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A series of inhibitors of the soluble epoxide hydrolase (sEH) containing imidazolidine-2,4,5-trione or pirimidine-2,4,6-trione has been synthesized. Inhibition potency of the described compounds ranges from 8.4 μM to 0.4 nM. The tested compounds possess higher water solubility than their preceding ureas. Molecular docking indicates new bond between the triones and the active site of sEH that in part explain the observed potency of the new pharmacophores. While less potent than the corresponding ureas, the modifications of urea group reported herein yield compounds with higher water solubility, thus permitting easier formulation.

The [1,2,4]triazolo[1,5-a]pyrimidines comprise a promising class of non-naturally occurring microtubule (MT)-active compounds. Prior studies revealed that different triazolopyrimidine substitutions can yield molecules that either promote MT stabilization or disrupt MT integrity. These differences can have important ramifications in the therapeutic applications of triazolopyrimidines and suggest that different analogues may exhibit different binding modes within the same site or possibly interact with tubulin/MTs at alternative binding sites. To help discern these possibilities, a series of photoactivatable triazolopyrimidine congeners was designed, synthesized and evaluated in cellular assays with the goal of identifying candidate probes for photoaffinity labeling experiments. These studies led to the identification of different derivatives that incorporate a diazirine ring in the amine substituent at position 7 of the triazolopyrimidine heterocycle, resulting in molecules that either promote stabilization of MTs or disrupt MT integrity. These photoactivatable candidate probes hold promise to investigate the mode of action of MT-active triazolopyrimidines.

[Display omitted] • A novel series of pyrimidine linked thiazolidinedione derivatives were synthesized. • All the compounds were evaluated for their in vitro antimicrobial and anti-TB activity. • Compound 5g , 5i and 5j showed the most potent antimicrobial and anti-TB activity. • All the compounds were found non-toxic at 50 μM against normal WI-38 cell line. • The biological screening results were supported by the molecular docking studies. The design and development of novel antimicrobial agents are highly desired to combat the emergence of medication resistance against microorganisms that cause infections. A series of new pyrimidine-linked thiazolidinedione derivatives (5a-j) were synthesized, characterized, and their antimicrobial properties assessed in the current investigation. Here, novel pyrimidine-linked thiazolidinedione compounds were designed using the molecular hybridization approach. Elemental and spectral techniques were used to determine the structures of the synthesized hybrids. The majority of compounds showed encouraging antibacterial properties. Among the active compounds, 5g , 5i , and 5j showed 1.85, 1.15, and 1.38 times the activity of streptomycin against S. aureus , respectively, with MIC values of 6.4, 10.3, and 8.6 µM. With MIC values of 10.8, 21.9, and 15.4 µM, respectively, the compounds 5g , 5i , and 5j showed 2.14, 1.05, and 1.50 times the activity of linezolid against the methicillin-resistant S. aureus (MRSA) strain. Furthermore, when compared to the reference medications, compounds 5g , 5i , and 5j demonstrated broad-range antimicrobial efficacy against all tested strains of bacteria and fungus. Out of all the compounds that were investigated, compounds 5g , 5i , and 5j showed noteworthy anti-tubercular activity. 5g is the most effective, 1.59 times more effective than reference drug isoniazid. To anticipate the binding manner, the synthesized potent compounds were subjected to molecular docking into the active binding site of MRSA and the mycobacterial membrane protein large 3 (MmpL3) protein. The compounds 5g , 5i , and 5j may eventually serve as lead compounds in the search for antimicrobial and anti-TB therapeutic agents. [ABSTRACT FROM AUTHOR]

[Display omitted] • New indol-fused pyrano-[2,3- d ]pyrimidines 11a-l were designed and synthesized. • The plausible mechanism for formation of compounds 11a-l was described. • Their α-glucosidase and acetylcholinesterase inhibitory activities were evaluated. • α-Glucosidase inhibitors 11d , e were around 93-fold more potent than acarbose. • Product 11 k exhibited good acetylcholinesterase inhibitory activity. In this study, new indol-fused pyrano[2,3- d ]pyrimidines were designed and synthesized. These products were obtained in moderate to good yields and their structures were assigned by NMR, MS, and IR analysis. Afterwards, the biological important of the products was highlighted by evaluating in vitro for α-glucosidase inhibitory activity as well as acetylcholinesterase (AChE) inhibitory activity. Eleven products revealed substantial inhibitory activity against α-glucosidase enzyme, among which, two most potent products 11d,e were approximately 93-fold more potent than acarbose as a standard antidiabetic drug. Besides that, product 11 k exhibited good AChE inhibition. The substituents on the 5-phenyl ring, attached to the pyran ring, played a critical role in inhibitory activities. The biological potencies have provided an opportunity to further investigations of indol-fused pyrano[2,3- d ]pyrimidines as potential anti-diabetic agents. [ABSTRACT FROM AUTHOR]

