Pyrimidine-based Derivatives Research Articles

Synthesis and Antimicrobial Evaluation of New 1,2,4-Triazolo[1,5-a]pyrimidine-Based Derivatives as Dual Inhibitors of Bacterial DNA Gyrase and DHFR

Synthesis and Antimicrobial Evaluation of New 1,2,4-Triazolo[1,5-<i>a</i>]pyrimidine-Based Derivatives as Dual Inhibitors of Bacterial DNA Gyrase and DHFR

Design and Synthesis of New Dihydropyrimidine Derivatives with a Cytotoxic Effect as Dual EGFR/VEGFR-2 Inhibitors.

We developed and synthesized tetrahydropyrimidine derivatives as possible cytotoxic agents to inhibit EGFR and VEGFR-2 in the present study. Our study completely assesses the cytotoxic efficiency of pyrimidine-based derivatives 4-15 against various cancer cell lines, revealing derivatives 12 and 15 for their remarkable activity with GI50 values of 37 and 35 nM, respectively, when compared to the reference erlotinib (33 nM). In vitro enzyme assays showed that target compounds, particularly 12, 14, and 15, effectively inhibited EGFR and VEGFR-2. In vitro enzyme testing revealed that compound 15 was the most promising, with IC50 values of 84 and 3.50 nM for EGFR and VEGFR-2, respectively. Additionally, an in vitro assessment of the novel targets' apoptotic potential revealed that both pro-apoptotic and antiapoptotic behaviors were promising, indicating that the apoptotic induction pathway is a strongly proposed action method for the newly developed targets. Finally, molecular docking experiments are elaborately discussed to corroborate the exact binding interactions of the most active hybrids 12 and 15 with the EGFR and VEGFR-2 active sites.

Discovery of Novel Pyrimidine-Based Derivatives as Nav1.2 Inhibitors with Efficacy in Mouse Models of Epilepsy.

Dysfunction of voltage-gated sodium channel Nav1.2 causes various epileptic disorders, and inhibition of the channel has emerged as an attractive therapeutic strategy. However, currently available Nav1.2 inhibitors exhibit low potency and limited structural diversity. In this study, a novel series of pyrimidine-based derivatives with Nav1.2 inhibitory activity were designed, synthesized, and evaluated. Compounds 14 and 35 exhibited potent activity against Nav1.2, boasting IC50 values of 120 and 65 nM, respectively. Compound 14 displayed favorable pharmacokinetics (F = 43%) following intraperitoneal injection and excellent brain penetration potency (B/P = 3.6). Compounds 14 and 35 exhibited robust antiepileptic activities in the maximal electroshock test, with ED50 values of 3.2 and 11.1 mg/kg, respectively. Compound 35 also demonstrated potent antiepileptic activity in a 6 Hz (32 mA) model, with an ED50 value of 18.5 mg/kg. Overall, compounds 14 and 35 are promising leads for the development of new small-molecule therapeutics for epilepsy.

Benzo[4,5]imidazo[1,2-a]pyrimidine-based structure-inherent targeting fluorescent sensor for imaging lysosomal viscosity and diagnosis of lysosomal storage disorders

Benzo[4,5]imidazo[1,2-a]pyrimidine-based derivatives play crucial roles in medicines, pesticides, tracers and photoelectric materials. However, their synthesis approach still needs to be optimized, and their fluorescent properties in intracellular microenvironment are unclear. Here, a Cu(II)-catalyzed cascade coupling cyclization reaction was successfully developed to synthesize benzo[4,5]imidazo[1,2-a]pyrimidine scaffold with mild reaction conditions, broad substrate scopes and high yields. After a system study, we found that compound 4aa displayed an optimal viscosity-specific response with remarkable fluorescence enhancement (102-fold) for glycerol at 490 nm. Particularly, 4aa possessed excellent structure-inherent targeting (SIT) capability for lysosome (P = 0.95) with high pH stability and large Stokes shift. Importantly, 4aa was validated for its effectiveness in diagnosing lysosomal storage disorders (LSD) in living cells. The 4aa also showed its potential to map the micro-viscosity and its metabolism process in zebrafish. This work not only affords an efficient protocol to fabricate benzo[4,5]imidazo[1,2-a]pyrimidine derivatives, reveals this skeleton has excellent SIT features for lysosome, but also manifests that 4aa can serve as a practical tool to monitor lysosomal viscosity and diagnose LSD.

