- New 2,4-disubstituted-2-thiopyrimidines as VEGFR-2 inhibitors: Design, synthesis, and biological evaluation
-
A new series of 2,4-disubstituted-2-thiopyrimidines 6a–t, 9a, and 9b was efficiently designed and synthesized as antiangiogenic and cytotoxic agents. Compounds 6j, 6l, and 6d showed IC50 values of 1.23, 3.78, and 3.84 μM, respectively, against the vascular endothelial growth factor receptor-2 (VEGFR-2). Most of the synthesized 2-thiouracils showed antiproliferative activity against the HepG2 cell line (hepatocellular carcinoma) in the micromolar range, for instance, 9b, 6l, 6m, 6n, and 6j displayed IC50 = 7.92, 8.35, 8.51, 9.59, and 13.06 μM, respectively, relative to sorafenib (III; IC50 = 10.99 μM). Also, compounds 6j, 9a, 6m, and 6s (IC50 = 15.21, 16.96, 17.68, and 18.15 μM, respectively) are the most potent compounds against the UO-31 cell line. Further evaluation of the effect of the synthesized candidates on VEGFR-2 in the HepG2 cell line demonstrated that compounds 6j and 6l exhibit VEGFR-2 inhibitory activity of 87% and 84%, respectively, relative to sorafenib (III; 92%). In silico docking of the synthesized hits into the binding site of VEGFR-2 showed their ability to perform the main binding interactions with the key amino acids in the binding site. Studying the in silico predicted ADME (absorption, distribution, metabolism, and excretion) parameters for the synthesized thiouracils demonstrated that they have favorable pharmacokinetic and drug-likeness properties. These results demonstrate that the 2,4-disubstituted thiouracils 6 and 9 have not only favorable antiangiogenic and antiproliferative activity but also satisfy the criteria required for the development of orally bioavailable drugs. Consequently, they represent a biologically active scaffold that should be further optimized for future discovery of potential hits.
- Abdel-Mohsen, Heba T.,Girgis, Adel S.,Mahmoud, Abeer E. E.,Ali, Mamdouh M.,El Diwani, Hoda I.
-
-
Read Online
- Antitubercular 2-Pyrazolylpyrimidinones: Structure-Activity Relationship and Mode-of-Action Studies
-
Phenotypic screening of a Medicines for Malaria Venture compound library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds were bactericidal against replicating Mtb and retained potency against clinical isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure-activity relationship studies identified potent compounds with good physicochemical properties and in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.
- Soares De Melo, Candice,Singh, Vinayak,Myrick, Alissa,Simelane, Sandile B.,Taylor, Dale,Brunschwig, Christel,Lawrence, Nina,Schnappinger, Dirk,Engelhart, Curtis A.,Kumar, Anuradha,Parish, Tanya,Su, Qin,Myers, Timothy G.,Boshoff, Helena I. M.,Barry, Clifton E.,Sirgel, Frederick A.,Van Helden, Paul D.,Buchanan, Kirsteen I.,Bayliss, Tracy,Green, Simon R.,Ray, Peter C.,Wyatt, Paul G.,Basarab, Gregory S.,Eyermann, Charles J.,Chibale, Kelly,Ghorpade, Sandeep R.
-
supporting information
p. 719 - 740
(2021/02/03)
-
- Structure optimization of positive allosteric modulators of GABAB receptors led to the unexpected discovery of antagonists/potential negative allosteric modulators
-
Positive allosteric modulators (PAMs) of GABAB receptor represent an interesting alternative to receptor agonists such as baclofen, as they act on the receptor in a more physiological way and thus are devoid of the side effects typically exerted by the agonists. Based on our interest in the identification of new GABAB receptor PAMs, we followed a merging approach to design new chemotypes starting from selected active compounds, such as GS39783, rac-BHFF, and BHF177, and we ended up with the synthesis of four different classes of compounds. The new compounds were tested alone or in the presence of 10 μM GABA using [35S]GTPγS binding assay to assess their functionality at the receptor. Unexpectedly, a number of them significantly inhibited GABA-stimulated GTPγS binding thus revealing a functional switch with respect to the prototype molecules. Further studies on selected compounds will clarify if they act as negative modulators of the receptor or, instead, as antagonists at the orthosteric binding site.
