- Br?nsted acid-promoted ‘on–water’ C(sp3)-H functionalization for the synthesis of isoindolinone/[1,2,4]triazolo[1,5-a]pyrimidine derivatives targeting the SKP2-CKS1 interaction
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The isoindolinone and biaryl scaffolds are prevalent in natural products and drug molecules, which have showed broad and interesting biological activities. The efficient construction of such hybridized molecules and biological evaluation are of great interest to medicinal chemistry community. In this communication, we report an efficient Br?nsted acid-promoted C(sp3)-H functionalization approach that enables the rapid construction of biologically important isoindolinone/[1,2,4]triazolo[1,5-a]pyrimidine hybrids from 5-methyl-7-(2,4,6-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine, 2-formylbenzoic acid and various anilines. The title compounds were generated in high to excellent yields (up to 96%) regardless of the electronic nature and steric effects of the substituents. In this reaction, an isoindolinone scaffold, one C[sbnd]C single bond, and two C[sbnd]N bonds were formed simultaneously with high atom economy. In this work, we have envisioned that the methyl group linked to the electron-deficient N-heterocycles could be used as a new synthetic handle for late-state diversification and may have broad applications in the field of organic and medicinal chemistry. Besides, the title compounds have exhibited promising activity against the SKP2-CKS1 interaction.
- Yuan, Shuo,Wang, Sixi,Zhao, Min,Zhang, Danqing,Chen, Jinjie,Li, Jian-Xin,Zhang, Jingya,Song, Yihui,Wang, Jinyi,Yu, Bin,Liu, Hongmin
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- Anti-diabetic and anti-parasitic properties of a family of luminescent zinc coordination compounds based on the 7-amino-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine ligand
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We report on the formation of a triazolopyrimidine derivative ligand, 7-amino-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine (7-amtp), and a new family of coordination compounds based on this ligand and zinc as metal ion, synthesized by conventional routes. These materials possess different mononuclear structures, namely [ZnCl2(7-amtp)2] (1), [Zn(7-amtp)2(H2O)4](NO3)2·2(7-amtp)·6H2O (2) and [Zn(7-amtp)2(H2O)4](SO4)·1.5H2O (3) derived from the use of different zinc (II) salts, in such a way that the counterions govern the crystallization to a large extent. These compounds present and show variable luminescent properties based on ligand-centred charge transfers which have been deeply studied by Time Dependent Density Functional Theory (TD-DFT) calculations. When these compounds are transferred to solution, preserving complex entities as corroborated by NMR studies, they present interesting anti-diabetic and anti-parasitic capabilities, with a comparatively higher selectivity index than other previously reported triazolopyrimidine-based materials. The results derived from in vivo experiments conducted in mice also confirm their promising activity as anti-diabetic drug being capable of dropping glucose levels after oral administration. Therefore, these new materials may be considered as excellent candidates to be further investigated in the field of luminescent coordination compounds with biomedical applications.
- Esteban-Parra, Ginés M.,Sebastián, Eider San,Cepeda, Javier,Sánchez-González, Cristina,Rivas-García, Lorenzo,Llopis, Juan,Aranda, Pilar,Sánchez-Moreno, Manuel,Quirós, Miguel,Rodríguez-Diéguez, Antonio
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- Design and synthesis of new indole containing biaryl derivatives as potent antiproliferative agents
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A new series of indole containing biaryl derivatives were designed and synthesized, and further biological evaluations of their antiproliferative activity against cancer cell lines (MGC-803 and TE-1 cells) were also conducted. Of these synthesized biaryls, compound 4-methyl-2-((5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)methyl)quinazoline (23) performed as the most potent antiproliferative agent that inhibited cell viability of MGC-803 cells with an IC50 value of 8.28 μM. In addition, investigation of mechanism exhibited that the compound 4-methyl-2-((5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)methyl)quinazoline (23) could inhibit the expression of c-Myc and glycolysis related proteins, decrease the ATP and lactate production, and further induce apoptosis by activating the AMP-activated protein kinase (AMPK) and p53 signaling pathways.
