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A group of EGFR inhibitors derived from thieno[2,3-d]pyrimidine nucleus was designed, synthesised, and examined as anti-proliferative lead compounds. MCF-7 and A549 cell lines were inhibited by 5b, the most active member. It had inhibitory partialities of 37.19 and 204.10 nM against EGFRWT and EGFRT790M, respectively. Compound 5b was 2.5 times safer against the WI-38 normal cell lines than erlotinib. Also, it demonstrated considerable potentialities for both early and late apoptosis induction in A549. Simultaneously, 5b arrested A549's growth at G1 and G2/M phases. Harmoniously, 5b upregulated the BAX and downregulated the Bcl-2 genes by 3-fold and increased the BAX/Bcl-2 ratio by 8.3-fold comparing the untreated A549 cells. Molecular docking against EGFRWT and EGFRT790M indicated the correct binding modes. Furthermore, MD simulations confirmed the precise binding of 5b against the EGFR protein over 100 ns. Finally, various computational ADMET studies were carried out and indicated high degrees of drug-likeness and safety. [ABSTRACT FROM AUTHOR]

A group of EGFR inhibitors derived from thieno[2,3-d]pyrimidine nucleus was designed, synthesised, and examined as anti-proliferative lead compounds. MCF-7 and A549 cell lines were inhibited by 5b, the most active member. It had inhibitory partialities of 37.19 and 204.10 nM against EGFRWT and EGFRT790M, respectively. Compound 5b was 2.5 times safer against the WI-38 normal cell lines than erlotinib. Also, it demonstrated considerable potentialities for both early and late apoptosis induction in A549. Simultaneously, 5b arrested A549’s growth at G1 and G2/M phases. Harmoniously, 5b upregulated the BAX and downregulated the Bcl-2 genes by 3-fold and increased the BAX/Bcl-2 ratio by 8.3-fold comparing the untreated A549 cells. Molecular docking against EGFRWT and EGFRT790M indicated the correct binding modes. Furthermore, MD simulations confirmed the precise binding of 5b against the EGFR protein over 100 ns. Finally, various computational ADMET studies were carried out and indicated high degrees of drug-likeness and safety.

The present work deals with synthesis and biological evaluation of novel compounds as potential inhibitors of dihydrofolate reductase (DHFR) from opportunistic microorganisms – Pneumocystis carinii (pc), Toxoplasma gondii (tg) and Mycobacterium avium (ma). A set of 6 lipophilic and 1 classical antifolates of thieno[2,3-d]pyrimidine series were designed and synthesised with key pharmacophoric features of DHFR inhibitors and aminomethylene bridge joining the aromatic part and 2-amino-4-oxothieno[2,3-d]pyrimidine nucleus. Investigation of the DHFR inhibitory activity of the synthesised compounds revealed that 2-amino-6-[(4-methoxyphenylamino)-, 6--[(4-chlorophenylamino)- and 6-[(2,5-dichlorophenylamino)methyl]thieno[2,3-d]pyrimidin-4(3H)- ones had a moderate activity (IC50 56.5, 49.9 and 23 μM, respectively) against pcDHFR. Activity of those compounds against tgDHFR (IC50 6.0, 2.8 and 2.3 μM, respectively) was comparable to that of trimethoprim (IC50 2.7 μM). No synthesised lipophilic antifolates showed activity towards maDHFR. The classical antifolate 2-{4-[(2-amino-4-oxo-3,4- dihydrothieno[2,3-d]pyrimidin-6-yl)methylamino]benzamido}-L-glutamic acid inhibited DHFRs from all microorganisms (IC50 6.6 μM for pcDHFR, 1.06 μM for tgDHFR and 16.9 μM for maDHFR). [ABSTRACT FROM AUTHOR]

