Substituted 4-anilino-7-phenyl-3-quinolinecarbonitriles as Src kinase inhibitors

A series of substituted 4-anilino-7-phenyl-3-quinolinecarbonitriles has been prepared as Src kinase inhibitors. Optimal activity is observed with compounds that have basic amines attached via the para position of the 7-phenyl ring, and a hydrogen atom at the C-6 position. The best compounds are low nanomolar inhibitors of Src kinase, and have potent activity against Src-transformed fibroblast cells.     

QSAR studies on 4-anilino-3-quinolinecarbonitriles as Src kinase inhibitors using robust PCA and both linear and nonlinear models

Quantitative structure-activity relationship (QSAR) studies have been carried out on 4-anilino-3-quinolinecarbonitriles, a set of novel Src kinase inhibitors, with the aim of dissecting the structural requirements for Src inhibitory activities. After outlier identification using robust principal component analysis (robust PCA), linear models based on forward selection combined with multiple linear regression, (FS-MLR), enhanced replacement method followed by multiple linear regression (ERM) and a nonlinear model using support vector regression (SVR) were constructed and compared. All models were rigorously validated using leave-one-out cross-validation (LOOCV), 5-fold cross-validations (5-CV) and shuffling external validation (SEVs). ERM seems to outperform both FS-MLR and SVR evidenced by better prediction performance (n?=?35, R²_training?=?0.918, R²_pred?=?0.928). Robustness and predictive ability of ERM model were also evaluated. The generated QASR model revealed that the Src inhibitory activity of 4-anilino-3-quinolinecarbonitriles could be associated with the size of substituents in the C7 position and the steric hindrance effect. The results of the present study may be of great help in designing novel 4-anilino-3-quinolinecarbonitriles with more potent Src kinase inhibitory activity.     

Inhibition of Src kinase activity by 4-anilino-7-thienyl-3-quinolinecarbonitriles

Based on a screening lead from a yeast-based assay to identify Src family kinase inhibitors, a series of 4-anilino-7-thienyl-3-quinolinecarbonitriles was prepared. When the thiophene ring was substituted with a water-solubilizing group in a 2,5-, 3,5- or 2,4-pattern, potent inhibition of Src kinase activity was observed.     

Synthesis and biological evaluation of 2-anilino-4-substituted-7H-pyrrolopyrimidines as PDK1 inhibitors

PDK1, a biological target that has attracted a large amount of attention recently, is responsible for the positive regulation of the PI3K/Akt pathway that is often activated in a large number of human cancers. A series of second-generation 2-anilino-4-substituted-7H-pyrrolopyrimidines were synthesised by installation of various functions at the 4-position of the 7H-pyrrolopyrimidine scaffold. All compounds were screened against the isolated PDK1 enzyme and dose response analysis was obtained on the best compounds of the series.     

Synthesis and inhibition of Src kinase activity by 7-ethenyl and 7-ethynyl-4-anilino-3-quinolinecarbonitriles

A series of 7-ethynyl and 7-ethenyl-4-anilino-3-quinolinecarbonitriles were synthesized and tested for Src inhibition. Derivatives bearing a C-6 methoxy group and 2,4-dichloro-5-methoxyaniline at C-4 showed optimal inhibition of Src enzymatic and cellular activity. The ethenyl and ethynyl groups were incorporated at C-7 utilizing a Stille, Heck, or Sonogashira coupling reaction.     

4-Anilino-7-pyridyl-3-quinolinecarbonitriles as Src kinase inhibitors

A series of 4-anilino-7-pyridyl-3-quinolinecarbonitriles was prepared as Src kinase inhibitors. A systematic SAR study of substitutions on both the pyridine ring and the 3-quinolinecarbonitrile core established the requirements for optimal activity. The lead compound, 17, showed potent activity in both the Src enzyme assay and cell assays, and demonstrated in vivo anti-tumor activity in a xenograft model.     