- Mugnaini, Claudia,Brizzi, Antonella,Mostallino, Rafaela,Castelli, Maria Paola,Corelli, Federico
-
-
- Pyrimidone molecule for promoting SOD activity in cosmetics and preparation method and application thereof
-
The invention discloses a pyrimidone molecule for prompting the SOD activity in cosmetics and a preparation method and application thereof, and belongs to the technical field of synthesis of proteaseagonists. According to the technical scheme, the molecule is characterized in that the pyrimidone molecule is of the structure shown in the specification, methyl benzoate with the low cost is adoptedas a starting raw material, and the novel pyrimidone molecule of the novel structure can be obtained through condensation substitution, ring formation, chlorination, cyanogroup substitution, aethrization and other poly-step reactions. The molecule is easy and rapid to operate, high in yield and suitable for industrial mass production, can effectively improve the activity of SOD in cosmetics, and has the potential as a domestic auxiliary additive.
- -
-
Paragraph 0031-0033
(2019/06/07)
-
- α-Amino-β-carboxymuconate-?-semialdehyde Decarboxylase (ACMSD) Inhibitors as Novel Modulators of de Novo Nicotinamide Adenine Dinucleotide (NAD+) Biosynthesis
-
NAD+ has a central function in linking cellular metabolism to major cell-signaling and gene-regulation pathways. Defects in NAD+ homeostasis underpin a wide range of diseases, including cancer, metabolic disorders, and aging. Although the beneficial effects of boosting NAD+ on mitochondrial fitness, metabolism, and lifespan are well established, to date, no therapeutic enhancers of de novo NAD+ biosynthesis have been reported. Herein we report the discovery of 3-[[[5-cyano-1,6-dihydro-6-oxo-4-(2-thienyl)-2-pyrimidinyl]thio]methyl]phenylacetic acid (TES-1025, 22), the first potent and selective inhibitor of human ACMSD (IC50 = 0.013 μM) that increases NAD+ levels in cellular systems. The results of physicochemical-property, ADME, and safety profiling, coupled with in vivo target-engagement studies, support the hypothesis that ACMSD inhibition increases de novo NAD+ biosynthesis and position 22 as a first-class molecule for the evaluation of the therapeutic potential of ACMSD inhibition in treating disorders with perturbed NAD+ supply or homeostasis.
- Pellicciari, Roberto,Liscio, Paride,Giacchè, Nicola,De Franco, Francesca,Carotti, Andrea,Robertson, Janet,Cialabrini, Lucia,Katsyuba, Elena,Raffaelli, Nadia,Auwerx, Johan
-
p. 745 - 759
(2018/02/17)
-
- Discovery of wtRET and V804MRET Inhibitors: From Hit to Lead
-
Oncogenic activation of RET kinase has been found in several neoplastic diseases, like medullary thyroid carcinoma, multiple endocrine neoplasia, papillary thyroid carcinoma, and non-small-cell lung cancer. Currently approved RET inhibitors were not originally designed to be RET inhibitors, and their potency against RET kinase has not been optimized. Hence, novel compounds able to inhibit both wild-type RET (wtRET) and its mutants (e.g., V804MRET) are needed. Herein we present the development and the preliminary evaluation of a new sub-micromolar wtRET/V804MRET inhibitor, N-(2-fluoro-5-trifluoromethylphenyl)-N′-{4′-[(2′′-benzamido)pyridin-4′′-ylamino]phenyl}urea (69), endowed with a 4-anilinopyridine structure, starting from our previously identified 4-anilinopyrimidine hit compound. Profiling against a panel of kinases indicated 69 as a multi cKIT/wtRET/V804MRET inhibitor.