In human cells, receptor-interacting protein kinase 2 (RIPK2) is mainly known to mediate downstream enzymatic cascades from the nucleotide-binding oligomerization domain-containing receptors 1 and 2 (NOD1/2), which are regulators of pro-inflammatory signaling. Thus, the targeted inhibition of RIPK2 has been proposed as a pharmacological strategy for the treatment of a variety of pathologies, in particular inflammatory and autoimmune diseases. In this work, we designed and developed novel thieno[2,3 d ]pyrimidine derivatives, in order to explore their activity and selectivity as RIPK2 inhibitors. Primary in vitro evaluations of the new molecules against purified RIPKs (RIPK1-4) demonstrated outstanding inhibitory potency and selectivity for the enzyme RIPK2. Moreover, investigations for efficacy against the RIPK2-NOD1/2 signaling pathways, conducted in living cells, showed their potency could be tuned towards a low nanomolar range. This could be achieved by solely varying the substitutions at position 6 of the thieno[2,3 d ]pyrimidine scaffold. A subset of lead inhibitors were ultimately evaluated for selectivity against 58 human kinases other than RIPKs, displaying great specificities. We therefore obtained new inhibitors that might serve as starting point for the preparation of targeted tools, which could be useful to gain a better understanding of biological roles and clinical potential of RIPK2. [Display omitted] [ABSTRACT FROM AUTHOR]

The kidney urea transport protein UT-B is an attractive target for the development of small-molecule inhibitors with a novel diuretic ('urearetic') action. Previously, two compounds in the triazolothienopyrimidine scaffold (1a and 1c) were reported as UT-B inhibitors. Compound 1c incorporates a 1,1-difluoroethyl group, which affords improved microsomal stability when compared to the corresponding ethyl-substituted compound 1a. Here, a small focused library (4a-4f) was developed around lead inhibitor 1c to investigate the requirement of an amidine-linked thiophene in the inhibitor scaffold. Two compounds (4a and 4b) with nanomolar inhibitory potency (IC50≈40 nM) were synthesized. Computational docking of lead structure 1c and 4a-4f into a homology model of the UT-B cytoplasmic surface suggested binding with the core heterocycle buried deep into the hydrophobic pore region of the protein.

[Display omitted] • The synergistic effects of JMJD3 and HDAC inhibitors in cancer cells; • Designs and synthesizes a series of hydroxamic acid derivatives as novel dual JMJD3 and HDAC inhibitors; • Compound A5b displayed potent antiproliferative activity, lead to cell cycle arrest and induce apoptosis in cancer cells. The Jumonji domain-containing protein demethylase 3 (JMJD3) and histone deacetylase (HADC) are related to various cancers and regard as antitumor targets for drug discovery. In this study, based on rational drug design strategy, we designed and synthesized a series of pyrimidine derivatives with hydroxamic acid as novel dual JMJD3 and HDAC inhibitors for synergistic cancer treatment. Compound A5b exhibited inhibitory potency against JMJD3 and HDAC1/6 simultaneously and favorable cytotoxicity against human cancer cells such as A549 and U937. Furthermore, mechanistic studies showed that A5b treatment in A549 cells increased the hypermethylation of histone H3K27 and hyperacetylation of H3K9, suppressed clonogenicity, migration and invasion of cancer cells. Besides, A5b induced apoptosis via the cleavage of caspase-7 and PARP, and G1 cell cycle arrest via upregulated p21 expression. All these results suggested that A5b was the first dual inhibitor against JMJD3 and HDAC and can be a potential compound for cancer therapy. [ABSTRACT FROM AUTHOR]

Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii (pj) can lead to serious health consequences in patients with an immunocompromised system. Trimethoprim (TMP), used as first-line therapy in combination with sulfamethoxazole, is a selective but only moderately potent pj dihydrofolate reductase (pjDHFR) inhibitor, whereas non-clinical pjDHFR inhibitors, such as, piritrexim and trimetrexate are potent but non-selective pjDHFR inhibitors. To meet the clinical needs for a potent and selective pjDHFR inhibitor for PCP treatment, fourteen 6-substituted pyrido[3,2- d ]pyrimidines were developed. Comparison of the amino acid residues in the active site of pjDHFR and human DHFR (hDHFR) revealed prominent amino acid differences which could be exploited to structurally design potent and selective pjDHFR inhibitors. Molecular modeling followed by enzyme assays of the compounds revealed 15 as the best compound of the series with an IC 50 of 80 nM and 28-fold selectivity for inhibiting pjDHFR over hDHFR. Compound 15 serves as the lead analog for further structural variations to afford more potent and selective pjDHFR inhibitors. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is one of the most serious complications of diabetes worldwide. It is depicted as the leading cause of end-stage renal disease. Oxidative stress plays a key role in hyperglycemia-induced DN. The preparation and characterization of novel mono-, di-, and trisubstituted- s -triazines endowed with uracil and/or thymine are described in this paper. The synthesis of the title compounds was realized through selective nucleophilic substitution reactions of cyanuric chloride with the corresponding hydrazide nucleobases. In this study, we assessed the effects of these derivatives on the progression of diabetic nephropathy. Our results show that trisubstituted- s -triazines endowed with acylhydrazides attenuate high-glucose induced glomerular mesangial cells proliferation and matrix protein accumulation in vitro. Notably, these derivatives also display anti-oxidative properties. This suggests that the novel trisubstituted- s -triazine derivatives provide renal protection through a reactive oxygen species (ROS)-dependent mechanism. Our data provide evidence that these derivatives may serve as potential therapeutic candidates in the treatment of DN. [ABSTRACT FROM AUTHOR]