Optimization of 7-alkene-3-quinolinecarbonitriles as Src kinase inhibitors

The 7-alkene-3-quinolinecarbonitrile 20, a potent inhibitor of Src enzymatic and cellular activity with IC₅₀ values of 2.1 and 58 nM, respectively, had comparable efficacy to bosutinib in a colon tumor xenograft study.     

Synthesis and evaluation of sphingoid analogs as inhibitors of sphingosine kinases

Sphingosine 1-phosphate (S1P), a product of sphingosine kinases (SphK), mediates diverse biological processes such as cell differentiation, proliferation, motility, and apoptosis. In an effort to search and identify specific inhibitors of human SphK, the inhibitory effects of synthetic sphingoid analogs on kinase activity were examined. Among the analogs tested, we found two, SG12 and SG14, that have specific inhibitory effects on hSphK2. N,N-Dimethylsphingosine (DMS), a well-known SphK inhibitor, displayed inhibitory effects for both SphK1 and SphK2, as well as protein kinase C. In contrast, SG12 and SG14 exhibited selective inhibitory effects on hSphK2. Furthermore, SG14 did not affect PKC. In isolated platelets, SG14 blocked the conversion of sphingosine into sphingosine 1-phosphate significantly. This is the first report on the identification of a hSphK2-specific inhibitor, which may provide a useful tool for studying the biological functions of hSphK2.     

MEK (MAPKK) inhibitors. Part 2: structure-activity relationships of 4-anilino-3-cyano-6,7-dialkoxyquinolines

A series of 4-anilino-3-cyano-6,7-dialkoxyquinolines with different substituents attached to the 4-anilino group has been prepared that are potent MEK (MAP kinase kinase) inhibitors. The best activity is obtained when a phenyl or a thienyl group is attached to the para-position of the aniline through a hydrophobic linker, such as an oxygen, a sulfur, or a methylene group. The most active compounds show low nanomolar IC(50)'s against MEK (MAP kinase kinase), and have potent growth inhibitory activity in LoVo cells (human colon tumor line).     

Synthesis and biological evaluation of 6,7-disubstituted 4-aminopyrido[2,3-d]pyrimidines as adenosine kinase inhibitors

The synthesis and structure-activity relationship of a series of 6,7-disubstituted 4-aminopyrido[2,3-d]pyrimidines as novel non-nucleoside adenosine kinase inhibitors is described. A variety of substituents, primarily aryl, at the C6 and C7 positions of the pyridopyrimidine core were found to yield analogues that are potent inhibitors of adenosine kinase. In contrast to the 5,7-disubstituted and 5,6,7-trisubstituted pyridopyrimidine series, these analogues exhibited only modest potency to inhibit AK in intact cells.     

Synthesis, SAR studies, and pharmacological evaluation of 3-anilino-4-(3-indolyl) maleimides with conformationally restricted structure as orally bioavailable PKCbeta-selective inhibitors

Conformationally restricted 3-anilino-4-(3-indolyl)maleimide derivatives were designed and synthesized aiming at discovery of novel protein kinase Cbeta (PKCbeta)-selective inhibitors possessing oral bioavailability. Among them, compounds having a fused five-membered ring at the indole 1,2-position inhibited PKCbeta2 with IC50 of nM-order and showed good oral bioavailability. One of the most potent compounds was found to be PKCbeta-selective over other 6 isozymes and exhibited ameliorative effects in a rat diabetic retinopathy model via oral route.     

Synthesis and in vitro antiplasmodial evaluation of 4-anilino-2-trichloromethylquinazolines

To identify a new safe antiplasmodial molecular scaffold, an original series of 2-trichloromethylquinazolines, functionalized in position 4 by an alkyl- or arylamino substituent, was synthesized from 4-chloro-2-trichloromethylquinazoline 1, via a cheap, fast and efficient solvent-free operating procedure. Among the 40 molecules prepared, several exhibit a good profile with both a significant antiplasmodial activity on the W2 Plasmodium falciparum strain (IC₅₀ values: 0.4–2.2 μM) and a promising toxicological behavior regarding human cells (HepG2/W2 selectivity indexes: 40–83), compared to the antimalarial drug compounds chloroquine and doxycycline. The in vitro antitoxoplasmic and antileishmanial evaluations were conducted in parallel on the most active molecules, showing that these ones specifically display antiplasmodial properties.     