Background. In the production of hybrid medicines, the principle of hybrid blocks of molecules is used. Of interest are the processes of combining fragments with biological activity - thienopyrimidine and benzotriazole, synthesis and study of their structure. Purpose Reaction of nucleophilic substitution of 5,6-disubstituted 4-chlorothieno[2,3-d]pyrimidine with 1H-1,2,3-benzotriazole in the presence of tertiary amines and synthesis of new types of hybrid molecules. Methodology. Derivatives of the target product were studied by IR, 1H, 13C NMR spectroscopy and mass spectrometry. Originality. Synthesis of substituted-4-chlorothieno[2,3-d]pyrimidine derivatives under various conditions was carried out, a new type of thienopyrimidine-benzotriazole hybrid molecules was synthesized, and their physicochemical properties were determined. Findings. Hybrid molecules with alternating fragments of different activity, and substances in the molecules of which there was a C (sp2) - N bond were obtained. The structure was studied. [ABSTRACT FROM AUTHOR]

Aim: Design and synthesis of thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors.Material and methods: A series of novel 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidine derivatives with different substituents on C-4 position was synthesized and evaluated for their anticancer activity against MCF-7 cell line. EGFR, VEGFR-2 inhibitory assay, the cell cycle analysis and apoptosis induction ability of the most potent compound 5f were evaluated.Results: Most of the compounds showed moderate to significant anticancer activity. Compound 5f exhibited the most potent anticancer activity being 1.73- and 4.64-folds more potent than erlotinib and doxorubicin, respectively. Compound 5f showed potent EGFR inhibitory activity being 1.18-folds more potent than reference standard erlotinib and it also showed good VEGFR-2 inhibitory activity at the micromolar level with IC50 value 1.23 µM. Compound 5f caused induction of cell cycle arrest at G2/M phase and accumulation of cells in pre-G1 phase. Compound 5f induced cellular apoptosis.

The review discusses the use of the Dimroth rearrangement in the synthesis of condensed pyrimidines which are key structural fragments of antiviral agents. The main attention is given to publications over the past 10 years. The bibliography includes 107 references. [ABSTRACT FROM AUTHOR]

This work describes the synthesis and anticancer activity against kinase enzymes of newly designed thiophene and thieno[2,3-d]pyrimidine derivatives, along with their potential to activate autophagic and apoptotic cell death in cancer cells. The designed compounds were scanned for their affinity for kinases. The results were promising with affinity ranges from 46.7% to 13.3%. Molecular docking studies were performed, and the compounds were then screened for their antiproliferative effects. Interestingly, compounds 8 and 5 resulted in higher cytotoxic effects than the reference standard against MCF-7 and HepG-2. The compounds were evaluated for their induction of apoptosis and/or necrosis on HT-29 and HepG-2. Three compounds induced significant early apoptosis compared to untreated control HT-29 cells, and four derivatives were more significant compared to untreated HepG-2 cells. We further investigated the effect of four compounds on the autophagy process within HT-29, HepG-2, and MCF-7 cells with flow cytometry. Similar to the apoptosis results, compound 5 showed the highest autophagic induction among all compounds. The potential inhibitory activity of the synthesized compounds on kinases was assessed. Screened compounds showed inhibition activity ranging from 41.4% to 83.5%. Compounds recorded significant inhibition were further investigated for their specific FLT3 kinase inhibitory activity. Noticeably, Compound 5 exhibited the highest inhibitory activity against FLT3.

Aim. To find novel anticancer lead molecules among easily available spiro-fused thieno[2,3-d] pyrimidines. Methods. Organic synthesis, spectral methods and molecular docking. Results. New spiro heterocycles were synthesized by condensation of 2-aminothiophene-3-carbonitriles with cyclic ketones via Gevald reaction. Other model spirocyclic compounds were prepared by the reaction of 3-aminothieno[2,3-b]pyridine-2-carboxamides with cyclohexanone under acidic conditions. According to the docking studies against the EGFRWT the synthesized compounds revealed good binding energies ranging from -8.4 to -10.2 kcal/mol. The compounds were tested as inhibitors of protein kinase CK; 7',8',9',10'-tetrahydro-1'H-spiro[cyclohexane- 1,2'-pyrimido[4',5':4,5]thieno[2,3-b]quinolin]-4'(3'H)-one showed the best binding energy while be bound by a hydrogen bond to Val66 amino acid residue. This compound also showed good results as a potential inhibitor of B-Raf kinase. Conclusion. New spiro-fused thieno[2,3- d]pyrimidines have been synthesized. The inhibition activity of novel compounds as potential inhibitors of the EGFR, CK2, FGFR1 and B-raf kinases was examined. We found that spirofused thieno[2,3-d]pyrimidines undergo the rearrangement under Vilsmeier-Haack conditions to afford hitherto undescribed thienopyrimidines and -quinolines. The docking studies revealed that the rearranged products do not tend to form hydrogen bonds with the kinase amino acid residues and show moderate binding energies. Therefore, in contrast to the spiro-fused thieno[2,3-d]pyrimidines, the rearranged products cannot be considered as perspective targets for further screening. [ABSTRACT FROM AUTHOR]