[Display omitted] In this study, a series of nitric oxide (NO) -releasing 5-cyano-6-phenyl-2, 4-disubstituted pyrimidine derivatives were designed and synthesized. In the in vitro biological evaluation, compound 24l exhibited optimal antiproliferative activity against MGC-803 cells with the IC 50 value of 0.95 µM, significantly better than that of the positive control 5-FU. In addition, preliminary mechanistic studies indicated that 24l inhibited colony formation and blocked MGC-803 cells in the G0/G1 phase. DAPI staining, reactive oxygen species and apoptosis assays demonstrated that 24l induced apoptosis of MGC-803 cells. Particularly, the most potent compound 24l produced the highest level of NO, and the antiproliferative activity was significantly reduced after preincubation with NO scavengers. In conclusion, compound 24l may be considered as a potential candidate antitumor agent. [ABSTRACT FROM AUTHOR]

[Display omitted] The clinical use of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer was limited by the drug resistance caused by EGFRC797S mutation. Therefore, in order to overcome the drug resistance, we designed and synthesized a series of 2-aminopyrimidine derivatives as EGFRC797S-TKIs. Among these compounds, compounds A5 and A13 showed significant anti-proliferative activity against the KC-0116 (EGFRdel19/T790M/C797S) cell line with high selectivity. A5 inhibited EGFR phosphorylation and induced apoptosis of KC-0116 cell, arrested KC-0116 cell at G2/M phase. Molecular docking results showed that A5 and brigatinib bind to EGFR in a similar pattern. In addition to forming two important hydrogen bonds with Met793 residue, A5 also formed a hydrogen bond with Lys745 residues, which may play an important role for the potent inhibitory activity against EGFRdel19/T790M/C797S. Based on these results, A5 turned out to be effective reversible EGFRC797S-TKIs which can be further developed. [ABSTRACT FROM AUTHOR]