- Mologni, Luca,Dalla Via, Martina,Chilin, Adriana,Palumbo, Manlio,Marzaro, Giovanni
-
supporting information
p. 1390 - 1398
(2017/09/01)
-
- INHIBITORS OF α-AMINO-β-CARBOXYMUCONIC ACID SEMIALDEHYDE DECARBOXYLASE
-
The present disclosure discloses compounds capable of modulating the activity of α-amino-β-carboxymuconic acid semialdehyde decarboxylase (ACMSD), which are useful for the prevention and/or the treatment of diseases and disorders associated with defects in NAD+ biosynthesis, e.g., metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, kidney diseases, and diseases associated with ageing. The present application also discloses pharmaceutical compositions comprising said compounds and the use of such compounds as a medicament.
- -
-
Page/Page column 109
(2016/03/22)
-
- Evaluation of a large library of (thiazol-2-yl)hydrazones and analogues as histone acetyltransferase inhibitors: Enzyme and cellular studies
-
Recently we described some (thiazol-2-yl)hydrazones as antiprotozoal, antifungal and anti-MAO agents as well as Gcn5 HAT inhibitors. Among these last compounds, CPTH2 and CPTH6 showed HAT inhibition in cells and broad anticancer properties. With the aim to identify HAT inhibitors more potent than the two prototypes, we synthesized several new (thiazol-2-yl)hydrazones including some related thiazolidines and pyrimidin-4(3H)-ones, and we tested the whole library existing in our lab against human p300 and PCAF HAT enzymes. Some compounds (1x, 1c', 1d', 1i' and 2m) were more efficient than CPTH2 and CPTH6 in inhibiting the p300 HAT enzyme. When tested in human leukemia U937 and colon carcinoma HCT116 cells (100 μM, 30 h), 1x, 1i' and 2m gave higher (U937 cells) or similar (HCT116 cells) apoptosis than CPTH6, and were more potent than CPTH6 in inducing cytodifferentiation (U937 cells).
- Carradori, Simone,Rotili, Dante,De Monte, Celeste,Lenoci, Alessia,D'Ascenzio, Melissa,Rodriguez, Veronica,Filetici, Patrizia,Miceli, Marco,Nebbioso, Angela,Altucci, Lucia,Secci, Daniela,Mai, Antonello
-
p. 569 - 578
(2014/06/09)
-
- HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase
-
The identification of novel, non-purine based inhibitors of xanthine oxidase is described. After a high-throughput screening campaign, an NMR based counterscreen was used to distinguish actives, which interact with XO in a reversible manner, from assay artefacts. This approach identified pyrimidone 1 as a reversible and competitive inhibitor with good lead-like properties. A hit to lead campaign gave compound 41, a nanomolar inhibitor of hXO with efficacy in the hyperuricemic rat model after oral dosing.
- Even?s, Johan,Edfeldt, Fredrik,Lepist?, Matti,Svitacheva, Naila,Synnergren, Anna,Lundquist, Britta,Gr?nse, Mia,R?nnholm, Anna,Varga, Mikael,Wright, John,Wei, Min,Yue, Sherrie,Wang, Junfeng,Li, Chong,Li, Xuan,Chen, Gang,Liao, Yong,Lv, Gang,Tj?rnebo, Ann,Narjes, Frank
-
supporting information
p. 1315 - 1321
(2014/03/21)
-
- Synthesis and biological evaluation of novel pyrimidine-benzimidazol hybrids as potential anticancer agents
-
A series of pyrimidine-benzimidazol hybrids was synthesized and evaluated for anticancer activity on four human cancer cell lines including MCF-7, MGC-803, EC-9706 and SMMC-7721. Some of the synthesized compounds exhibited moderate to potent activity against MGC-803 and MCF-7. Among them, compounds 5a-b and 6a-b showed most effective activity. Compounds 5b and 6b were more cytotoxic than 5-fluorouracil against all tested four human cancer cell lines, with IC50 values ranging from 2.03 to 10.55 μM and 1.06 to 12.89 μM, respectively. Flow cytometry analysis demonstrated that treatment of MGC-803 with 6b led to cell cycle arrest at G2/M phase accompanied by an increase in apoptotic cell death.