- Yuan, Shuo,Feng, Si-Qi,Li, An-Qi,Zuo, Jia-Hui,Zhang, Dan-Qing,Xing, Yu-Jie,Xie, Zhiyu,Yu, Bin,Liu, Hong-Min
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- Discovery of [1,2,4]triazolo[1,5-a]pyrimidine derivatives as new bromodomain-containing protein 4 (BRD4) inhibitors
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Targeting bromodomain-containing protein 4 (BRD4) has been proved to be an effective strategy for cancer therapy. To date, numerous BRD4 inhibitors and degraders have been identified, some of which have advanced into clinical trials. In this work, a focused library of new [1,2,4]triazolo[1,5-a]pyrimidine derivatives were discovered to be able to inhibit BRD4. WS-722 inactivated BRD4 (BD1/BD2), BRD2 (BD1/BD2) and BRD3 (BD1/BD2) broadly with the IC50 values less than 5 μmol/L. Besides, WS-722 inhibited growth of THP-1 cells with an IC50 value of 3.86 μmol/L. Like (+)-JQ1, WS-722 inhibited BRD4 in a reversible manner and enhanced protein stability. Docking studies showed that WS-722 occupied the central acetyl-lysine (Kac) binding cavity and formed a hydrogen bond with Asn140. In THP-1 cells, WS-722 showed target engagement to BRD4. Cellular effects of WS-722 on THP-1 cells were also examined, showing that WS-722 could block c-MYC expression, induce G0/G1 phase arrest and p21 up-regulation, and promote differentiation of THP-1 cells. BRD4 inhibition by WS-722 resulted in cell apoptosis and up-regulated expression of cleaved caspased-3/7 and PARP in THP-1 cell lines. The [1,2,4]triazolo[1,5-a]pyrimidine is a new template for the development of new BRD4 inhibitors.
- Wang, Shuai,Shen, Dandan,Zhao, Lijie,Yuan, Xiaohan,Cheng, Jialing,Yu, Bin,Zheng, Yichao,Liu, Hongmin
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- An Unequivocal Synthesis of Some Substituted 1,2,4-TriazoloPyrimidines
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An unequivocal synthesis of 5-chloro-7-methyl- (8) and 7-methyl-1,2,4-triazolopyrimidine (10) from 2-amino-4-chloro-6-methylpyrimidine (5) through the corresponding amidine 6 and formamide oxime 7 was developed.It was unambigously shown by comparison of the chemical shifts and the magnitude of coupling constants that the compounds obtained by condensation of 3-amino-1,2,4-triazole (12) and ethyl acetoacetate (13) and some further transformations are isomeric 5-methyl substituted 1,2,4-triazolopyrimidines 1, 9, and 11. - Keywords: 1,2,4-Triazolopyrimidines; Cyclization with N-N bond formation; Structure determination by NMR
- Stanovnik, Branko,Urleb, Uros,Tisler, Miha
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- Comparative study between the anti-P. falciparum activity of triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives and the identification of new PfDHODH inhibitors
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In this work, we designed and synthesized 35 new triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives as P. falciparum inhibitors (3D7 strain). Thirty compounds exhibited anti-P. falciparum activity, with IC50 values ranging from 0.030 to 9.1 μM. The [1,2,4]triazolo[1,5-a]pyrimidine derivatives were more potent than the pyrazolo[1,5-a]pyrimidine and quinoline analogues. Compounds 20, 21, 23 and 24 were the most potent inhibitors, with IC50 values in the range of 0.030–0.086 μM and were equipotent to chloroquine. In addition, the compounds were selective, showing no cytotoxic activity against the human hepatoma cell line HepG2. All [1,2,4]triazolo[1,5-a]pyrimidine derivatives inhibited PfDHODH activity in the low micromolar to low nanomolar range (IC50 values of 0.08–1.3 μM) and did not show significant inhibition against the HsDHODH homologue (0–30% at 50 μM). Molecular docking studies indicated the binding mode of [1,2,4]triazolo[1,5-a]pyrimidine derivatives to PfDHODH, and the highest interaction affinities for the PfDHODH enzyme were in agreement with the in vitro experimental evaluation. Thus, the most active compounds against P. falciparum parasites 20 (R = CF3, R1 = F; IC50 = 0.086 μM), 21 (R = CF3; R1 = CH3; IC50 = 0.032 μM), 23, (R = CF3, R1 = CF3; IC50 = 0.030 μM) and 24 (R = CF3, 2-naphthyl; IC50 = 0.050 μM) and the most active inhibitor against PfDHODH 19 (R = CF3, R1 = Cl; IC50 = 0.08 μM - PfDHODH) stood out as new lead compounds for antimalarial drug discovery. Their potent in vitro activity against P. falciparum and the selective inhibition of the PfDHODH enzyme strongly suggest that this is the mechanism of action underlying this series of new [1,2,4]triazolo[1,5-a]pyrimidine derivatives.
- Silveira, Flávia F.,de Souza, Juliana O.,Hoelz, Lucas V.B.,Campos, Vinícius R.,Jabor, Valquíria A.P.,Aguiar, Anna C.C.,Nonato, M. Cristina,Albuquerque, Magaly G.,Guido, Rafael V.C.,Boechat, Nubia,Pinheiro, Luiz C.S.