Some novel thienopyrimidine derivatives were synthesized via the reaction of 5- methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-5-carbohydrazide with different carbonyl compounds such as anhydrides, acid chlorides, carbon disulfide, phenyl isothiocyanate, triethyl orthoformate, diethyl acetylene dicarboxylate, acetylacetone, pyrazole-4-carboxaldehyde, and isatin. Also, the reaction of this carbohydrazide derivative with sodium nitrite in the presence of hydrochloric acid to give the corresponding azide derivative was discussed. The latter azide derivative was reacted with different amines to give the corresponding diheteryl urea derivatives. The antitumor activity evaluation of some representative examples of the synthesized compounds was examined against HePG2 and MCF-7 cell lines. Some of the newly synthesized compounds showed significant activity. [ABSTRACT FROM AUTHOR]

Aim: Design and synthesis of thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors.Material and methods: A series of novel 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidine derivatives with different substituents on C-4 position was synthesized and evaluated for their anticancer activity against MCF-7 cell line. EGFR, VEGFR-2 inhibitory assay, the cell cycle analysis and apoptosis induction ability of the most potent compound 5f were evaluated.Results: Most of the compounds showed moderate to significant anticancer activity. Compound 5f exhibited the most potent anticancer activity being 1.73- and 4.64-folds more potent than erlotinib and doxorubicin, respectively. Compound 5f showed potent EGFR inhibitory activity being 1.18-folds more potent than reference standard erlotinib and it also showed good VEGFR-2 inhibitory activity at the micromolar level with IC50 value 1.23 µM. Compound 5f caused induction of cell cycle arrest at G2/M phase and accumulation of cells in pre-G1 phase. Compound 5f induced cellular apoptosis. [ABSTRACT FROM AUTHOR]

Abstract We recently described a structurally novel series of negative allosteric modulators (NAMs) of the dopamine D 2 receptor (D 2 R) based on thieno[2,3- d ]pyrimidine 1 , showing it can be structurally simplified to reveal low molecular weight, fragment-like NAMs that retain robust negative cooperativity, such as 3. Herein, we report the synthesis and functional profiling of analogues of 3 , placing specific emphasis on examining secondary and tertiary amino substituents at the 4-position, combined with a range of substituents at the 5/6-positions (e.g. aromatic/aliphatic carbocycles). We identify analogues with diverse pharmacology at the D 2 R including NAMs with sub- μ M affinity (9h) and, surprisingly, low efficacy partial agonists (9d and 9i). Graphical abstract Image 1 Highlights • Structural changes furnished allosteric fragment-like cores with improved ligand efficiency. • Substituents at the thieno[2,3- d ]pyrimidine core are crucial for binding and function at the D 2 R. • Subtle variations cause a change in pharmacology from that of a D 2 R NAM to that of a weak D 2 R agonist. [ABSTRACT FROM AUTHOR]