Synthesis and molecular modeling study of new pyrimidine-based derivatives as anticonvulsant agents

Synthesis and molecular modeling study of new pyrimidine-based derivatives as anticonvulsant agents

Synthesis and antimicrobial/antioxidant evaluation of novel pyrimidine-based derivatives with pendant pyrazoles using vinamidinum salts

Synthesis and antimicrobial/antioxidant evaluation of novel pyrimidine-based derivatives with pendant pyrazoles using vinamidinum salts

New thieno[3,2-d]pyrimidine-based derivatives: Design, synthesis and biological evaluation as antiproliferative agents, EGFR and ARO inhibitors inducing apoptosis in breast cancer cells

An array of newly synthesized thieno[3,2-d]pyrimidine-based derivatives and thienotriazolopyrimidines hybridized with some pharmacophoric anticancer fragments were designed, synthesized and assessed for their in vitro antiproliferative activity against MCF-7 and MDA-MB-231 breast cancer cell lines using erlotinib and pictilisib as reference standards in the MTT assay. In general, many compounds were endowed with considerable antiproliferative activity (IC50 = 0.43–1.31 µM). Some of the tested compounds, namely 3c, 5b, 5c, 9d, 10, 11b and 13 displayed remarkable antiproliferative activity against both cell lines. Meanwhile, compounds 2c-e, 3b, 4a, 5a, 9c and 15b showed noticeable selectivity against MCF-7 cells while compounds 2b, 3a, 4b, 6a-c, 7, 8, 9b and 12 exhibited considerable selectivity against MDA-MB-231 cells. Further mechanistic evidences for their anticancer activities were provided by screening the most potent compounds against MCF-7 and/or MDA-MB-231 cells for EGFR and ARO inhibitory activities using erlotinib and letrozole as reference standards respectively. Results proved that, in general, tested compounds were better EGFRIs than ARIs. In addition, significant overexpression in caspase-9 level in treated MCF-7 breast cell line samples was observed for all tested compounds with the 4-fluorophenylhydrazone derivative 2d exhibiting the highest activation. In treated MDA-MB-231 breast cell line samples, 11b was found to highly induce caspase-9 level thereby inducing apoptosis. Cell cycle analysis and Annexin V-FITC/PI assay were also assessed for active compounds where results indicated that all tested compounds induced preG1 apoptosis and cell cycle arrest at G2/M phase. Compound 9d, as an inhibitor of ARO, was observed to downregulate the downstream signaling proteins HSP27 and p-ERK in MCF-7 cells. Furthermore, compound 11b downregulated EGFR expression as well as the downstream signaling protein p-AKT. Docking experiments on EGFR and ARO enzymes supported their in vitro results. Thus, the thienotriazolopyrimidines 11b and 12 showing good EGFR inhibition and the thieno[3,2-d]-pyrimidine derivatives 3b and 9d, eliciting the best ARO inhibition activity, can be considered as new candidates as anti-breast cancer agents that necessitate further development.

Discovery and Synthesis of a Pyrimidine-Based Aurora Kinase Inhibitor to Reduce Levels of MYC Oncoproteins.

The A-type Aurora kinase is upregulated in many human cancers, and it stabilizes MYC-family oncoproteins, which have long been considered an undruggable target. Here, we describe the design and synthesis of a series of pyrimidine-based derivatives able to inhibit Aurora A kinase activity and reduce levels of cMYC and MYCN. Through structure-based drug design of a small molecule that induces the DFG-out conformation of Aurora A kinase, lead compound 13 was identified, which potently (IC50 < 200 nM) inhibited the proliferation of high-MYC expressing small-cell lung cancer (SCLC) cell lines. Pharmacokinetic optimization of 13 by prodrug strategies resulted in orally bioavailable 25, which demonstrated an 8-fold higher oral AUC (F = 62.3%). Pharmacodynamic studies of 25 showed it to effectively reduce cMYC protein levels, leading to >80% tumor regression of NCI-H446 SCLC xenograft tumors in mice. These results support the potential of 25 for the treatment of MYC-amplified cancers including SCLC.

