl boronic acids. A bis-Suzuki coupling was also performed to generate bis-aryl thienopyrimidine derivatives. The synthesized compounds were screened for the hydrolytic activity of h-NTPdase1, h-NTPdase2, h-NTPdase3, and h-NTPdase8. The compound N-benzyl-N-methyl-7-phenylthieno[3,2-d]pyrimidin-4-amine 3 j selectively inhibits the activity of h-NTPdase1 with IC50 value of 0.62±0.02 μM whereas, the compound 4 d was the most potent inhibitor of h-NTPdase2 with sub-micromolar IC50 value of 0.33±0.09 μM. Similarly, compounds 4 c and 3 b were found to be selective inhibitors for isozymes h-NTPdase3 (IC50 =0.13±0.06 μM) and h-NTPdase8 (IC50 =0.32±0.10 μM), respectively. The molecular docking study of the compounds with the highest potency and selectivity revealed the interactions with the important amino acid residues.

REGIOSELECTIVITY OF THE TELLURIUM-INDUCED CYCLISATION OF TERMINALLY SUBSTITUTED ALLYL, BUTENYL AND PROPARGYL THIOETHERS OF THIENOPYRIMIDINE

The method of electrophilic intramolecular cyclization is widely used for the synthesis of condensed thienopyrimidine derivatives. In this work, the regioselectivity of the process of electrophilic intramolecular cyclization of terminally substituted allylic derivatives, but-1-enyl and propargyl thioethers of thienopyrimidine with p-methoxyphenyltellurttrichloride was investigated.
 It was established that as a result of the tellurium-induced cyclization of butenyl thioethers of 5,6-dimethyl-3-phenylthieno[2,3-d]pyrimidin-4(3H)-one with p-methoxyphenyltellurium trichloride, angular tricyclic chlorides ― 8-(dichloro(4-methoxyphenyl)-tellanyl)-2,3,9-trimethyl-4-oxo-5-phenyl-5,7,8,9-tetrahydro-4H-thieno[3',2':5,6]pyrimido[2,1-b][1,3]thiazine-10-ium and 9-((dichloro(4-methoxyphenyl)-tellanyl)methyl)-2,3-dimethyl-4-oxo-5-phenyl-5,7,8,9-tetrahydro-4H-thieno­[3',2':5,6]pyrimido[2,1-b][1,3]thiazine-10-ium with an annealed six-membered ring in the form of complexes with p-methoxyphenyltellurium trichloride. It was proved that the electrophilic intramolecular cyclization of 5,6-dimethyl-2-(prop-2-yn-1-ylthio)-3-phenylthieno[2,3-d]pyrimidin-4(3H)-one with aryltellurium trichloride occurs with the formation of an aryltellurium trichloride complex with angular chloride 8-((dichloro(4-methoxyphenyl)-tallanyl)methylidene)-2,3-dimethyl-4-oxo-5-phenyl-4,5,7,8-tetrahydrothiazolo[3,2-a]thieno [3,2-e]pyrimidin-9-ium in the form of one geometric isomer.
 Keywords: electrophilic heterocyclization; p-methoxyphenyltellurium trichloride; organotellurium compounds; chloride 4H-thieno[3',2':5,6]pyrimido[2,1-b][1,3]thiazine-10-ium; chloride 4H-thieno[3',2':5,6]pyrimido[2,1-b][1,3]thiazine-10-ium; chloride thiazolo[3,2-a]thieno[3,2-e]pyrimidin-9-ium.

Design, synthesis and antitumor activity of coumarin, isoxazole, pyrazole, pyridine and pyrimidine compounds: 3β-hydroxypregn-5-ene-20-one derivatives