Motivated by the widely reported anticancer activity of thieno[2,3-d]pyrimidines a series of 24 new 2-substitutedhexahydrocycloocta[4,5] thieno[2,3-d]pyrimidines with different substituents at C-4 position and hexahydrocycloocta[4,5]thieno[3,2-e]-1,2,4-triazolo[4,3-c]pyrimidines were synthesized. The anticancer activity of 17 compounds were evaluated by National Cancer Institute (USA) using a two stage process utilizing 59 different human tumor cell lines representing leukemia, melanoma, cancers of lung, colon, central nervous system (CNS), ovary, kidney, prostate as well as breast. Compound 9c showed broad spectrum potent anticancer activity in nano molar to micro molar range against 56 human tumor cell lines with GI 50 less than 10 μM ranging from 0.495 to 5.57 μM, also it is worth mentioning that compound 9c had the marked highest selectivity against the two cell lines T-47D and MDA-MB-468 belonging to breast cancer with GI 50 = 0.495 and 0.568 μM respectively, and its effect was further studied on cell cycle progression and induction of apoptosis in the MDA-MB-468 cell line. Results showed that compound 9c induced cell cycle arrest at G2/M phase and also, showed accumulation of cells in pre-G1 phase which may result from, degradation or fragmentation of the genetic materials indicating a possible role of apoptosis in compound 9c- induced cancer cell death and cytotoxicity and verifying this compound as promising selective anticancer lead. Compound 6c was selective against K-562, SR and MOLT-4 cell lines belonging to leukemia showing growth inhibition percentages 86.38, 65.76 and 60.40 at a single dose test, at the same time it showed lethal activity against HOP-92 representing non-small cell lung cancer. Interestingly, leukemia SR, CNS cancer SNB-75 and renal cancer UO-31 cell lines proved to be sensitive to compound 6d with growth inhibition percentages 52.86, 50.94 and 53.99 respectively. Additionally, compound 6d demonstrated lethal activity to HOP-92 belonging non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

Abstract: A novel series of 6-alkenylamides of 4-anilinothieno[2,3-d]pyrimidine derivatives was designed, synthesized and evaluated as irreversible inhibitors of the epidermal growth factor receptor (EGFR). Most of the compounds exhibited good potency against EGFR wild type (EGFR wt) and EGFR T790M/L858R. Among these, the half-maximal inhibitory concentration (IC50) values of 17 compounds against EGFR wt were less than 0.020μM, and those of 12 compounds were less than 0.010μM. The IC50 values of 10 compounds against EGFR T790M/L858R were less than 0.005μM. Compounds 8l, 9n, 9o, 9q and 9v almost completely blocked the phosphorylation of EGFR in the A431 cell line at 1μM. Compounds 8l, 9n, 9o, 9q and 9v blocked the autophosphorylation of EGFR in NCI-H1975 cells at high concentration (1μM), and compound 8l was confirmed to be an irreversible inhibitor through the dilution method. [Copyright &y& Elsevier]

Abstract: Two series of new tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines namely 2,3-disubstituted derivatives 3a–z and 2,4-disubstituted ones 6a–c were prepared and tested for their antitumor and antibacterial activities. The structures of the prepared compounds were confirmed by spectral and elemental analyses. Compound 3z exhibited the highest antitumor activity against breast MCF-7 with IC50 = 0.19 μM compared to Doxorubicin (IC50 = 5.46 μM), while 3r was the most active one against liver HEPG-2 cancer cell line with IC50 = 1.29 μM as regard to Doxorubicin (IC50 = 7.36 μM). Concerning the antibacterial activity, compounds 3m and 3z exerted remarkable activity against the tested bacterial species compared to Ampicillin, whereas compound 6c showed good activity against only Gram positive species. [Copyright &y& Elsevier]

Abstract: This study represents the synthesis of a new series of N-substituted phenyl-5-methyl-6-(5-(4-substituted phenyl)-1,3,4-oxadiazol-2-yl)thieno[2,3-d]pyrimidin-4-amine derivatives (4a–l) and substituted phenylamino-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid derivatives (3a–d). The newly synthesized compounds were characterized by 1H NMR, 13C NMR, LC–MS and IR analyses. All these novel compounds were screened for their in vitro antioxidant activity by employing DPPH, hydrogen peroxide, and nitric oxide radical scavenging assays. Compounds 4k, 4j, 4d, and 4e showed significant radical scavenging due to the presence of electron donating substituent on both sides of the thienopyrimidine ring enhances the activity and electron withdrawing groups like nitro decrease. [Copyright &y& Elsevier]