Graphical abstract Compound 22 exhibited potent anti-proliferative effect in human tumor cell lines through targeting inhibition of Aurora kinases and disrupted spindle formation in HeLa cells. Highlights • Fifteen nitroxide labeled pyrimidines have been synthesized. • Most of target compounds showed potent anti-proliferative effect. • Compound 22 exhibited potent Aurora kinases inhibitory activities. • Compound 22 down-regulated the level of p-HisH3, TPX2, Eg5 and Bora. • Compound 22 disrupted spindle formation in HeLa cells. Abstract To find novel effective Aurora kinases inhibitors, a series of structurally interesting nitroxide labeled pyrimidines were synthesized and evaluated their anti-proliferative and Aurora kinases inhibitory activities. Among them, butyl 2-(3-((5-fluoro-2-((4-((1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)carbamoyl) phenyl) amino)pyrimidin-4-yl)amino)-1 H -pyrazol-5-yl)acetate (22) possessed the most potent anti-proliferative effects against four carcinoma cell lines with IC 50 values in range of 0.89–11.41 μM, and kinases inhibition against Aurora A and B with the IC 50 values were 9.3 and 2.8 nM, respectively. Furthermore, compound 22 blocked the phosphorylation of Aurora A (T288), Aurora B (Thr232) and HisH3, decreased the expression of proteins TPX2, Eg5 and Bora, as well as disrupted the mitotic spindle formation in HeLa cells. Molecular docking studies indicated that compound 22 well interact with both Aurora A and B. The results showed that compound 22 is a potential anticancer agent as promising pan-Aurora kinase inhibitor. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Synthesis of novel 7-amino-thiazolo[5,4- d ]pyrimidine derivatives is reported. • The compounds were tested for their affinity and potency at human adenosine receptors. • Docking studies at hA 1 , A 2A and A 3 adenosine receptor structures were performed. Abstract This paper describes the synthesis of novel 7-amino-thiazolo[5,4- d ]pyrimidines bearing different substituents at positions 2, 5 and 7 of the thiazolopyrimidine scaffold. The synthesized compounds 2 – 27 were evaluated in radioligand binding (A 1 , A 2A and A 3) and adenylyl cyclase activity (A 2B and A 2A) assays, in order to evaluate their affinity and potency at human adenosine receptor subtypes. The current study allowed us to support that affinity and selectivity of 7-amino-thiazolo[5,4- d ]pyrimidine derivatives towards the adenosine receptor subtypes can be modulated by the nature of the groups attached at positions 2, 5 and 7 of the bicyclic scaffold. To rationalize the hypothetical binding mode of the newly synthesized compounds, we also performed docking calculations in human A 2A , A 1 and A 3 structures. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Twenty-six new compounds were designed, synthesized and evaluated for their in vitro anti-HIV activity. • Five compounds exhibited good potency with EC 50(IIIB) values against wild-type HIV-1. • Molecule docking studies were also carried out to illustrate structure-affinity relationships of these compounds. Abstract A novel series of substituted piperazine-1-yl-pyrimidine derivatives were designed and synthesized as a new type of HIV-1 non-nucleoside inhibitors. Various N -substituted aromatic groups were incorporated into the piperazine ring through a simple and practical route to investigate the biological activity of these target compounds against wild-type and resistant strains of HIV-1. All of the target compounds were also evaluated as HIV-1 reverse transcriptase inhibitors in MT-4 cell cultures. The biological results showed that six of these compounds displayed inhibitory activities against the wild-type strain, among of which 7q and 7t were found to be the two most active analogues possessing EC 50 values of 31.50 μM and 3.36 μM, respectively. Molecular modeling studies of 7q provide valuable information for developing new anti-HIV-1 inhibitors. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Synthesis of pyrazolo[3,4- d ]pyrimidines derivatives endowed with nM K i values. • Best compound exerted good cytotoxicity activity against neuroblastoma cells. • Optimization process based on SAR study and ADME profile. Abstract The proto-oncogene c-Src is a non-receptor tyrosine kinase which is involved in the regulation of many cellular processes, such as differentiation, adhesion and survival. c-Src hyperactivation has been detected in many tumors, including neuroblastoma (NB), one of the major causes of death from neoplasia in infancy. We already reported a large family of pyrazolo[3,4- d ]pyrimidines active as c-Src inhibitors. Interestingly, some of these derivatives resulted also active on SH-SY5Y NB cell line. Herein, starting from our previous Free Energy Perturbation/Monte Carlo calculations, we report an optimization study which led to the identification of a new series of derivatives endowed with nanomolar K i values against c-Src, interesting antiproliferative activity on SH-SY5Y cells and a suitable ADME profile. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Novel series of covalent and selective pyridine and pyrimidine Btk inhibitors was discovered. • Compounds were based on the elaboration of a fragment that bound to the ATP active site of Btk. • Optimization led to compound 17 with excellent biochemical, cellular, and whole blood potency. • Compound 17 did not attain sufficient oral bioavailability in a low dose mouse pK study to be considered a lead compound. Abstract Btk is an attractive target for the treatment of a range of Bcell malignancies as well as several autoimmune diseases such as murine lupus and rheumatoid arthritis. Several covalent irreversible inhibitors of Btk are currently in development including ibrutinib which was approved for treatment of B-cell malignancies. Herein, we describe our efforts using X-ray guided structure based design (SBD) to identify a novel chemical series of covalent Btk inhibitors. The resulting pyridine carboxamides were potent and selective inhibitors of Btk having excellent enzymatic and cellular inhibitory activity. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Identification of a novel class of 4-sulfamoylnaphthyl series ALK2 inhibitor. • Excellent selectivity for ALK2 over ALK3 with additional overall kinome selectivity. • Key distinctive features identified in the ALK3 homology model to explain ALK2 vs ALK3 selectivity. Abstract The pyrazolo[1,5- a ]pyrimidine LDN-193189 is a potent inhibitor of activin receptor-like kinase 2 (ALK2) but is nonselective for highly homologous ALK3 and shows only modest kinome selectivity. Herein, we describe the discovery of a novel series of potent and selective ALK2 inhibitors by replacing the quinolinyl with a 4-(sulfamoyl)naphthyl, yielding ALK2 inhibitors that exhibit not only excellent discrimination versus ALK3 but also high kinome selectivity. In addition, the optimized compound 23 demonstrates good ADME and in vivo pharmacokinetic properties. [ABSTRACT FROM AUTHOR]

Chagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, affects 8–10 million people across the Latin American population and is responsible for around 12,500 deaths per annum. The current frontline treatments, benznidazole and nifurtimox, are associated with side effects and lack efficacy in the chronic stage of the disease, leading to an urgent need for new treatments. A high throughput screening campaign against the physiologically relevant intracellular form of the parasite identified a series of 2,4-diamino-6-methylpyrimidines. Demonstrating the series did not work through the anti-target Tc CYP51, and was generally cytocidal, confirmed its suitability for further development. This study reports the optimisation of selectivity and metabolic stability of the series and identification of a suitable lead for further optimisation. [ABSTRACT FROM AUTHOR]