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- Discovery of the Triazolo[1,5- a]Pyrimidine-Based Derivative WS-898 as a Highly Efficacious and Orally Bioavailable ABCB1 Inhibitor Capable of Overcoming Multidrug Resistance
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Targeting P-glycoprotein (ABCB1 or P-gp) has been recognized as a promising strategy to overcome multidrug resistance. Here, we reported our medicinal chemistry efforts that led to the discovery of the triazolo[1,5-a]pyrimidine derivative WS-898 as a highly effective ABCB1 inhibitor capable of reversing paclitaxel (PTX) resistance in drug-resistant SW620/Ad300, KB-C2, and HEK293/ABCB1 cells (IC50 = 5.0, 3.67, and 3.68 nM, respectively), more potent than verapamil and zosuquidar. WS-898 inhibited the efflux function of ABCB1, thus leading to decreased efflux and increased intracellular PTX concentration in SW620/Ad300 cells. The cellular thermal shift assay indicated direct engagement of WS-898 to ABCB1. Furthermore, WS-898 stimulated the ATPase activity of ABCB1 but had minimal effects on cytochrome P450 3A4 (CYP3A4). Importantly, WS-898 increased PTX sensitization in vivo without obvious toxicity. The results suggest that WS-898 is a highly effective triazolo[1,5-a]pyrimidine-based ABCB1 inhibitor and shows promise in reversing ABCB1-mediated PTX resistance.
- Wang, Shuai,Wang, Sai-Qi,Teng, Qiu-Xu,Lei, Zi-Ning,Chen, Zhe-Sheng,Chen, Xiao-Bing,Liu, Hong-Min,Yu, Bin
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p. 16187 - 16204
(2021/11/18)
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- Quinoline carboxamide core moiety-based compounds inhibit P. falciparum falcipain-2: Design, synthesis and antimalarial efficacy studies
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Targeting Falcipain-2 (FP2) for the development of antimalarials is a promising and established concept in antimalarial drug discovery and development. FP2, a member of papain-family cysteine protease of the malaria parasite Plasmodium falciparum holds an important role in hemoglobin degradation pathway. A new series of quinoline carboxamide-based compounds was designed, synthesized and evaluated for antimalarial activity. We integrated molecular hybridization strategy with in-silico drug design to develop FP2 inhibitors. In-vitro results of FP2 inhibition by Qs17, Qs18, Qs20 and Qs21 were found to be in low micromolar range with IC50 4.78, 7.37, 2.14 and 2.64 μM, respectively. Among the 25 synthesized compounds, four compounds showed significant antimalarial activities. These compounds also depicted morphological and food-vacuole abnormalities much better than that of E-64, an established FP2 inhibitor. Overall these aromatic substituted quinoline carboxamides can serve as promising leads for the development of novel antimalarial agents.
- Singh, Anju,Kalamuddin, Md,Maqbool, Mudasir,Mohmmed, Asif,Malhotra, Pawan,Hoda, Nasimul
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- ISOTOPICALLY-LABELLED TRAPIDIL DERIVATIVES
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Provided are isotopically-labelled Trapidil derivatives useful for the treatment of Parkinson's disease and movement disorders associated with Parkinson's disease. The isotopically-labelled Trapidil derivatives include deuterated Trapidil derivatives. Additionally provided are combination therapies of isotopically-labelled Trapidil derivatives and additional therapeutic agents for the treatment of Parkinson's disease and movement disorders associated with Parkinson's disease.
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Paragraph 00177; 00178
(2021/10/02)
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- Discovery of new [1,2,4] Triazolo[1,5-a]Pyrimidine derivatives that Kill gastric cancer cells via the mitochondria pathway
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Mitochondria are known as “powerhouse of cells” and play the role of a bridge in redox balance, cell apoptosis, and autophagy. ROS accumulation can cause mitochondria damage, while the injured mitochondria will further enhance ROS levels reciprocally. Herein, we synthesized a novel series of [1,2,4]triazolo[1,5-a]pyrimidine-based compounds 4a-4v and tested their anti-proliferation efficacy against gastric cancer cell line MGC-803. Among them, compounds 4o and 4p inhibited gastric cancer cells at micromolar level. Compound 4o caused G2/M arrest and induced mitochondria-dependent apoptosis in MGC-803 and SGC-7901. However, inhibiting apoptosis pathway cannot prevent the inhibitory activity of compound 4o against gastric cancer cell. To our surprising, ROS level was increased by compound 4o and elevation of ROS could be rescued by NAC. In accordance with that, NAC absolutely prevented the anti-proliferation efficacy of compound 4o. We further found that autophagy inhibitor CQ rather than 3-MA partially reversed inhibitory activity of compound 4o in MGC-803 cells. Taken together, compound 4o exhibited its anti-proliferative activity via increasing ROS level and inducing autophagy, thus leading to apoptosis of gastric cancer cells. Therefore, compound 4o may support further development of lead compounds for gastric cancer therapy via mitochondria pathway.