Discovery of thieno[2,3-d]pyrimidine-based derivatives as potent VEGFR-2 kinase inhibitors and anti-cancer agents

Vascular endothelial growth factor-2 (VEGFR-2) is considered one of the most important factors in tumor angiogenesis, and consequently a number of anticancer therapeutics have been developed to inhibit VEGFR-2 signaling. Accordingly, eighteen derivatives of thieno[2,3-d]pyrimidines having structural characteristics similar to VEGFR-2 inhibitors were designed and synthesized. Anticancer activities of the new derivatives were assessed against three human cancer cell lines (HCT-116, HepG2, and MCF-7) using MTT. Sorafenib was used as positive control. Compounds 17c-i, and 20b showed excellent anticancer activities against HCT-116 and HepG2 cell lines, while compounds 17i and 17g was found to be active against MCF-7 cell line. Compound 17f exhibited the highest cytotoxic activities against the examined cell lines, HCT-116 and HepG2, with IC50 values of 2.80 ± 0.16 and 4.10 ± 0.45 µM, respectively. Aiming at exploring the mechanism of action of these compounds, the most active cytotoxic derivatives were in vitro tested for their VEGFR-2 inhibitory activity. Compound 17f showed high activity against VEGFR-2 with an IC50 value of 0.23 ± 0.03 µM, that is equal to that of reference, sorafenib (IC50 = 0.23 ± 0.04 µM). Molecular docking studies also were performed to investigate the possible binding interactions of the target compounds with the active sites of VEGFR-2. The synthesized compounds were analyzed for their ADMET and toxicity properties. Results showed that most of the compounds have low to very low BBB penetration levels and they have non-inhibitory effect against CYP2D6. All compounds were predicted to be non-toxic against developmental toxicity potential model except compounds 17b and 20b.

Discovery of Novel Pyrrolo[2,3-d]pyrimidine-based Derivatives as Potent JAK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors.

It remains a big challenge to develop HDAC inhibitors effective for solid tumors. Previous studies have suggested that the feedback activation of JAK-STAT3 pathway represents a key mechanism leading to resistance to HDAC inhibitors in breast cancer, suggesting the therapeutic promise of JAK/HDAC dual inhibitors. In this work, we discovered a series of pyrrolo[2,3-d]pyrimidine-based derivatives as potent JAK and HDAC dual inhibitors. Especially, compounds 15d and 15h potently inhibited JAK1/2/3 and HDAC1/6 and displayed antiproliferative and proapoptotic activities in triple-negative breast cancer cell lines. Besides, compounds 15d and 15h also diminished the activation of LIFR-JAK-STAT signaling triggered by tumor-associated fibroblasts, which suggests that these compounds could potentially overcome the drug resistance caused by the tumor microenvironment. More importantly, compound 15d effectively inhibited the tumor growth in MDA-MB-231 xenograft tumor model. Overall, this work provides valuable leads and novel antitumor mechanisms for the treatment of the SAHA-resistant triple-negative breast cancers.

Design, synthesis, biological evaluation, and docking studies of novel (imidazol-5-yl)pyrimidine-based derivatives as dual BRAFV600E/p38α inhibitors

The synergistic effect of dual inhibition of serine/threonine protein kinases that are involved in the same signalling pathway of the diseases can exert superior biological benefits for treatment of these diseases. In the present work, a new series of (imidazol-5-yl)pyrimidine was designed and synthesized as dual inhibitors of BRAFV600E and p38α kinases which are considered as key regulators in mitogen-activated protein kinase (MAPK) signalling pathway. The target compounds were evaluated for dual kinase inhibitory activity. The tested compounds exhibited nanomolar scale IC50 values against BRAFV600E and low to sub-micromolar IC50 range against p38α. Compound 20h was identified as the most potent dual BRAFV600E/p38α inhibitor with IC50 values of 2.49 and 85nM, respectively. Further deep investigation revealed that compound 20h possesses inhibitory activity of TNF-α production in lipopolysaccharide-induced RAW 264.7 macrophages with IC50 value of 96.3nM. Additionally, the target compounds efficiently frustrated the proliferation of LOX-IMVI melanoma cell line. Compound 20h showed a satisfactory antiproliferative activity with IC50 value of 13μM, while, compound 18f exhibited the highest cytotoxicity potency with IC50 value of 0.9μM. Compound 18f is 11.11-fold more selective toward LOX-IMVI melanoma cells than IOSE-80PC normal cells. The newly reported compounds represent therapeutically promising candidates for further development of BRAFV600E/p38α inhibitors in an attempt to overcome the acquired resistance of BRAF mutant melanoma.