The design, synthesis and biological evaluation of 4-substituted 5-methyl-furo[2,3- d ]pyrimidines is described. The Ullmann coupling of 5-methyl-furo[2,3- d ]pyrimidine with aryl iodides was successfully optimized to synthesize these analogs. Compounds 6 – 10 showed single-digit nanomolar inhibition of EGFR kinase. Compounds 1 and 6 – 10 inhibited VEGFR-2 kinase better than or equal to sunitinib. Compounds 1 and 3 – 10 were more potent inhibitors of PDGFR-β kinase than sunitinib. In addition, compounds 4 – 11 had higher potency in the CAM angiogenesis assay than sunitinib. Compound 1 showed in vivo efficacy in an A498 renal xenograft model in mice. Multiple RTK and tubulin inhibitory attributes of 1 , 4 , 6 and 8 indicates that these compounds may be valuable preclinical single agents targeting multiple intracellular targets. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) is essential for physiological functions of tissues and neovasculature. VEGFR signaling is associated with the progression of pathological angiogenesis in various types of malignancies, making it an attractive therapeutic target in cancer treatment. In the present work, we report the synthesis of 1,4-disubstituted 1,2,3-triazoles and 1,2,4-triazolo[1, 5- a ]pyrimidine derivatives via copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and screened for their anticancer activity against MCF7 cells. We identified 1-(2′-ethoxy-4′-fluoro-[1,1′-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole (EFT) as lead cytotoxic agent against MCF7 cell lines with an IC 50 value of 1.69 µM. Further evaluation revealed that EFT induces cytotoxicity on Ishikawa, MDA-MB-231 and BT474 cells with IC 50 values of 1.97, 4.81 and 4.08 µM respectively. However, EFT did not induce cytotoxicity in normal lung epithelial (BEAS-2B) cells. Previous reports suggested that 1,2,3-triazoles are the inhibitors of VEGFR1 and therefore, we evaluated the effect of EFT on the expression of VEGFR1. The results demonstrated that EFT downregulates the expression of VEGFR1 in MCF7 cells. In summary, we identified a potent cytotoxic agent that imparts its antiproliferative activity by targeting VEGFR1 in breast cancer cells. The novel compound could serve as a lead structure in developing VEGFR1 inhibitors. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel inhibitors of microtubule protein polymerization targeting the colchicine site were designed and synthesized. • K10 exhibited nanomolar anti-proliferative efficacies with IC 50 values of 0.07–0.80 μM against four cancer cell lines. • K10 caused cycle arrest and apoptosis and inhibit tubulin polymerization by binding to the colchicine site. • K10 inhibited the migration and invasion of HepG2 cells in a dose-dependent manner. A library of new pyrimidine analogs was designed and synthesized of these, compound K10 bearing a 1,4‑benzodioxane moiety and 3,4,5‑trimethoxyphenyl group, exhibiting the most potent activity, with IC 50 values of 0.07–0.80 μM against four cancer cell lines. Cellular-based mechanism studies elucidated that K10 inhibited microtubule polymerization, blocked the cell cycle at the G2/M phase, and eventually induced apoptosis of HepG2 cells. Additionally, K10 inhibited the migration and invasion of HepG2 cells in a dose-dependent manner. Overall, our work indicates that the tubulin polymerization inhibitor incorporating pyrimidine and the 3,4,5‑trimethoxyphenyl ring may deserve consideration for cancer therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • New pyrimidine arylthioacetamides were synthesized as potential antibacterials. • Two amides were more potent compared to the tuberculosis drug ethambutol. • One of the hit amides may selectively target cyclopropane mycolic acid synthase 1. • Promising azine-containing analogs of the hit amide were in silico discovered. The synthesis of 2-[(2-amino-6-methylpyrimidin-4-yl)sulfanyl]- N -arylacetamides 6a-j was encouraged by their antibacterial activity and drug-likeness predictions. Of the compounds, two bearing 4‑isopropylphenyl 6c and 2,5‑dichlorophenyl 6i moieties were found to be threefold more potent than the first-line tuberculosis drug ethambutol. A molecular docking study revealed that compound 6c may selectively bind to cyclopropane mycolic acid synthase 1, an enzyme essential for the construction of the tuberculosis bacteria cell wall. Keeping this in mind, a recently developed ligand-based virtual screening strategy combining the molecular similarity search and docking approaches was adopted to identify more potent analogs of the parent compound. As a result, a series of new ligands 18p-w with phenyl-substituted azinyl amide groups were in silico discovered. Due to their high binding affinities to the enzyme and improved toxicity profiles, the ligands are undoubtedly worth future synthetic efforts. [ABSTRACT FROM AUTHOR]

Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson’s disease. Herein we disclose the discovery of a 4-ethoxy-7 H -pyrrolo[2,3- d ]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7 , which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome. Moreover, compound 7 was able to penetrate into the CNS, and in vivo pharmacology studies revealed significant inhibition of Ser935 phosphorylation in the brain of both rats (30 and 100 mg/kg) and mice (45 mg/kg) following oral administration. [ABSTRACT FROM AUTHOR]