The synthetic potency of readily accessible, ethyl 2-amino-4-methyl-5-(4-nitrophenoxy)thiophene-3-carboxylate (1) as a versatile precursor for the synthesis of novel polyfunctionally substituted thienopyrimidines is reported. The latter derivatives undergo further heterocyclisation to the related polycyclic fused systems via reactions with different reagents. [ABSTRACT FROM AUTHOR]

Ethyl 2-amino-5-ethylthiophene-3- carboxylate 1, obtained from the reaction of butyraldehyde, ethyl cyanoacetate, sulfur, and triethylamine, reacted with benzoylisothiocyanate to give the corresponding ureido derivatives 2 in a high yield. Further reactions of the compound 2 with an aqueous-alcohol solution of potassium hydroxide and then with hydrochloric acid gave the 2-thio-thieno[2,3-d]pyrimidine-4-ones 3, which were reacted with RX to give novel compounds 4a-4i. Treating the compound 3 with dibromoalkane led to the formation of triacylic compounds 5j-5m. Their structures were clearly verified by IR, 1H NMR, EI-MS spectroscopy, and elemental analysis. The results of a preliminary bioassay indicated that some compounds possess excellent inhibitory activities against the root and the stalk of Brassica napus (rape) and Echinochloa crusgalli (barnyard grass) at a dosage of 100 mg/L. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. [ABSTRACT FROM AUTHOR]

Abstract: In the course of search for new therapeutic agents against epilepsy new inhibitors for the kainate receptor subtypes GluR5 and GluR6 were synthesized. We were able to synthesize new substituted thieno[2,3-d]pyrimidines 3a,b, 4a,b, 5a,b as well as thiophene-3-carboxamides 2a-d and a multitude of substituted 4-methyl-5-phenylthiophene-3-carboxylic acids. All compounds described herein were tested for their antagonistic effect towards the kainate receptor subtypes GluR5 and GluR6. The highest activity was observed for ethyl 2-amino-4-methyl-5-phenylthiophene-3-carboxylate 1c with an IC50 =0.75μM at the GluR6 receptor. [Copyright &y& Elsevier]

A variety of novel thieno[2,3-d]pyrimidine derivatives, comprising amino acids 3a-l, imidazothieno-pyrimidines 4A, 4b-h, and 7, were obtained via the reaction of 4-chloro-5,6-dimethylthieno[2,3-d]pyrimidine 1 with a variety of reagents. The structures of these compounds were confirmed by microanalysis, IR, 1H NMR, and mass spectrometry. Some of the obtained compounds showed promising radioprotective and antitumor activities. [ABSTRACT FROM AUTHOR]

Abstract: Two series of 5-ethyl-2-amino-3-pyrazolyl-4-methylthiophenecarboxylate and 2-thioxo-N 3-aminothieno[2,3-d]pyrimidines were prepared from 3,5-diethyl-2-amino-4-methylthio-phenecaboxylate and evaluated as anti-inflammatory, analgesic and ulcerogenic activities. Among the compounds studied, compounds which containing the substituted hydrazide at C-3 position 7, 16, and 17a showed more potent anti-inflammatory and analgesic activities than the standard drug (Indomethacin and Aspirin), along without ulcerogenity. While compounds 2, 5, 9, 10, and 11c showed moderate activities. Some of the newly synthesized compounds have good to excellent antimicrobial activity. [Copyright &y& Elsevier]

Abstract: A series of novel 2-unsubstituted 4-(substituted)anilinothieno[2,3-d]pyrimidines is synthesized through the chlorination of the corresponding 2-unsubstituted-thieno[2,3-d]-pyrimidin-4-ones, followed by the nucleophilic displacement of the 4-Cl group of 9, with a variety of anilines. All four steps of this synthesis involve microwave irradiation (MWI) and the entire synthesis requires only 2h. [Copyright &y& Elsevier]