Synthesis and evaluation of novel dimethylpyridazine derivatives as hedgehog signaling pathway inhibitors

We report herein the design and synthesis of a series of structural modified dimethylpyridazine compounds as novel hedgehog signaling pathway inhibitors. The bicyclic phthalazine core and 4-methylamino-piperidine moiety of Taladegib were replaced with dimethylpyridazine and different azacycle building blocks, respectively. The in vitro Gli-luciferase assay results demonstrate that the new scaffold still retained potent inhibitory potency. Piperidin-4-amine moiety was found to be the best linker between pharmacophores dimethylpyridazine and fluorine substituted benzoyl group. Furthermore, the optimization of 1-methyl-1H-pyrazol and 4-fluoro-2-(trifluoromethyl)benzamide by different aliphatic or aromatic rings were also investigated and the SAR were described. Several new derivatives were found to show potent Hh signaling inhibitory activity with nanomolar IC₅₀ values. Among these compounds, compound 11c showed the highest inhibitory potency with an IC₅₀ value of 2.33?nM, which was comparable to the lead compound Taladegib. In vivo efficacy of 11c in a ptch^+/?p53^?/? mouse medulloblastoma allograft model also indicated encouraging results.     

Synthesis and evaluation of 4-triazolylflavans as new aromatase inhibitors

Aromatase is a target of pharmacological interest for the treatment of estrogen-dependent cancers. Azole derivatives such as letrozole or anastrozole have been developed for aromatase inhibition and are used for the treatment of breast tumors. In this paper, four 4-triazolylflavans were synthesized and were found to exhibit moderate to high inhibitory activity against aromatase.     

Synthesis and biological evaluation of benzamides and benzamidines as selective inhibitors of VEGFR tyrosine kinases

A series of benzamidines and benzamides was synthesized as selective inhibitors of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, and tested for inhibitory activity toward autophosphorylation by the enzyme assay. Selective inhibition of VEGFR-2 tyrosine kinase was observed in the salicylic amide 4e and the anthranilic amidine 5a, and their percent inhibitions of VEGFR-2 tyrosine kinase were 44-60% at a 10 microM concentration of compounds. The salicylic amide 4a showed inhibition of both VEGFR-1 and VEGFR-2 tyrosine kinases at a 10 microM concentration.     

Identification of 4-anilino-6-aminoquinazoline derivatives as potential MERS-CoV inhibitors

New therapies for treating coronaviruses are urgently needed. A series of 4-anilino-6-aminoquinazoline derivatives were synthesized and evaluated to show high anti-MERS-CoV activities. N⁴-(3-Chloro-4-fluorophenyl)-N⁶-(3-methoxybenzyl)quinazoline-4,6-diamine (1) has been identified in a random screen as a hit compound for inhibiting MERS-CoV infection. Throughout optimization process, compound 20 was found to exhibit high inhibitory effect (IC₅₀ = 0.157 μM, SI = 25) with no cytotoxicity and moderate in vivo PK properties.     

Synthesis and antiproliferative evaluation of certain 4-anilino-8-methoxy-2-phenylquinoline and 4-anilino-8-hydroxy-2-phenylquinoline derivatives