Design, synthesis and biological evaluation of pyrimidine-based derivatives as antitumor agents

Design, synthesis and biological evaluation of pyrimidine-based derivatives as antitumor agents

A Raman Spectroscopic and Computational Study of New Aromatic Pyrimidine-Based Halogen Bond Acceptors

Two new aromatic pyrimidine-based derivatives designed specifically for halogen bond directed self-assembly are investigated through a combination of high-resolution Raman spectroscopy, X-ray crystallography, and computational quantum chemistry. The vibrational frequencies of these new molecular building blocks, pyrimidine capped with furan (PrmF) and thiophene (PrmT), are compared to those previously assigned for pyrimidine (Prm). The modifications affect only a select few of the normal modes of Prm, most noticeably its signature ring breathing mode, ν1. Structural analyses afforded by X-ray crystallography, and computed interaction energies from density functional theory computations indicate that, although weak hydrogen bonding (C–H···O or C–H···N interactions) is present in these pyrimidine-based solid-state co-crystals, halogen bonding and π-stacking interactions play more dominant roles in driving their molecular-assembly.

Molecular docking and receptor-based QASR studies on pyrimidine derivatives as potential phosphodiesterase 10A inhibitors

In the present work, molecular docking methodology in combination with quantitative structure–activity relationship (QSAR) was employed to predict the inhibition activity of 87 structurally diverse pyrimidine-based derivatives as phosphodiestrae10A (PDE10A) inhibitors due to their potential in the treatment of schizophrenia. In this method, compounds in their preferred enzyme-docked conformations were utilized to derive interaction-based quantitative descriptors in order to explain reported PDE10A inhibitory activities. Multiple linear regression (MLR), artificial neural network (ANN), and least square support vector regression (LS-SVR) were exploited to developing the structure-based quantitative structure–activity relationship models. Among these models, LS-SVR model showed more satisfactory statistical parameters with regard to both internal (Rtrain = 0.951, Q2 = 0.804, RMSEtrain = 0.494) and external validation (Rtest = 0.941, RMSEtest = 0.549) test results. Information from the most relevant descriptors suggests that incorporating steric effect, electronegativity, and the number of substituted aromatic carbon correlate the activity with structural features of the studied compounds. Molecular docking analysis of the most potent inhibitor explored that hydrogen bond formation and hydrophobicity participated in the binding interaction of PDE10A complex active pocket which these findings are in line with those obtained from QSAR model. The reliability assessment of compounds predictions was checked by model applicability domain (AD) analysis.

Identification of Pyrrolo[2,3- d]pyrimidine-Based Derivatives as Potent and Orally Effective Fms-like Tyrosine Receptor Kinase 3 (FLT3) Inhibitors for Treating Acute Myelogenous Leukemia.

A series of pyrrolo[2,3- d]pyrimidine derivatives were prepared and optimized for cytotoxic activities against FLT3-ITD mutant cancer cells. Among them, compound 9u possessed nanomolar FLT3 inhibitory activities and subnanomolar inhibitory activities against MV4-11 and Molm-13 cells. It also showed excellent inhibitory activities in FLT3-ITD-D835V and FLT3-ITD-F691L cells which were resistant to quizartinib. Furthermore, 9u exhibited over 40-fold selectivity toward FLT3 relative to c-Kit kinase, which might reduce myelosuppression toxicity. Cellular assays demonstrated that 9u inhibited phosphorylated FLT3 and downstream signaling factors and also induced cell cycle arrest in the G0/G1 stage and apoptosis in MV4-11 and Molm-13 cells. Oral administration of 9u at 10 mg/kg could achieve rapid tumor extinction in the MV4-11 xenograft model and significantly inhibit the tumor growth in the MOLM-13 xenograft model with a tumor growth inhibitory rate of 96% without obvious toxicity. Additionally, 9u demonstrated high bioavailability ( F = 59.5%) and suitable eliminated half-life time ( T1/2 = 2.06 h), suggesting that 9u may be a potent candidate for treating acute myelogenous leukemia.