2-(2-Arylvinyl)-6-methyl-4-mercapto-5-acetylpyrimidine derivatives 3a - d, were synthesized form the reaction of the appropriate isothiocyanate derivatives 1 with α,β -unsaturated aminoketone 2. Compound 3 was alkylated with methyl iodide, ethyl chloroacetate and/or bromosugar to afford 6, 9, and 22a - c respectively. Cyanoethylation of 3b afforded 6b which upon cyclization with hydrazine hydrate gave pyrazolopyrimidine 7. Bromination of 6b gave dibromo compound 8. Thieno[2,3-d]pyrimidines 10 and 12 were obtained by ring closure of the alkylated product 9 with TEA/EtOH and/or through cyclization of the hydrazide 11 with NaOEt/EtOH. While, Thieno[2,3-d]pyrimidine 14 was obtained directly by alkylation of 3b with chloroacetone in both TEA/EtOH and Na2CO3 solution. The cycloaddition products 15 and 16 were obtained by reaction of 3b with diethylmaleate and/or maleic anhydride. Formation of 1,3,4-oxadiazole 17, pyrazoles 18 and 19 where obtained by treating the hydrazide 11 with carbon disulphide, triethyl orthoformate and acetylacetone respectively. While, reaction of 11 with p-chlorobenzaldehyde resulted in the Schiff's base 20 which, cyclizes with thioglycolic acid to afford thiazolidone 21. Hydrolysis of 22a - c in TEA/MeOH afforded the free sugar 23a - c. The structures of all the new compounds were confirmed using IR, 1H, and 13C NMR spectra and microanalysis. Selected members of the synthesized compound were screened for antimicrobial activity. [ABSTRACT FROM AUTHOR]

The reaction of compounds 1, 2, 3, 4, or 13 with 2-chloroethyl methyl ether or 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide, afforded some acyclic and cyclic nucleosides of thieno[2,3-d]pyrimidine derivatives. Furthermore, cyclic C-nucleosides 24 and 25 were prepared from the reaction of 20, 21 or from 26, 27 with D-glucose. The antimicrobial evaluation of some prepared products showed promising antimicrobial activity. [ABSTRACT FROM AUTHOR]

Some novel 5-subistituted amino-3-methylthiophene-2,4-dicarboxylic acid diethyl ester (3–6), 3,5-dimethyl-4-oxo-2-thioxo-1,2,3,4-tetra-hydro-thieno[2,3-d]pyrimi-dine (7), imidazothienopyrimidene (8), and 1,2,4-triazolo-thienopyrimidine (11) were synthesized via a reaction of the isothiocyanate 2 with different reagents. The identification of the new compounds was established by elemental analysis, and IR, 1 H NMR, and mass spectral data. Some prepared compounds were tested for their radioprotective and anticancer activities. Compounds 7 and 16 showed significant activities against EAC cells, while compound 5 exhibited radioprotective activity. [ABSTRACT FROM AUTHOR]

This work describes the synthesis and anticancer activity against kinase enzymes of newly designed thiophene and thieno[2,3- d ]pyrimidine derivatives, along with their potential to activate autophagic and apoptotic cell death in cancer cells. The designed compounds were scanned for their affinity for kinases. The results were promising with affinity ranges from 46.7% to 13.3%. Molecular docking studies were performed, and the compounds were then screened for their antiproliferative effects. Interestingly, compounds 8 and 5 resulted in higher cytotoxic effects than the reference standard against MCF-7 and HepG-2. The compounds were evaluated for their induction of apoptosis and/or necrosis on HT-29 and HepG-2. Three compounds induced significant early apoptosis compared to untreated control HT-29 cells, and four derivatives were more significant compared to untreated HepG-2 cells. We further investigated the effect of four compounds on the autophagy process within HT-29, HepG-2, and MCF-7 cells with flow cytometry. Similar to the apoptosis results, compound 5 showed the highest autophagic induction among all compounds. The potential inhibitory activity of the synthesized compounds on kinases was assessed. Screened compounds showed inhibition activity ranging from 41.4% to 83.5%. Compounds recorded significant inhibition were further investigated for their specific FLT3 kinase inhibitory activity. Noticeably, Compound 5 exhibited the highest inhibitory activity against FLT3.