- Wang, Shuai,Ma, Xu-Bin,Yuan, Xiao-Han,Yu, Bin,Xu, Yi-Chao,Liu, Hong-Min
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- Discovery of tofacitinib derivatives as orally active antitumor agents based on the scaffold hybridization strategy
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In this work, a novel series of tofacitinib analogs were designed and synthesized based on the scaffold hybridization strategy and then evaluated for their antiproliferative activity toward three gastric cancer cell lines, leading to the identification of compound C18 which exhibited potent inhibitory activity against MGC-803 cell lines with an IC50 value of 2.68 μM. Compound C18 could effectively inhibit the colony formation, suppress the cell migration and induce apoptosis of MGC-803 cells through activating the p38 and JNK signaling pathways, while C18 showed no obvious effect on the cell cycle distribution in MGC-803 cells. In addition, C18 could initiate mitochondrial dysfunction of MGC-803 cells. Besides, in vivo antitumor studies indicated that C18 could inhibit gastric cancer tumor growth in vivo without obvious global toxicity.
- Shi, Xiao-Jing,Wang, Shuai,Li, Xiao-Jing,Yuan, Xiao-Han,Cao, Li-Juan,Yu, Bin,Liu, Hong-Min
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- Br?nsted Acid-Catalyzed Direct C(sp2)?H Heteroarylation Enabling the Synthesis of Structurally Diverse Biaryl Derivatives
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Biaryl scaffold is an important class of structural frameworks that exists in many natural products and drug molecules. The development of transition metal-catalyzed approaches for the efficient construction of biaryl scaffolds has long been pursued because of the interesting structural features and broad biological profiles of biaryl scaffolds. Herein, we describe the Br?nsted acid-catalyzed direct C(sp2)?H heteroarylation that enables the synthesis of biaryl fragments (70 examples) in moderate to excellent yields (up to 99% yield), which was also performed at a gram scale and successfully applied to the privileged quinazoline scaffolds of the first-generation epidermal growth factor receptor (EGFR) inhibitors Gefitinib and Erlotinib, offering rapid access to a series of quinazoline-based biaryl compounds. Additionally, the late-stage diversifications were performed based on the compound 3 b, generating a library of structurally diverse and complex biaryl compounds. (Figure presented.).
- Yuan, Shuo,Yu, Bin,Liu, Hong-Min
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supporting information
p. 59 - 66
(2019/01/16)
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- Experience-based discovery (EBD) of aryl hydrazines as new scaffolds for the development of LSD1/KDM1A inhibitors
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Phenelzine was first employed to design new aryl hydrazine-based LSD1 inhibitors based on the experience-based discovery (EBD) strategy. Among these compounds, D8 potently inhibited LSD1 (IC50 = 882.30 nM) in a reversible manner. Compound D8 was selective to LSD1 over MAO-A/B and showed H3K4me2 competitive binding to LSD1. The interaction between H3K4me2 and LSD1 was also confirmed by the Co-IP assay. In LSD1 overexpressed A549 cells, compound D8 dose-dependently induced accumulation of LSD1 substrates H3K4me1/2 and H3K9me1/2, showed cellular target engagement to LSD1 and significantly inhibited cell migration of A549 cells. Docking studies suggested that compound D8 occupied the peptide binding region and therefore blocked the access of the peptide substrate to the FAD, finally leading to the demethylase activity inhibition of LSD1. The findings indicate that aryl hydrazines are new scaffolds for the design of LSD1 inhibitors, the identification of D8 provides further evidence for our previously proposed general principle that fused heterocycles with an amine group are potentially active toward LSD1 by competitive binding to LSD1 with H3 peptide substrates.