- Shao, Kun-Peng,Zhang, Xu-Yao,Chen, Peng-Ju,Xue, Deng-Qi,He, Peng,Ma, Li-Ying,Zheng, Jia-Xin,Zhang, Qiu-Rong,Liu, Hong-Min
-
p. 3877 - 3881
(2014/09/03)
-
- Synthesis and antitumor activity evaluation of pyrimidine analogues bearing urea moiety
-
A series of 4-anilino-6-phenylpyrimidines containing urea moiety were synthesized and the structures of all products were confirmed by 1H NMR, 13C NMR and HRMS. The antiproliferative activities of these compounds were evaluated against three human tumor cell lines (MGC-803, MCF-7 and EC-109) by applying the MTT assay method. compounds 4a, 4b and 6a showed the most effective activity, among which, 6a was more cytotoxic than 5-fluorouracil against all tested human cancer cell lines with IC50 values ranging from 1.80 to 2.72 μmol·L-1. A series of 4-anilino-6-phenylpyrimidines containing urea moiety were synthesized. The antiproliferative activities of these compounds were evaluated against three human tumor cell lines (MGC-803, MCF-7 and EC-109) by applying the MTT assay method. compounds 4a, 4b and 6a showed most effective activity, among which, 6a was more cytotoxic than 5-fluorouracil against all tested three human cancer cell lines with IC50 values ranging from 1.80 to 2.72 μmol·L-1. Copyright
- Shao, Kunpeng,Zhang, Xuyao,Zhang, Xiaosong,Xue, Dengqi,Ma, Liying,Zhang, Qiurong,Liu, Hongmin
-
p. 443 - 447
(2014/06/10)
-
- Identification of substituted 2-thio-6-oxo-1,6-dihydropyrimidines as inhibitors of human lactate dehydrogenase
-
A novel 2-thio-6-oxo-1,6-dihydropyrimidine-containing inhibitor of human lactate dehydrogenase (LDH) was identified by high-throughput screening (IC 50 = 8.1 μM). Biochemical, surface plasmon resonance, and saturation transfer difference NMR experiments indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of the screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50 = 0.48 μM). A crystal structure of an optimized compound bound to human LDHA was obtained and explained many of the observed structure-activity relationships.
- Dragovich, Peter S.,Fauber, Benjamin P.,Corson, Laura B.,Ding, Charles Z.,Eigenbrot, Charles,Ge, Hongxiu,Giannetti, Anthony M.,Hunsaker, Thomas,Labadie, Sharada,Liu, Yichin,Malek, Shiva,Pan, Borlan,Peterson, David,Pitts, Keith,Purkey, Hans E.,Sideris, Steve,Ultsch, Mark,Vanderporten, Erica,Wei, Binqing,Xu, Qing,Yen, Ivana,Yue, Qin,Zhang, Huihui,Zhang, Xuying
-
p. 3186 - 3194
(2013/06/27)
-
- Microwave assisted one-pot synthesis of nitrogen and oxygen containing heterocycles from acyl Meldrum's acid
-
One-pot syntheses of biologically active nitrogen and oxygen containing heterocyclic compounds such as uracils and thiouracils and 1,4-benzothiazines, 4-methylcoumarins and 4H-1,4- dihydropyridines, using acyl Meldrum's acids are reported.
- More,Mahulikar
-
experimental part
p. 745 - 747
(2011/06/27)
-
- Novel uracil-based 2-aminoanilide and 2-aminoanilide-like derivatives: Histone deacetylase inhibition and in-cell activities
-
A novel series of non-hydroxamate HDAC inhibitors (HDACi) showing a uracil group at the left and a 2-aminoanilide/2-aminoanilide-like portion at the right head have been reported. In particular, the new compounds incorporating a 2-aminoanilide moiety behaved as class I-selective HDACi. Compound 8, the most potent and class I-selective, showed weak apoptosis (higher than MS-275) joined to cytodifferentiating activity on U937 cells. Surprisingly, the highest differentiation was observed with 13, through an effect that seems to be unrelated to HDAC inhibition.
- Mai, Antonello,Perrone, Andrea,Nebbioso, Angela,Rotili, Dante,Valente, Sergio,Tardugno, Maria,Massa, Silvio,De Bellis, Floriana,Altucci, Lucia
-
p. 2530 - 2535
(2008/12/21)
-
- NOVEL PYRIMIDINE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM
-
The present invention provides new heterocyclic compounds, particularly substituted pyrimidines, methods and compositions for making and using these heterocyclic compounds, and methods for treating a variety of diseases and disease states, including atherosclerosis, arthritis, restenosis, diabetic nephropathy, or dyslipidemia, or disease states mediated by the low expression of Perlecan.