A series of thieno[2,3- d ]pyrimidine alkyne Mannich base derivatives ( 7a-e, 8a-e ) and thieno[2,3- d ]pyrimidine 1,3,4-oxadiazole derivatives ( 9a-e, 10a-e ) have been synthesized and evaluated for their neuroprotective and neurotoxicity activities where 9a, 10d displayed good neuroprotection 10.6 and 11.88 µg/mL respectively against the H 2 O 2 induced cell death at the EC 50 values and 9b , 9d showed respective toxic effects on PC12 cells at CC 50 86.12 and 94.16 µg/mL. Compounds 9a, 9e, 10a and 10b showed strong antibacterial activity against two gram positive ( S. aureus , B. subtilis ) and two gram-negative strains ( E. coli , P. aeruginosa ) and showed good binding affinities with C(30) carotenoid dehydrosqualene synthase, Gyrase A and LpxC. This is the first report for the demonstration of thieno[2,3-d] pyrimidine derivatives as promising neuroprotective agents against H 2 O 2 induced neurotoxicity on PC12 cells. [ABSTRACT FROM AUTHOR]

Microtubule-targeting agents are important tools in cancer treatment. Generating novel microtubule targeting agents with novel pharmacology could dramatically expand the utility of this class of drugs. Here we characterize the pharmacology of recently described small molecule microtubule polymerization inhibitors. Pharmacokinetic experiments show oral bioavailability through gastric absorption. In vitro assays designed to predict absorption, distribution, metabolism, and excretion (ADME) and safety reveal a scaffold that is metabolically stable, evades P-glycoprotein, does not inhibit CYP enzymes, occurs as a significant free fraction in serum, and has exceptionally high cellular permeability. Together with in vivo efficacy models, pharmacology supports further development as a treatment for solid tumors. [ABSTRACT FROM AUTHOR]

The development of a new series of apoptosis signal-regulating kinase 1 (ASK1) inhibitors is described. Starting from purine, pyrimidine and quinazoline scaffolds identified by high throughput screening, we used tools of structure-based drug design to develop a series of potent kinase inhibitors, including 2-arylquinazoline derivatives 12 and 23 , with submicromolar inhibitory activities against ASK1. Kinetic analysis demonstrated that the 2-arylquinazoline scaffold ASK1 inhibitors described herein are ATP competitive. [ABSTRACT FROM AUTHOR]

BTK is a promising target for the treatment of multiple diseases such as B cell malignances, asthma, and rheumatoid arthritis. Here, we report the discovery of a series of novel pyrimidine analogs as potent, highly selective, non-covalent inhibitors of BTK. Compound 25d demonstrated higher affinity to an unactivated conformation of BTK that resulted in an excellent kinase selectivity. Compound 25d showed a good oral bioavailability in mice, and significantly inhibits the PCA reaction in mice. [ABSTRACT FROM AUTHOR]

Novel thienopyrimidine compounds 2 and 3 were discovered from high-throughput screening as Natriuretic Peptide Receptor A (NPR-A) agonists. Scaffold hopping of a thienopyrimidine ring to a quinazoline ring, introduction of the basic functional group and optimization of the substituent on the 6-position of the benzene ring of quinazoline led to improved agonistic activity. We discovered compound 48 , which showed potent agonistic activity for NPR-A with an EC 50 value of 0.073 μM, indicating 350-fold potency compared to the hit compound 3 . [ABSTRACT FROM AUTHOR]

Reported herein are efforts to profile 4-aryl- N -phenylpyrimidin-2-amines in terms of their anti-cancer activity towards non small-cell lung carcinoma (NSCLC) cells. We have synthesized new 4-aryl- N -phenylpyrimidin-2-amines and assessed them in terms of their cytotoxicity (A549, NCI-H187, MCF7, Vero & KB) and physicochemical properties (logD 7.4 and solubility). 13f and 13c demonstrated potent anti-cancer activity in A549 cells (0.2 µM), compared to 0.4 μM for the NSCLC drug Doxorubicin. 13f also displayed low experimental logD 7.4 (2.9) and the best solubility (∼40 μM). Compounds 13b and 13d showed the best balance of A549 anti-cancer activity and selectivity. 13g showed good activity and selectivity comparable with the anti-cancer drug Doxorubicin. [ABSTRACT FROM AUTHOR]

Substituted 2-amino-7-((6-(4-(2-hydroxyethyl) piperazin-1-yl)-2-methylpyrimidin-4-yl)oxy)-4-phenyl-4H-chromene-3-carbonitriles and 2-amino-7-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)oxy)-4-phenyl-1,4-dihydroquinoline-3-carbonitriles were synthesized via an efficient multi-component one pot synthesis under mild conditions. These compounds 1 – 20 were evaluated against human breast cancer cell lines (MCF-7) and human embryonic kidney cells (HEK293) for cytotoxic activities. Among them, compounds 6 , 7 , 15 , 17 and 19 showed better anti-proliferative activities as (IC 50 value 48 ± 1.70 , 65 ± 1.13 , 92 ± 1.18 , 30 ± 1.17 and 16 ± 1.10 µM) than curcumin drug ( 48 ± 1.11 µM). Molecular docking was also performed with active compounds 6 , 7 and 15 against Bcl-2 protein which gave good binding affinity ( ΔG = −9.08, −8.29 and −7.70 kcal/mol) respectively. Furthermore, the structure-activity relationship (SAR) analysis revealed that the chromene and quinoline moieties, when attached with pyrimide and piperazine moieties, enhanced anti-proliferative activities. [ABSTRACT FROM AUTHOR]