- Li, Zhong-Rui,Wang, Shuai,Yang, Linlin,Yuan, Xiao-Han,Suo, Feng-Zhi,Yu, Bin,Liu, Hong-Min
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p. 432 - 444
(2019/02/12)
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- Synthesis, structure-activity relationship studies and biological characterization of new [1,2,4]triazolo[1,5-a]pyrimidine-based LSD1/KDM1A inhibitors
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The histone lysine specific demethylase 1 (LSD1/KDM1A) is implicated in the development of cancers, targeting LSD1 has been recognized as a promising strategy for cancer therapy. To date, some small-molecule inhibitors are currently being investigated in clinical trials. Herein we report the design, synthesis and biochemical characterization of [1,2,4]triazolo[1,5-a]pyrimidine derivatives as new LSD1 inhibitors. Of these compounds, compound C26 inhibited LSD1 in a reversible manner (IC50 = 1.72 μM) and showed selectivity to LSD1 over MAO-A/B. Besides, compound C26 displayed FAD-competitive binding to LSD1. Interestingly, C26 did not inhibit horseradish peroxidase (HRP) and quench H2O2, thus excluding the possibility that LSD1 inhibition by C26 was due to the HRP inhibition and consumption of H2O2. In LSD1 overexpressed A549 cells, compound C26 concentration-dependently induced accumulation of H3K4me1/me2 and H3K9me2 and showed cellular target engagement to LSD1. Additionally, compound C26 significantly inhibited migration of A549 cells in a concentration-dependent manner, further western blot analysis showed that C26 increased expression levels of epithelial cell markers E-Cadherin and Claudin-1, down-regulated mesenchymal cell marker N-Cadherin and the upstream transcription factors Snail and Slug. Docking studies were also performed to rationalize the potency of C26 toward LSD1. To conclude, the [1,2,4]triazolo[1,5-a]pyrimidine could serve as a promising scaffold for the development of new LSD1 inhibitors.
- Wang, Shuai,Li, Zhong-Rui,Suo, Feng-Zhi,Yuan, Xiao-Han,Yu, Bin,Liu, Hong-Min
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p. 388 - 401
(2019/02/19)
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- Development of Highly Potent, Selective, and Cellular Active Triazolo[1,5- a]pyrimidine-Based Inhibitors Targeting the DCN1-UBC12 Protein-Protein Interaction
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The cullin-RING ubiquitin ligases (CRLs) are responsible for about 20% of cellular protein degradation and regulate diverse cellular processes, and the dysfunction of CRLs is implicated in human diseases. Targeting the CRLs has become an emerging strategy for the treatment of human diseases. Herein, we describe the discovery of a hit compound from our in-house library and further structure-based optimizations, which have enabled the identification of new triazolo[1,5-a]pyrimidine-based inhibitors targeting the DCN1-UBC12 interaction. Compound WS-383 blocks the DCN1-UBC12 interaction (IC50 = 11 nM) reversibly and shows selectivity over selected kinases. WS-383 exhibits cellular target engagement to DCN1 in MGC-803 cells. WS-383 inhibits Cul3/1 neddylation selectively over other cullins and also induces accumulation of p21, p27, and NRF2. Collectively, targeting the DCN1-UBC12 interaction would be a viable strategy for selective neddylation inhibition of Cul3/1 and may be of therapeutic potential for disease treatment in which Cul3/1 is dysregulated.
- Wang, Shuai,Zhao, Lijie,Shi, Xiao-Jing,Ding, Lina,Yang, Linlin,Wang, Zhi-Zheng,Shen, Dandan,Tang, Kai,Li, Xiao-Jing,Mamun,Li, Huiju,Yu, Bin,Zheng, Yi-Chao,Wang, Shaomeng,Liu, Hong-Min
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- A multifunctional therapeutic approach: Synthesis, biological evaluation, crystal structure and molecular docking of diversified 1H-pyrazolo[3,4-b]pyridine derivatives against Alzheimer's disease
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2-(piperazin-1-yl)–N-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetamides are described as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and amyloid β aggregation inhibitors. Formation of synthesized compounds (P1–P9) was justified via H1 NMR, C13 NMR, mass spectra and single crystal X-Ray diffraction study. All compounds were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activity, inhibition of self-mediated Aβ aggregation and Cu(II)-mediated Aβ aggregation. Also, docking study carried out was in concordance with in vitro results. The most potent molecule amongst the derivatives exhibited excellent anti-AChE activity (IC50 = 4.8 nM). Kinetic study of P3 suggested it to be a mixed type inhibitor. In vitro study revealed that all the compounds are capable of inhibiting self-induced β-amyloid (Aβ) aggregation with the highest inhibition percentage to be 81.65%. Potency of P1 and P3 to inhibit self-induced Aβ1-42 aggregation was ascertained by TEM analysis. Compounds were also evaluated for their Aβ disaggregation, antioxidation, metal-chelation activity.
- Umar, Tarana,Shalini, Shruti,Raza, Md Kausar,Gusain, Siddharth,Kumar, Jitendra,Seth, Prerna,Tiwari, Manisha,Hoda, Nasimul
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- Pyrimidotriazole-indole compound and preparation method and application thereof
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The invention discloses a pyrimidotriazole-indole compound having a general formula as shown in I (shown in the description). The invention also provides a preparation method and application of the above compound. An in vitro BRD4 enzymatic activity inhibition test proves that the pyrimidotriazole-indole compound has potential inhibition effects on various tumor cells by inhibiting the enzymatic activity of BRD4, and can be used as a lead compound for antitumor drug preparation. In addition, a preparation method of the compound, provided by the present invention, has the advantages of mild reaction conditions, simple operation and high yield.