In continuation of our reserach for synthesizing heterocyclic derivatives with a broad range of biological activities, the current research was performed to synthesize 3β-hydroxypregn-5-ene-20-one derivatives of coumarin, isoxazole, pyrazole, pyridine and pyrimidine and screen for antitumor activity. Synthesis of amino-thiopephen derivatives (1a-1b) was performed through reaction of 3β-hydroxypregn-5-ene-20-one with ethyl cyanoacetate or malononitrile and sulphur. 3β-Hydroxypregn-5-ene-20-one was reacted with ethyl cyanoacetate in the presence of hydrazine, urea or thiourea to obtain aminopyrazole (3), aminopyrimidine (4a-4b) derivatives, respectively. The amino-thiophene derivatives (1a-1b) further reacted with either phenylisothiocyanate or benzoylisothiocyanate to form fused thienopyrimidine derivatives (5a-5d). The products 1a and 1b were also treated with ethyl cyanoacetate to afford cyanoacetamidothiophene derivatives (6a-6b) which were converted to fused thienopyridone derivatives (7a-7b) through cyclization reaction. The compounds 6a and 6b were allowed to react with different carbonyl compounds including salicyaldehyde, cyclopentanone-sulphur mixture, acetylacetone and malonaldehyde to prepare coumarin (8a-8b), cyclopentylthiophene (9a-9b) and 2-pyridinone (10a-10d) derivatives respectively. Furthermore, the reactions of hydroxylamine hydrochloride and benzoylacetonitrile with the compounds 6a-6b separately afforded new aminoisoxazole (12a-12b) and phenylpyridone (14a-14b) derivatives, respectively. The structures of new products were established through IR, 1H NMR, 13C NMR spectroscopic and mass spectrometric analysis. The synthesized compounds (1a-1b to 14a-14b) displayed in-vitro antitumor activity against human cell-lines, including MCF-7 (breast adenocarcinoma), SF-268 (CNS cancer) and NCI-H460 (non-small lung cancer cell). The results suggested that all the screened products exhibited cell growth inhibitory activity in a dose-dependents manner. However, the compound 12a showed highest level of inhibition against all three cell-lines.

Synthesis, crystal and molecular structure, vibrational properties, DFT and Hirshfeld surface analyses of ethyl 1-isobutyl-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate

Thienopyrimidine derivatives exhibit extensive pharmacological properties in medicinal chemistry. In this study, ethyl 1-isobutyl-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carboxylate with a thienopyrimidine core is synthesized using a four-step reaction design. And subsequently characterized by 1H NMR, 13C NMR, FT-IR, and mass spectroscopy. Further, X-ray diffraction (XRD) is used to detect the single-crystal structure of the target compound, whereas the density functional theory is used to optimize its molecular structure. Evidently the calculated values and those obtained from the XRD are fully consistent. To further understand the physicochemical properties of the compound, its molecular electrostatic potential and leading edge molecular orbitals are determined. Finally, a reliable vibration assignment of the compound is performed according to the characteristic vibrational absorption band, and the atom-pair contacts of the crystal are explained by Hirschfeld surface analysis.

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 Aβ 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 Aβ 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 densityfunctional 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 Aβ aggregation inhibitory action than donepezil. Additionally, compound 6b exerted significant antioxidant activity.

Synthesis and Cytotoxicity Assay of Aniline Substituted Thienopyrimidines for Anti-Colorectal Cancer Activity

Colorectal cancer ranks third among all cancers worldwide. Colorectal cancer is treated using a variety of therapies and methods. Almost 1 million deaths are caused every year. The treatment is very ineffective against the cancer cells. Today, drug resistance is a major problem in the fight against cancer. In order to address this, new drugs must be developed. The focus of the article is the synthesis of small molecules of aniline-substituted thieno(2,3-d) pyrimidine derivatives and the evaluation of their anticancer activities. Based on the bioisosterism theory and results from earlier research, thienopyrimidine is substituted with aniline derivatives. Using the HCT116 cell line, the synthesized compounds were tested for cytotoxicity. When compared to standard 5-Fluorouracil (IC50 = 435.59 μg/ml), the compound MS4e has a lower IC50 value (357.12 μg/ml). When aniline was substituted with halogen (F, Cl) cytotoxic properties are observed. It seems to hold special potential for the treatment of colorectal cancer, as the compound MS4e has less IC50 value than the standard.

Thienopyrimidine Derivatives as GPR55 Receptor Antagonists: Insight into Structure-Activity Relationship.

GPR55 is an orphan G-protein coupled receptor involved in various pathophysiological conditions. However, there are only a few noncannabinoid GPR55 ligands reported so far. The lack of potent and selective GPR55 ligands precludes a deep exploration of this receptor. The studies presented here focused on a thienopyrimidine scaffold based on the GPR55 antagonist ML192, previously discovered by high-throughput screening. The GPR55 activities of the new synthesized compounds were assessed using β-arrestin recruitment assays in Chinese hamster ovary cells overexpressing human GPR55. Some derivatives were identified as GPR55 antagonists with functional efficacy and selectivity versus CB1 and CB2 cannabinoid receptors.

Thienopyrimidine-based agents bearing diphenylurea: Design, synthesis, and evaluation of antiproliferative and antiangiogenic activity.