Stimulation of cultured epithelial cells with scatter factor/hepatocyte growth factor (HGF) results in individual cells detaching and assuming a migratory and invasive phenotype. Epithelial scattering recapitulates cancer progression and studies have implicated HGF signaling as a driver of cancer metastasis. Inhibitors of HGF signaling have been proposed to act as anti-cancer agents. We previously screened a small molecule library for compounds that block HGF-induced epithelial scattering. Most hits identified in this screen exhibit anti-mitotic properties. Here we assess the biological mechanism of a compound that blocks HGF-induced scattering with limited anti-mitotic activity. Analogs of this compound have one of two distinct activities: inhibiting either cell migration or cell proliferation with cell cycle arrest in G2/M. Each activity bears unique structure–activity relationships. The mechanism of action of anti-mitotic compounds is by inhibition of microtubule polymerization; these compounds entropically and enthalpically bind tubulin in the colchicine binding site, generating a conformational change in the tubulin dimer. [ABSTRACT FROM AUTHOR]

We describe the discovery and optimization of a novel series of furo[3,2- d ]pyrimidines as G protein-coupled receptor 119 agonists. Agonistic activity of 4 (EC 50 = 129 nM) was improved by replacing the intramolecular hydrogen bond between the fluorine atom and the aniline hydrogen in the head moiety with a covalent C-C bond to enhance conformational restriction, which consequently gave a lead compound 12 (EC 50 = 53 nM). Optimized compound 26 , which was identified by the further optimization of 12 , exhibited potent activity (EC 50 = 42 nM) with improved clearance in liver microsomes and induced a 33% reduction in blood glucose area under the curve at a dose of 10 mg/kg in an oral glucose tolerance test in C57BL/6N mice. [ABSTRACT FROM AUTHOR]

PI3Kα/mTOR ATP-competitive inhibitors are considered as one of the promising molecularly targeted cancer therapeutics. Based on lead compound A from the literature, two similar series of 2-substituted-4-morpholino-pyrido[3,2- d ]pyrimidine and pyrido[2,3- d ]pyrimidine analogs were designed and synthesized as PI3Kα/mTOR dual inhibitors. Interestingly, most of the series gave excellent inhibition for both enzymes with IC 50 values ranging from single to double digit nM. Unlike many PI3Kα/mTOR dual inhibitors, our compounds displayed selectivity for PI3Kα. Based on its potent enzyme inhibitory activity, selectivity for PI3Kα and good therapeutic index in 2D cell culture viability assays, compound 4h was chosen to be evaluated in 3D culture for its IC 50 against MCF7 breast cancer cells as well as for docking studies with both enzymes. [ABSTRACT FROM AUTHOR]

Pyrazolo[3,4- d ]pyrimidine derivatives 1 – 5 , active as c-Src inhibitors, have been selected to be formulated as drug-loaded human serum albumin (HSA) nanoparticles, with the aim of improving their solubility and pharmacokinetic properties. The present study includes the optimization of a desolvation method-based procedure for preparing HSA nanoparticles. First, characterization by HPLC-MS and Dynamic Light Scattering (DLS) showed a good entrapment efficacy, a controllable particle size (between 100 and 200 nm) and an optimal stability over time, confirmed by an in vitro drug release assay. Then, 1 – 4 and the corresponding NPs were tested for their antiproliferative activity against neuroblastoma SH-SY5Y cell line. Notably, 3-NPs and 4-NPs were identified as the most promising formulation showing a profitable balance of stability, small size and a similar activity compared to the free drugs in cell-based assays. In addition, albumin formulations increase the solubility of pyrazolo[3,4- d ]pyrimidine avoiding the use of DMSO as solubilizing agent. [ABSTRACT FROM AUTHOR]

Herein we report the discovery of a series of new small molecule inhibitors of histone lysine demethylase 4D (KDM4D). Molecular docking was first performed to screen for new KDM4D inhibitors from various chemical databases. Two hit compounds were retrieved. Further structural optimization and structure-activity relationship (SAR) analysis were carried out to the more selective one, compound 2 , which led to the discovery of several new KDM4D inhibitors. Among them, compound 10r is the most potent one with an IC 50 value of 0.41 ± 0.03 μM against KDM4D. Overall, compound 10r could be taken as a good lead compound for further studies. [ABSTRACT FROM AUTHOR]

A facile two-step synthetic approach to fluorinated and non-fluorinated 5-aryl-4-(5-nitrofuran-2-yl)-pyrimidines from readily available 5-bromo-4-(furan-2-yl)pyrimidine has been developed. All synthesized compounds were screened in vitro for their antibacterial activities against twelve various bacterial strains. It is demonstrated that some of these compounds exhibited significant antibacterial activities against strains Neisseria gonorrhoeae and Staphylococcus aureus , comparable and even higher with that commercial drug Spectinomycin. [ABSTRACT FROM AUTHOR]