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Paragraph 0055; 0064; 0069
(2019/01/08)
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- Pd-catalyzed Suzuki/Sonogashira cross-coupling reaction and the direct sp3 arylation of 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine
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A rapid and efficient method is reported for the synthesis of the [1,2,4]triazolo[1,5-a]pyrimidine motif. Palladium catalyzed Suzuki and Sonogashira cross coupling reactions on 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine were performed. The direct sp3 arylation of compounds resulting from the Suzuki reaction was then carried out.
- Loubidi, Mohammed,Moutardier, Ana?s,Campos, Joana F.,Berteina-Raboin, Sabine
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supporting information
p. 1050 - 1054
(2018/02/14)
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- Rational design, synthesis and biological screening of triazine-triazolopyrimidine hybrids as multitarget anti-Alzheimer agents
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In our endeavor towards the development of potent multitarget ligands for the treatment of Alzheimer's disease, a series of triazine-triazolopyrimidine hybrids were designed, synthesized and characterized by various spectral techniques. Docking and scoring techniques were used to design the inhibitors and to display their interaction with key residues of active site. Organic synthesis relied upon convergent synthetic routes were mono and di-substituted triazines were connected with triazolopyrimidine using piperazine as a linker. In total, seventeen compounds were synthesized in which the di-substituted triazine-triazolopyrimidine derivatives 9a-d showed better acetylcholinesterase (AChE) inhibitory activity than the corresponding tri-substituted triazine-triazolopyrimidine derivatives 10a-f. Out of the disubstituted triazine-triazolopyrimidine based compounds, 9a and 9b showed encouraging inhibitory activity on AChE with IC50 values 0.065 and 0.092?μM, respectively. Interestingly, 9a and 9b also demonstrated good inhibition selectivity towards AChE over BuChE by ～28 folds. Furthermore, kinetic analysis and molecular modeling studies showed that 9a and 9b target both catalytic active site as well as peripheral anionic site of AChE. In addition, these derivatives effectively modulated Aβ self-aggregation as investigated through CD spectroscopy, ThT fluorescence assay and electron microscopy. Besides, these compounds exhibited potential antioxidants (2.15 and 2.91 trolox equivalent by ORAC assay) and metal chelating properties. In silico ADMET profiling highlighted that, these novel triazine derivatives have appropriate drug like properties and possess very low toxic effects in the primarily pharmacokinetic study. Overall, the multitarget profile exerted by these novel triazine molecules qualified them as potential anti-Alzheimer drug candidates in AD therapy.
- Jameel, Ehtesham,Meena, Poonam,Maqbool, Mudasir,Kumar, Jitendra,Ahmed, Waqar,Mumtazuddin, Syed,Tiwari, Manisha,Hoda, Nasimul,Jayaram
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- The synthesis and evaluation of triazolopyrimidines as anti-tubercular agents
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We identified a di-substituted triazolopyrimidine with anti-tubercular activity against Mycobacterium tuberculosis. Three segments of the scaffold were examined rationally to establish a structure-activity relationship with the goal of improving potency and maintaining good physicochemical properties. A number of compounds displayed sub-micromolar activity against Mycobacterium tuberculosis with no cytotoxicity against eukaryotic cells. Non-substituted aromatic rings at C5 and a two-carbon chain connecting a terminal aromatic at C7 were preferred features; the presence of NH at C7 and a lack of substituent at C2 were essential for potency. We identified compounds with acceptable metabolic stability in rodent and human liver microsomes. Our findings suggest that the easily-synthesized triazolopyrimidines are a promising class of potent anti-tubercular agents and warrant further investigation in our search for new drugs to fight tuberculosis.
- Zuniga, Edison S.,Korkegian, Aaron,Mullen, Steven,Hembre, Erik J.,Ornstein, Paul L.,Cortez, Guillermo,Biswas, Kallolmay,Kumar, Naresh,Cramer, Jeffrey,Masquelin, Thierry,Hipskind, Philip A.,Odingo, Joshua,Parish, Tanya
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p. 3922 - 3946
(2017/07/05)
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- Synthesis and screening of triazolopyrimidine scaffold as multi-functional agents for Alzheimer's disease therapies
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In present study a series of triazolopyrimidine-quinoline and cyanopyridine-quinoline hybrids were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs). Molecular docking and scoring was utilized for the design of inhibitors. The molecules were synthesized via an easily accessible, convergent synthetic route. Three triazolopyrimidine based compounds showed nanomolar activity towards acetylcholinesterase. Among them, Ethyl 6-fluoro-4-(4-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperazin-1-yl)quinoline-3-carboxylate (10d), strongly inhibited AChE with IC50 value of 42 nM. Furthermore compound 10d was identified as most promising compound with 12 fold selectivity against butyrylcholinesterase (BuChE). This compound displayed a composed multitargeted profile with promising inhibition of self-induced and AChE - induced Aβ aggregation and antioxidant activity.