A series of six novel and six known thieno[2,3-d]pyrimidin-4-amines 2-13 were synthesized, and further were used as a starting material for preparation of a small series of eight novel thieno[2,3-d]pyrimidin-4-phthalimides 14-21. Eight compounds, five amine and three phthalimide derivatives, inhibited bovine pancreatic DNase I with an IC 50 below 200 µM, being more effective than referent inhibitor crystal violet. Phthalimide derivatives 16, 18 and 19 exhibited higher DNase I inhibitory activity compared to their amine precursors 7, 10 and 11. Compound 19, as the most potent (IC 50  = 106 ± 16 µM), offers a good starting point for a design of new DNase I inhibitors. The Pharma RQSAR model showed a significant enhancement of thieno[2,3-d]pyrimidines activity using aryl substituents at R1 position. The E-State RQSAR model clarified the most important structural fragments relevant for DNase I inhibition. Molecular docking and Site Finder module defined the thieno[2,3-d]pyrimidines interactions with the most important catalytic residues of DNase I, including Glu 39, His 134, Asp 168 and His 252. We also found that steric effects and increase of molecular volume play a vital role in DNase I inhibition., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: 4-Substitutedaminoquinazoline scaffolds were reported to possess potent cytotoxic and EGFR inhibitory activity such as gefitinib (Iressa), erlotinib (Tarceva) and tandutinib., Objective: Synthesis of novel 4-substitutedaminothieno[2,3-d]pyrimidine derivatives as bioisosters of 4-substitutedaminoquinazoline derivatives with potential cytotoxic and EGFR inhibitory activity., Methods: Novel 4-substitutedaminothieno[2,3-d]pyrimidine derivatives 4a-i and 5a-c were synthesized via reacting corresponding 4-chlorothieno[2,3-d]pyrimidine derivatives 3a-c with N-methylpiperazine, morpholine, N-phenylpiperazine or 1,3-propanediamine. Six compounds (2a, 4d, 4e, 5a-c) were selected by the National Cancer Institute (USA) for evaluating their cytotoxic activity using 60 different human tumor cell lines using a single dose (10-5 Molar). The rest of the synthesized compounds (2b, 2c, 3a-c, 4a-c and 4f-i) were subjected to screening against T47D breast cancer cell line using a single dose (10-5 Molar) at Pharmacology lab., Cancer biology lab., Egyptian National Institute. Moreover, compounds 2a and 4b-e were subjected to further evaluation by IC50 determination. Finally, the inhibition of epidermal growth factor receptor (EGFR) was then investigated for the most active compounds 2a and 4d., Results: Compounds 2a and 4b-e showed significant cytotoxic activity. Compound 2a was more potent than doxorubicin against lung cancer cell line A549 with IC50 = 13.40 μM and comparable activity against MCF7. Compound 4d exhibited more potent activity than Doxorubicin against prostate PC3 (IC50 = 14.13 µM) while showed comparable activity against MCF7 and T47D., Conclusion: 4-Substitutedaminothieno[2,3-d]pyrimidine is a promising backbone for the design and synthesis of potent cytotoxic leads., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

A series of novel tetrahydrobenzothieno[2,3-d]pyrimidine urea derivatives was synthesized according to fragment-based design strategy. They were evaluated for their anticancer activity against MCF-7 cell line. Three compounds 9c, 9d and 11b showed 1.5-1.03 folds more potent anticancer activity than doxorubicin. In this study, a promising multi-sited enzyme small molecule inhibitor 9c, which showed the most potent anti-proliferative activity, was identified. The anti-proliferative activity of this compound appears to correlate well with its ability to inhibit topoisomerase II (IC 50  = 9.29 μM). Moreover, compound 9c showed excellent VEGFR-2 inhibitory activity, at the sub-micromolar level with IC 50 value 0.2 μM, which is 2.1 folds more potent than sorafenib. Moreover, activation of damage response pathway of the DNA leads to cell cycle arrest at G2/M phase, accumulation of cells in pre-G1 phase and annexin-V and propidium iodide staining, indicating that cell death proceeds through an apoptotic mechanism. Compound 9c showed potent pro-apoptotic effect through induction of the intrinsic mitochondrial pathway of apoptosis. This mechanistic pathway was confirmed by a significant increase in the expression of the tumor suppressor gene p53, elevation in Bax/BCL-2 ratio and a significant increase in the level of active caspase-3. Quantitative structure-activity relationship (QSAR) studies delivered equations of five 3D descriptors with R 2  = 0.814. This QSAR model provides an effective technique for understanding the observed antitumor properties and thus could be adopted for developing effective lead structures., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