The quinazoline scaffold is the main part of many marketed EGFR inhibitors. Resistance developments against those inhibitors enforced the search for novel structural lead compounds. We developed novel benzo-anellated 4-benzylamine pyrrolopyrimidines with varied substitution patterns at both the molecular scaffold and the attached residue in the 4-position. The structure-dependent affinities towards EGFR are discussed and first nanomolar derivatives have been identified. Docking studies were carried out for EGFR in order to explore the potential binding mode of the novel inhibitors. As the receptor tyrosine kinase VEGFR2 recently gained an increasing interest as an upregulated signaling kinase in many solid tumors and in tumor metastasis we determined the affinity of our compounds to inhibit VEGFR2. So we identified novel dually acting EGFR and VEGFR2 inhibitors for which first anticancer screening data are reported. Those data indicate a stronger antiproliferative effect of a VEGFR2 inhibition compared to the EGFR inhibition. [ABSTRACT FROM AUTHOR]

This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M 4 antagonists, based on a 4,6-disubstituted core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at both human and rat M 4 (IC 50 s < 300 nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma K p,uu = 0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CL p = 5.37 mL/min/kg). Surprisingly, this series displayed pan -muscarinic antagonist activity across M 1–5 , despite the absence of the prototypical basic or quaternary amine moiety, thus offering a new chemotype from which to develop a next generation of pan -muscarinic antagonist agents. [ABSTRACT FROM AUTHOR]

[Display omitted] Mutation of FLT3 protein kinase is often associated with deregulated cell proliferation in acute myeloid leukemia and the inhibition of this kinase is a potential therapeutic strategy. We report a novel series of 3,5,7-trisubstituted pyrazolo[1,5- a ]pyrimidines prepared in an effort to study their biological activity particularly toward FLT3-ITD and its downstream regulators as well as toward CDK2 and CDK9. Derivative 10b was capable to strongly inhibit all kinases and its selectivity in FLT3-ITD expressing cell lines MOLM13 and MV4-11 was in line with FLT3-ITD inhibition. Further biochemical analyses and molecular docking confirmed FLT3 as a cellular target of 10b. [ABSTRACT FROM AUTHOR]

A series of pyrido[3,4- d ]pyrimidine derivatives were designed and synthesized. Compound 30 showed the most effective inhibitory effect on MGC-803 cells and induced apoptosis. [Display omitted] In order to find high-efficiency and low-toxic anti-tumor drugs, 29 pyrido[3,4- d ]pyrimidine compounds were designed, synthesized and evaluated by MTT assay in vitro. The results presented that most of the compounds had good antitumor activities, among which compound 30 had the best anti-tumor activity on MGC803 cells (IC 50 = 0.59 μM). Mechanistic studies exhibited that compound 30 inhibited migration of MGC803 and induced apoptosis. It was proved that compound 30 up-regulated expression of Bid and PARP, down-regulated expression of CycD1 by western blot experiments. This study indicated that compound 30 might be served as a lead agent for the treatment of human gastric cancers. [ABSTRACT FROM AUTHOR]

[Display omitted] Using small molecules to induce readthrough of premature termination codons is a promising therapeutic approach to treating genetic diseases and cancers caused by nonsense mutations, as evidenced by the widespread use of ataluren to treat nonsense mutation Duchene muscular dystrophy. Herein we describe a series of novel guanidino quinazoline and pyrimidine scaffolds that induce readthrough in both HDQ-P1 mammary carcinoma cells and mdx myotubes. Linkage of basic, tertiary amines with aliphatic, hydrophobic substituents to the terminal guanidine nitrogen of these scaffolds led to significant potency increases. Further potency gains were achieved by flanking the pyrimidine ring with hydrophobic substituents, inducing readthrough at concentrations as low as 120 nM and demonstrating the potential of these compounds to be used either in combination with ataluren or as stand-alone therapeutics. [ABSTRACT FROM AUTHOR]

[Display omitted] Based on EGFR-TKI Osimertinib as lead compound, a series of novel macrocyclic derivatives bearing aniline pyrimidine scaffolds were designed and synthesized by macrocyclization. Their structures were identified by 1H NMR, 13C NMR, 19F NMR and HRMS. The pharmacological activities of the target compounds were tested and the preliminary structure–activity relationship was discussed. Among them, 17-membered ring compound H1 displayed the best inhibitory activities against EGFRL858R/T790M and EGFRd746-750/T790M with IC 50 value of 2.92 nM and 0.34 nM, respectively. Exhilaratingly, 17-membered ring compound H7 possessed the most potent antiproliferative activity against BaF3-EGFRdel19/T790M cell lines (IC 50 = 0.035 µm), which rivaled that of Osimertinib (IC 50 = 0.033 µm). [ABSTRACT FROM AUTHOR]