- Kumar, Jitendra,Meena, Poonam,Singh, Anju,Jameel, Ehtesham,Maqbool, Mudasir,Mobashir, Mohammad,Shandilya, Ashutosh,Tiwari, Manisha,Hoda, Nasimul,Jayaram
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p. 260 - 277
(2016/06/01)
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- Novel Selective Inhibitor of Leishmania (Leishmania) amazonensis Arginase
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Arginase is a glycosomal enzyme in Leishmania that is involved in polyamine and trypanothione biosynthesis. The central role of arginase in Leishmania (Leishmania) amazonensis was demonstrated by the generation of two mutants: one with an arginase lacking
- Da Silva, Edson R.,Boechat, Nubia,Pinheiro, Luiz C. S.,Bastos, Monica M.,Costa, Carolina C. P.,Bartholomeu, Juliana C.,Da Costa, Talita H.
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p. 969 - 978
(2015/10/28)
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- New trifluoromethyl triazolopyrimidines as Anti-Plasmodium falciparum agents
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According to the World Health Organization, half of the World's population, approximately 3.3 billion people, is at risk for developing malaria. Nearly 700,000 deaths each year are associated with the disease. Control of the disease in humans still relies on chemotherapy. Drug resistance is a limiting factor, and the search for new drugs is important. We have designed and synthesized new 2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidine derivatives based on bioisosteric replacement of functional groups on the anti-malarial compounds mefloquine and amodiaquine. This approach enabled us to investigate the impact of: (i) ring bioisosteric replacement; (ii) a CF3 group substituted at the 2-position of the [1,2,4]triazolo[1,5-a]pyrimidine scaffold and (iii) a range of amines as substituents at the 7-position of the of heterocyclic ring; on in vitro activity against Plasmodium falciparum. According to docking simulations, the synthesized compounds are able to interact with P. falciparum dihydroorotate dehydrogenase (PfDHODH) through strong hydrogen bonds. The presence of a trifluoromethyl group at the 2-position of the [1,2,4]triazolo [1,5-a]pyrimidine ring led to increased drug activity. Thirteen compounds were found to be active, with IC50 values ranging from 0.023 to 20 μM in the anti-HRP2 and hypoxanthine assays. The selectivity index (SI) of the most active derivatives 5, 8, 11 and 16 was found to vary from 1,003 to 18,478.
- Boechat, Nubia,Pinheiro, Luiz C.S.,Silva, Thiago S.,Aguiar, Anna C.C.,Carvalho, Alcione S.,Bastos, Monica M.,Costa, Carolina C.P.,Pinheiro, Sergio,Pinto, Angelo C.,Mendonca, Jorge S.,Dutra, Karen D.B.,Valverde, Alessandra L.,Santos-Filho, Osvaldo A.,Ceravolo, Isabela P.,Krettli, Antoniana U.
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scheme or table
p. 8285 - 8302
(2012/10/08)
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- Lead optimization of aryl and aralkyl amine-based triazolopyrimidine inhibitors of plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice
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Malaria is one of the leading causes of severe infectious disease worldwide; yet, our ability to maintain effective therapy to combat the illness is continually challenged by the emergence of drug resistance.We previously reported identification of a new class of triazolopyrimidine-based Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors with antimalarial activity, leading to the discovery of a new lead series and novel target for drug development. Active compounds from the series contained a triazolopyrimidine ring attached to an aromatic group through a bridging nitrogen atom. Herein, we describe systematic efforts to optimize the aromatic functionality with the goal of improving potency and in vivo properties of compounds from the series. These studies led to the identification of two new substituted aniline moieties (4-SF5-Ph and 3,5-Di-F-4- CF 3-Ph), which, when coupled to the triazolopyrimidine ring, showed good plasma exposure and better efficacy in the Plasmodium berghei mouse model of the disease than previously reported compounds from the series.
- Gujjar, Ramesh,El Mazouni, Farah,White, Karen L.,White, John,Creason, Sharon,Shackleford, David M.,Deng, Xiaoyi,Charman, William N.,Bathurst, Ian,Burrows, Jeremy,Floyd, David M.,Matthews, David,Buckner, Frederick S.,Charman, Susan A.,Phillips, Margaret A.,Rathod, Pradipsinh K.