Design, synthesis and biological evaluation of pyrimidine-based derivatives as VEGFR-2 tyrosine kinase inhibitors

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in tumor angiogenesis, and inhibition of the VEGFR-2 signaling pathway has already become an attractive approach for cancer therapy. In this study, a novel pyrimidine-based derivative 7j was designed as lead compound, and three series of potent VEGFR-2 inhibitors were synthesized and biologically evaluated against A549 and HepG2 cell lines. Compounds 7d, 9s and 13n exhibited superior inhibitory activities against A549 cell with IC50 ranged from 9.19 to 13.17 μM and HepG2 cell with IC50 ranged from 11.94 to 18.21 μM compared to those of Pazopanib (IC50 = 21.18 and 36.66 μM). In addition, molecular docking study was performed to investigate the binding capacity and binding mode between target compounds and VEGFR-2.

Discovery of Potent VEGFR-2 Inhibitors based on Furopyrimidine and Thienopyrimidne Scaffolds as Cancer Targeting Agents.

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In this study, a series of novel furo[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine based-derivatives were designed and synthesized as VEGFR-2 inhibitors, in accordance to the structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The synthesized compounds were evaluated for their ability to in vitro inhibit VEGFR-2 kinase enzyme. Seven compounds (15b, 16c, 16e, 21a, 21b, 21c and 21e) demonstrated highly potent dose-related VEGFR-2 inhibition with IC50 values in nanomolar range, of which the thieno[2,3-d]pyrimidine based-derivatives (21b, 21c and 21e) exhibited IC50 values of 33.4, 47.0 and 21 nM respectively. Moreover, furo[2,3-d]pyrimidine-based derivative (15b) showed the strongest inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 99.5% inhibition at 10 μM concentration. Consistent with our in vitro findings, compounds (21b and 21e) orally administered at 5 and 10 mg/kg/day for 8 consecutive days demonstrated potent anticancer activity in Erhlich ascites carcinoma (EAC) solid tumor murine model. Such compounds blunted angiogenesis in EAC as evidenced by reduced percent microvessel via decreasing VEGFR-2 phosphorylation with subsequent induction of apoptotic machinery. Furthermore, Miles vascular permeability assay confirmed their antiangiogenic effects in vivo. Intriguingly, such compounds showed no obvious toxicity.

Pharmacophore Design of p38&amp;#945; MAP Kinase Inhibitors with Either 2,4,5-Trisubstituted or 1,2,4,5-Tetrasubstituted Imidazole Scaffold

Synthetic compounds with a tri- and tetra-substituted imidazole scaffold are known as selective inhibitors of the p38 mitogen-activated protein (MAP) kinase responsible for proinflammatory cytokine release. The scope is to review the literature describing their design, synthesis and activity studies. To date a great plethora of crystal structures of p38 in complex with small organic ligands have been published. Cocrystallized ligand information is of particular interest to our review study, i.e. ATP itself, the reference inhibitor SB203580 with its aryl-pyridinyl-imidazoles and related imidazole and pyrimidine-based derivatives. The selective inhibitors bind to the pocket of adenosine 5'-triphoshate (ATP) replacing the latter. The hydrophobic region II, however, is not occupied by the natural binder ATP, but accommodates the pyridine substituents preserving the 4-fluorophenyl ring occupation in pocket I as a prerequisite to gain higher binding selectivity and potency than the reference compound SB203580 (4-[5-(4-fluoro-phenyl)-2-(4-methanesulfinyl-phenyl)-3himidazol-4-yl]-pyridine). Experimental and computed work is reviewed which evidence that the 2 position of the pyrimidine ring is amenable to the introduction of a side chain and the replacement of pyridine in SB203580 by a pyrimidine ring improves both inhibitory activity and selectivity for p38 over other kinases. All ligands with a pyridyl C2 side chain occupy the hydrophobic pocket II and in some cases a double hydrogen bond is reported between methionine 109 and glycine 110 of the hinge region, following an observed backbone shift. The substituted pyridine ring binds stronger than the two other side chains on the imidazole scaffold.