An important role has been considered forthe vascular endothelial growth factor receptor 2 (VEGFR-2) in the angiogenesis process, so that its inhibition is an important scientific way for cancer treatment. In this work, new thienopyrimidine derivatives were synthesized and evaluated. Compared with sorafenib, the majority of the target compounds had antiproliferative activity against the PC3, HepG2, MCF7, SW480, and HUVEC cell lines, especially 9h with IC50 values of 4.5-15.1 μM, confirming the noticeable cytotoxic effects on the listed cell lines (PC3, HepG2, SW480, and HUVEC). Analyses by flow cytometry on SW480 and HUVEC cells revealed that 9n, 9k, 9h, and 9q led to apoptotic cell death. The result of the chick chorioallantoic membrane assay showed that 9h effectively reduced the number of corresponding blood vessels. Finally, the inhibitory effect on VEGFR-2 phosphorylation was considered as the outcome of Western blot analysis of compound 9h.

Structure-Activity Relationship Studies Based on 3D-QSAR CoMFA/CoMSIA for Thieno-Pyrimidine Derivatives as Triple Negative Breast Cancer Inhibitors.

Triple-negative breast cancer (TNBC) is defined as a kind of breast cancer that lacks estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptors (HER2). This cancer accounts for 10-15% of all breast cancers and has the features of high invasiveness and metastatic potential. The treatment regimens are still lacking and need to develop novel inhibitors for therapeutic strategies. Three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses, based on a series of forty-seven thieno-pyrimidine derivatives, were performed to identify the key structural features for the inhibitory biological activities. The established comparative molecular field analysis (CoMFA) presented a leave-one-out cross-validated correlation coefficient q2 of 0.818 and a determination coefficient r2 of 0.917. In comparative molecular similarity indices analysis (CoMSIA), a q2 of 0.801 and an r2 of 0.897 were exhibited. The predictive capability of these models was confirmed by using external validation and was further validated by the progressive scrambling stability test. From these results of validation, the models were determined to be statistically reliable and robust. This study could provide valuable information for further optimization and design of novel inhibitors against metastatic breast cancer.

Nonacidic thiophene-based derivatives as potential analgesic and design, synthesis, biological evaluation, and metabolic stability study.

Nonsteroidal anti-inflammatory drugs represent one of the most popularly used classes of drugs. However, their long-term administration is associated with various side effects including gastrointestinal ulceration. One of the major reasons of NSAIDs ulcerogenicity is direct damage of the epithelial lining cells by the acidic moieties present in many drugs. Another drawback for this acidic group is its rapid metabolism and clearance through Phase II conjugation. Three series of thiophene and thienopyrimidine derivatives were designed and synthesized as nonacidic anti-inflammatory agents. In vivo testing of their analgesic activity indicated that compounds 2b and 7a-d showed higher PI values than that of the positive control drugs, indomethacin and celecoxib. The latter compounds 2b and 7a-d were subjected to further anti-inflammatory activity testing where they showed comparable percentage edema inhibition to that of indomethacin and celecoxib. Compounds 2b, 7a, 7c, and 7d inhibited PGE2 synthesis by 61.10%-74.54% (71.47% for indomethacin, and 80.11% for celecoxib). The same compounds inhibited the expression of rat mPGES-1 and cPGES3 by 74%-83% (77% for indomethacin, and 82% for celecoxib) and 48%-70% (62% for indomethacin, and 70% for celecoxib), respectively. The stability of the most active compound 2b in Nonenzymatic gastrointestinal fluids and in human plasma was tested. Additionally, studying the metabolic stability of compound 2b in S9 rat liver fraction showed that it displayed a slow in vitro clearance with half-life time 1.5-fold longer than indomethacin. The metabolites of 2b were predicted via UPLC-MS/MS. In silico ADMET profiling study was also included.

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 Aβ 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 Aβ 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.

Design and Optimization of Thienopyrimidine Derivatives as Potent and Selective PI3Kδ Inhibitors for the Treatment of B-Cell Malignancies.

Phosphoinositide 3-kinase δ (PI3Kδ) plays a critical role in B lymphocyte (B-cell) development and activation and has been a validated target for the treatment of B-cell malignancies. Herein, we report a series of thienopyrimidine derivatives as novel potent and selective PI3Kδ inhibitors based on a scaffold hopping design strategy. Among them, compound 6 exhibited nanomolar PI3Kδ potency and a favorable selectivity profile compared to other class I PI3K isoforms. In cellular assays, compound 6 showed antiproliferative activity against a panel of B-cell lymphoma cell lines in a low micromolar range, caused cell cycle arrest, and induced apoptosis in Pfeiffer and SU-DHL-6 cells. Further, compound 6 inhibited the activation of mouse B-cells. With support from in vivo pharmacokinetic studies, compound 6 demonstrated significant anticancer efficacy in a Pfeiffer xenograft mouse model. Overall, compound 6 is a promising PI3Kδ inhibitor worthy of further preclinical investigation for the treatment of B-cell malignancies.