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experimental part
p. 3935 - 3949
(2011/07/31)
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- Synthesis, antibacterial and insecticidal activities of a new series of 4-(5-methyl-[1,2,4] triazolo [1,5-a] pyrimidin-7-ylamino)-N-(aryl) benzamides
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A nevi/ series of 4-(5-methyl-[1,2,4] triazoio [1,5-a] pyrimidin-7-ylamino) -N-(aryl) benzamides (4a-i) were synthesized by coupling 4-(5-methyl-(1,2,4] triazoio [1,5-a] pyrimidin-7-ylamino) benzoic acid 3 with different substituted amines using O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) as coupling reagent. The key intermediate 4-(5-methyl-[1,2,4] triazoio [1,5-a] pyrimidin-7-ylamino) benzoic acid 3 was synthesized by the reaction of 7-chloro-5-methyl-[1,2,4] triazoio [1,5-a] pyrimidine 2 with p-aminobenzoic acid in ethanol. The structure of the newly synthesized compounds were confirmed by FT-IR,1H NMR, 13C NMR and Mass spectral analysis and were evaluated for their antimicrobial and insecticidal activities. Some of the synthesized compounds exhibited potent insecticidal activity and significant antibacterial activity with respect to the standard drugs.
- Himaja,Prathap, K. Jagadeesh,Mali, Sunil V.,Ramana
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p. 317 - 320
(2013/09/24)
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- THERAPEUTIC AGENTS
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The invention provides a compound of formula (I): wherein R1, and W have any of the values defined in the application; or a salt thereof. The compounds and salts thereof have beneficial therapeutic properties (e.g. immunosuppressant properties).
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Page/Page column 52
(2010/04/03)
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- Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice
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Plasmodium falciparum causes 1-2 million deaths annually. Yet current drug therapies are compromised by resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase (PfDHODH) that inhibited parasite growth in vitro; however, they showed no activity in vivo. Here we show that lack of efficacy against P. berghei in mice resulted from a combination of poor plasma exposure and reduced potency against P. berghei DHODH. For compounds containing naphthyl (DSM1) or anthracenyl (DSM2), plasma exposure was reduced upon repeated dosing. Phenyl-substituted triazolopyrimidines were synthesized leading to identification of analogs with low predicted metabolism in human liver microsomes and which showed prolonged exposure in mice. Compound 21 (DSM74), containing p-trifluoromethylphenyl, suppressed growth of P. berghei in mice after oral administration. This study provides the first proof of concept that DHODH inhibitors can suppress Plasmodium growth in vivo, validating DHODH as a new target for antimalarial chemotherapy.
- Gujjar, Ramesh,Marwaha, Alka,Mazouni, Farah El,White, John,White, Karen L.,Creason, Sharon,Shackleford, David M.,Baldwin, Jeffrey,Charman, William N.,Buckner, Frederick S.,Charman, Susan,Rathod, Pradipsinh K.,Phillips, Margaret A.
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scheme or table
p. 1864 - 1872
(2009/12/07)
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- DIHYDROOROTATE DEHYDROGENASE INHIBITORS WITH SELECTIVE ANTI-MALARIAL ACTIVITY
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Compounds according to Formula (I), Formula (II), Formula (III), Formula (V), Formula (VI), or to Formula (VII), and pharmaceutical compositions of compounds that conform to Formula (IV) or (Formula VIII): where R1 through R33 are prescribed, selectively inhibit P. falciparum dihydroorotate dehydrogenase. Accordingly, a method for preventing and treating malaria attaches to such compounds, as well as to pharmaceutically acceptable salts, solvates, stereoisomers, tautomers, and prodrugs thereof.
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Page/Page column 36-37
(2009/07/25)
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- Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum
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A Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitor that is potent (KI = 15 nM) and species-selective (>5000-fold over the human enzyme) was identified by high-throughput screening. The substituted triazolopyrimidine and its structural analogues were produced by an inexpensive three-step synthesis, and the series showed good association between PfDHODH inhibition and parasite toxicity. This study has identified the first nanomolar PfDHODH inhibitor with potent antimalarial activity in whole cells (EC 50 = 79 nM).
- Phillips, Margaret A.,Gujjar, Ramesh,Malmquist, Nicholas A.,White, John,El Mazouni, Farah,Baldwin, Jeffrey,Rathod, Pradipsinh K.
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supporting information; experimental part
p. 3649 - 3653
(2009/04/07)
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- DIHYDROOROTATE DEHYDROGENASE INHIBITORS WITH SELECTIVE ANTI-MALARIAL ACTIVITY
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Pharmaceutical compositions comprising compounds of the formula (I) where R1, R2, and R3 are described here, have therapeutic utility in selectively inhibiting P. falciparum dihydroorotate dehydrogenase. Accordingly, such compositions have use in the treatment and prevention of malaria.
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Page/Page column 23-24
(2008/06/13)
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