The present report describes the synthesis and antiproliferative evaluation of certain 4-anilino-8-methoxy-2-phenylquinoline and 4-anilino-8-hydroxy-2-phenylquinoline derivatives. The antiproliferative activity of 4'-COMe-substituted derivatives decreased in an order of 6-OMe (1, 3.89 microM) > 8-OMe (8, 10.47 microM) > 8-OH (9, 14.45 microM), indicating that the position of substitution at the quinoline ring is crucial. For 3'-COMe derivatives, the antiproliferative activity of 8-OH (11, 1.20 microM) is more potent than its 8-OMe counterpart (10, 8.91 microM), indicating that a H-bonding donating substituent is more favorable than that of a H-bonding accepting group. Comparison of 8-OH derivatives, the antiproliferative effect of COMe (11) is more potent than its oxime derivative (15a, 2.88 microM), which in turn is more potent than the methyloxime counterpart (15b, 5.50 microM). Compound 11 is especially active against the growth of certain solid cancer cells such as HCT-116 (colon cancer), MCF7, and MDA-MB-435 (breast cancer) with GI50 values of 0.07, <0.01, and <0.01 microM, respectively. Flow cytometric analyses revealed that growth inhibition by 11 and 15a was due to accumulation in S-phase. This result is interesting because 2-phenylquinolone derivatives have been reported to be antimitotic agents which induced cell cycle arrest in G2/M phase.     

Synthesis and evaluation of vitamin D3 analogues with C-11 modifications as inhibitors of Hedgehog signaling

Previous structure-activity relationship studies have provided potent and selective analogues of vitamin D3 as inhibitors of the Hedgehog (Hh) signaling pathway. These analogues contain both modified A- and seco-B ring motifs, and have been evaluated for anticancer therapeutic potential. To continue our studies on this scaffold, a new series of compounds were synthesized to explore additional interactions and spatial constraints. These compounds incorporate functional groups of varying size and hydrophobicity at the C-11 position. While large hydrophobic moieties (9c–e) resulted in significant loss of Hh inhibition, smaller or more flexible moieties (9a, 11) maintain anti-Hh activity. These results call for additional and continued studies to identify the binding pocket to better understand these structure-activity relationships.     

Design and synthesis of 7-alkoxy-4-heteroarylamino-3-quinolinecarbonitriles as dual inhibitors of c-Src kinase and nitric oxide synthase

Because both c-Src and iNOS are key regulatory enzymes in tumorigenesis, a new series of 4-heteroarylamino-3-quinolinecarbonitriles as potent dual inhibitors of both enzymes were designed, prepared, and evaluated for blocking multiple signaling pathways in cancer therapy. All compounds were evaluated by two related enzyme inhibition assays and an anti-proliferation assay in vitro. The results showed that most compounds could inhibit both enzymes, and several of them showed potent inhibition activity against different cancer cell lines. The best compound 20 (CPU-Y020) showed the IC(50) values of 6.58 and 7.61microM toward colon cancer HT-29 and liver cancer HepG2 cell lines.     

Synthesis and biological evaluation of 4'-(6,7-disubstituted-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-biphenyl-4-ol as potent Chk1 inhibitors

A new series of potent tricyclic pyrazole-based Chk1 inhibitors are described. Analogues disubstituted on the 6- and 7-positions show improved Chk1 inhibition potency compared with analogues with a single substituent on either the 6- or 7-position. Based on the lead compound 4'-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-biphenyl-4-ol (2), detailed SAR studies on the 6- and 7-positions were performed. 3'-morpholin-4'-yl-propoxy, pyridin-4'-ylmethoxy, pyridin-3'-ylmethoxy, 2'-(5'-ethyl-pyridin-2'-yl)-ethoxy, pyridin-2'-ylethoxy, (6'-methyl-pyridin-2'-yl)-propoxyethoxy, 2',3'-dihydroxyl-1'-yl-propoxy, and tetrahydro-furan-3'-yloxy have been identified as the best groups on the 6-position when the 7-position is substituted with methoxyl group. Pyridin-2'-ylmethoxy and pyridin-3'-ylmethoxy have been identified as the best substituents at the 7-position while the 6-position bearing methoxyl group. These compounds significantly potentiate the cytotoxicity of DNA-damaging antitumor agents in a cell-based assay and efficiently abrogate the doxorubicin-induced G2/M and the camptothecin-induced S checkpoints, suggesting that their potent biological activities are mechanism-based through Chk1 inhibition.