- -
-
Page/Page column 207
(2008/06/13)
-
- Microwave promoted efficient synthesis of substituted uracils and thiouracils under solvent-free conditions
-
Several substituted uracils and thiouracils were synthesized in good yields by one-pot condensation reaction of methyl or ethyl β-ketoesters and urea (or thiourea) in solvent-free conditions under microwave irradiation and in short time.
- Mojtahedi, Mohammad M.,Saidi, Mohammad R.,Shirzi, Jafar S.,Bolourtchian, Mohammad
-
p. 851 - 855
(2007/10/03)
-
- Aryl and heterocyclyl substituted pyrimidine derivatives as anti-coagulants
-
This invention is directed to aryl and heterocyclyl substituted pyrimidine derivatives selected from the following formulae: wherein Z1, Z2, R1, R2, R3, R4, R5and R6are defined herein. These compounds are useful as anti-coagulants.
- -
-
-
- Synthesis of pyrimidine, thiazolopyrimidine, pyrimidotriazine and triazolopyrimidine derivatives and their biological evaluation
-
Pyrimidin-4-one-2-thione (3) was synthesized via the reaction of thiourea (1) with ethyl henzoylacetate (2) and was taken as a starting material for the present study via its reactions with the halogen-containing reagents 6a-d and 10a-c to give the corresponding thiazolopyrimidines 8, 9 and 12a-c. The 2-hydrazino derivatives 5 were synthesized either via the reaction of 3 or 4 with hydrazine hydrate. Compound 5 reacted with 6a-c and 10a-c to give the corresponding pyrimidotriazines 17a-c and 19 respectively. Also, compound 5 reacted with the active methylene-containing reagents 13 and 2a,b to give the corresponding 2-pyrazolopyrimidines 15 and 22a,b respectively. On the other hand, the triazolopyrimidines 21a,b and 30a,b were also obtained via the reaction of 5 with each of formic acid, acetic anhydride, ethyl chloroformate and carbon disulfide respectively. Some of the newly synthesized heterocyclic derivatives were tested for their biological activity.
- Attaby, Fawzy A.,Eldin, Sanaa M.
-
p. 788 - 798
(2007/10/03)
-
- Dihydro(alkylthio)(naphthylmethyl)oxopyrimidines: Novel non-nucleoside reverse transcriptase inhibitors of the S-DABO series
-
Novel compounds related to 2-(cyclohexylthio)-3,4-dihydro-5-methyl-6- (3-methylbenzyl)-4-oxopyrimidine (3c, MC 639) have been synthesized and tested as inhibitors of human immunodeficiency virus type-1 (HIV-1). Reaction of thiourea with ethyl arylmethylacetoacetates furnished 5-alkyl-6- (arylmethyl)-3,4-dihydro-2-mercapto-4-oxopyrimidines which were then alkylated at the sulfur atom to afford the required 2-alkylthio or 2- cycloalkylthio derivatives (S-DABOs). Chemical modifications at N-3, C-4, and C-6 of the pyrimidine ring were attempted with the aim of improving antiretroviral activity. In particular, replacement of the benzyl group with the 1-naphthylmethyl moiety enhanced the activity of S-DABOs, whereas N-3 alkylation and C=O transformation into C=S at position 4 of the pyrimidine ring led to compounds devoid of anti-HIV-1 activity. Lower activity was generally observed when 1-naphthylmethyl was replaced by the isomeric 2- naphthylmethyl moiety. The most active compounds showed activity in the low micromolar range with EC50 values comparable to that of nevirapine.
- Mai, Antonello,Artico, Marino,Sbardella, Gianluca,Quartarone, Silvana,Massa, Silvio,Loi, Anna G.,De Montis, Antonella,Scintu, Franca,Putzolu, Monica,La Colla, Paolo
-
p. 1447 - 1454
(2007/10/03)
-