In an attempt to discover a new class of antibacterial agents with improved efficacy and to overcome the drug-resistant problems, some novel 4-substituted thieno[2,3-d]pyrimidines have been synthesized via microwave-assisted methodology and evaluated for their in vitro antibacterial activity against various pathogenic bacterial strains. Compounds 12b and 13c showed the promising inhibitory potencies against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Escherichia coli with MICs ranging from 2 to 10 μg/ml. Compound 13c was also found to be highly potent against methicillin-resistant S. aureus (MRSA) with MIC value of 4 μg/ml. Docking simulation studies have been performed to unravel the mode of action and association study indicate the binding of potent compounds with DHPS enzyme. In silico ADME studies suggest the drug-like characteristics of the potent compounds., (© 2017 John Wiley & Sons A/S.)

A series of different amino acid-bearing thieno[2,3-d]pyrimidine moiety was synthesized via green chemistry aspects incorporating water as a solvent to give 2a-f, which were then acidified to attain the target compounds 3-9. Moreover, a tricyclic imidazothienopyrimidine of the glycine derivative (3) was synthesized to give (10). The title compounds were characterized by FT-IR, Mass, 13 C- 1 HNMR spectroscopy and microanalysis. All the obtained amino acid-derivatives were screened for their post-irradiation protective efficacy in young rats. γ-Irradiation exposure was employed to induce oxidative stress. Radiation triggered significant alterations in the hematologic and blood - biochemical parameters. Further, a significant deterioration of hepatic antioxidant status was observed. Furthermore, a significant elevation of Nuclear Factor-kappa B (NF-κB) protein expression and level, which induced elevation in Cyclooxygenase-2 (COX-2) activity and cytochrome P450 2E1 (CYP2E1) gene expression were detected in hepatic tissues. Additionally, elevated levels of Tumor Necrosis Factor-alpha (TNF-α), and Interleukin-6 (IL-6) were perceived in serum of γ-irradiated young rats. However, most of the newly synthesized derivatives showed significant protective effects against injuries induced by γ-irradiation exposure, via ameliorating the altered hematopoietic system and activity of different biochemical parameters in blood. The results indicate that the antioxidant and anti-inflammatory mechanism of these compounds could be attributed to the significant down-regulation NF-κB protein expression in hepatic tissues. Subsequently, NF-κB could regulate TNF-α and IL-6 levels, COX-2 activity and CYP2E1 gene expression. Methionine derivative 8 was found to be the most active one., Conclusion: These new amino acid-derivatives showed promising outcomes as curative agents against γ-irradiation induced oxidative stress and physiological disturbance in different organs of young animals. Beyond, they may represent a novel selective class for treating liver injury induced by γ-irradiation in young rats, via down-regulation of NF-κB expression. Further investigations are warranted prior to the clinical use of these new compounds., (Copyright © 2016 Elsevier B.V. All rights reserved.)

A series of 4-anilinothieno[2,3-d]pyrimidine-based hydroxamic acid derivatives as novel HDACs inhibitors were designed, synthesized and evaluated. Most of these compounds displayed good to excellent inhibitory activities against HDAC1, 3, 6. The IC50 values of compound 10r against HDAC1, HDAC3, HDAC6 was 1.14 ± 0.03 nM, 3.56 ± 0.08 nM, 11.43 ± 0.12 nM. Compound 10r noticeably up-regulated the level of histone H3 acetylation compared to the SAHA. Most of the compounds showed the strong anti-proliferative activity against human cancer cell lines including RMPI8226 and HCT-116. The IC50 values of Compounds 10r and 10t against RPMI8226 was 2.39 ± 0.20 μM, 1.41 ± 0.44 μM, respectively, and the HCT-116 was sensitive to the compounds 10h, 10 m, 10r, 10 w with the IC50 values <1.9 μM., (Copyright © 2014 Elsevier Ltd. All rights reserved.)