Design, synthesis, in-vitro antiproliferative activity and kinase profile of new picolinamide based 2-amido and ureido quinoline derivatives.

New 2-amido and ureido quinoline derivatives substituted with 2-N-methylamido-pyridin-4-yloxy group at the 5-position of quinoline (18 final compounds) have been designed and synthesized as anticancer sorafenib congeners. Among the synthesized derivatives, fourteen compounds were selected for evaluation of their antiproliferative activity over a panel of 60 cancer cell lines at a single dose concentration of 10 µM at National Cancer Institute (NCI, USA). Four compounds, 9b-d and 9f showed promising mean growth inhibitions and thus were further tested at five-dose testing mode to determine their IC50 values. The data revealed that 2,4-difluorophenyl (9b) and 4-chloro-3-trifluoromethylphenyl (9d) urea compounds are the most active derivatives with significant efficacies and superior potencies than sorafenib in 36 and 12 cancer cell lines, respectively, belonging particularly to renal carcinoma cell (RCC), ovarian, and non small cell lung cancer (NSCL). Compound 9b and 9d were found to be six and two times more potent than sorafenib against A498 RCC line, with IC50 values of 0.42 µM and 1.36 µM, respectively. Accordingly, compound 9d was screened over a panel of 41 oncogenic kinases at a single dose concentration of 10 µM to profile its kinase inhibitory activity. Interestingly, the compound showed highly selective inhibitory activities ( 81.8% and 96.3%) against BRAF(V600E) and C-RAF kinases with IC50 values of 316 nM and 61 nM, respectively. In addition, molecular docking, cell cycle analysis, compliance to Lipinski's rule of five, and in silico toxicity assessment have been reported.

ABL kinase inhibitory and antiproliferative activity of novel picolinamide based benzothiazoles.

A series of novel picolinamide based benzothiazoles (17 final compounds), targeting both wild-type and the most resistant T315I mutant of Bcr-Abl kinase, has been designed and synthesized. Moreover, a selected array (8 compounds) was evaluated for its antiproliferative activity over a panel of 60 cancer cell lines. Compound 5l was the most potent derivative against both native and T315I mutant ABL with IC50 values of 18.2 and 39.9nM, respectively, and showed highly selective inhibitory activity (89.8%) towards the Bcr-Abl dependent leukemia cell (K-562) at 10µM concentration. Significance of C6-oxypicolinamide moiety and SAR study for the C2 aliphatic side chain of benzothiazole are discussed in detail.

Synthesis and biological evaluation of isoxazoline derivatives as potent M1 muscarinic acetylcholine receptor agonists.

A series of azacyclic compounds substituted with isoxazole and 5-substituted isoxazolines were synthesized as acyclic modifications of the oxime class M1 mACh receptor agonist. Among them, 3-(tetrahydropyrin-3-yl)-5-(2-pyrrolodin-1-yl)isoxazoline compound 4f displayed potent and selective M1 mACh receptor agonist activity in the functional calcium mobilization assay (EC50=31 nM). Introduction of 2-pyrrolidinone and 3-tetrahydropyridine groups are pivotal to the high potency. Moreover, 4f was found to facilitate non-amyloidogenic amyloid precursor protein (APP) processing by significantly increasing ERK1/2 phosphorylation and sAPPα secretion, known disease-modifying effects related to M1 mAChR agonists in Alzheimer's disease (AD).

Synthesis and in vitro evaluation of the antitubercular and antibacterial activity of novel oxazolidinones bearing octahydrocyclopenta[c]pyrrol-2-yl moieties.

A novel series of oxazolidinone-class antimicrobial agents with 5-substituted octahydrocyclopenta[c]pyrrole moieties at the C-ring of linezolid and an acetamide or 1,2,3-triazole ring as the C-5 side chain of the oxazolidinone ring were prepared. The resulting series of compounds were evaluated for in vitro antimicrobial activity against Mycobacterium tuberculosis and a panel of clinically important resistant Gram-positive and -negative bacteria. Among them, endo-alcohol 2a and exo-alcohol 2b showed potent inhibitory activity against M. tuberculosis H37Rv, which was superior to that of linezolid. Several analogues in this series showed potent in vitro antibacterial activity against the clinically important vancomycin-resistant bacteria and showed similar or better potency against linezolid-resistant methicillin-resistant Staphylococcus aureus (MRSA) strains. The hydroxyl group in the azabicyclic C-ring interacted with the same hydrophobic pocket as linezolid based on a docking study. Selected compounds with high antimicrobial activity showed good human microsomal stability and low CYP isozyme and monoamine oxidase (MAO) inhibition.

Synthesis and biological evaluation of 1-(isoxazol-5-ylmethylaminoethyl)-4-phenyl tetrahydropyridine and piperidine derivatives as potent T-type calcium channel blockers with antinociceptive effect in a neuropathic pain model.

New tetrahydropyridinyl and piperidinyl ethylamine derivatives were designed with hypothetical mapping on pharmacophore model generated from ligand-based virtual screening. The designed compounds were synthesized, and their inhibitory activities on T-type calcium channel were assayed using FDSS and patch-clamp assay. Among them, compounds 7b and 10b showed potent T-type calcium current blocking activity against Ca(v)3.1 (α(1G)) and Ca(v)3.2 (α(1H)) channel simultaneously. With hERG and pharmacokinetics studies, compounds 7b and 10b were evaluated for the antinociceptive effect on rat model of neuropathic pain. They were significantly effective in decreasing the pain responses to mechanical and cold allodynia induced by spinal nerve ligation. These results suggest that modulation of α(1G) and α(1H) subtype T-type calcium channels may provide a promising approach for the treatment of neuropathic pain.

Alpha-fluorovinyl Weinreb amides and alpha-fluoroenones from a common fluorinated building block.

Synthesis and reactivity of N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfonyl)fluoroacetamide, a building block for Julia olefination, is reported. This reagent undergoes condensation reactions with aldehydes and cyclic ketones to give alpha-fluorovinyl Weinreb amides. Olefination reactions proceed under mild, DBU-mediated conditions, or in the presence of NaH. DBU-mediated condensations proceed with either E- or Z-selectivity, depending upon reaction conditions, whereas NaH-mediated reactions are > or = 98% Z-stereoselective. Conversion of the Weinreb amide moiety in N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfanyl)fluoroacetamide to ketones, followed by oxidation, resulted in another set of olefination reagents, namely (1,3-benzothiazol-2-ylsulfonyl)fluoromethyl phenyl and propyl ketones. In the presence of DBU, these compounds react with aldehydes tested to give alpha-fluoroenones with high Z-selectivity. The use of N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfanyl)fluoroacetamide as a common fluorinated intermediate in the synthesis of alpha-fluorovinyl Weinreb amides and alpha-fluoroenones has been demonstrated. Application of the Weinreb amide to alpha-fluoro allyl amine synthesis is also shown.

Quantitative structure activity relationship (QSAR) study of estrogen derivatives based on descriptors of energy and softness.

Quantum chemical interaction of estrogen derivatives with their receptor has been explored by using Klopman atomic softness. Four series of estrogen derivatives were taken from the literature and the structure of receptor (PDB code 1QKT) was obtained from the protein databank. It is proposed that three Lys, a His, a Tyr and a Cys residues are important for binding. The basic softness values (E(m)(double dagger)) and acidic softness values (E(n)(double dagger)) of all atoms of estrogen derivatives were evaluated. The required parameters for Klopman equation were taken from PM3 results. The highest E(n)(double dagger) values for each molecules and highest E(m)(double dagger) value for each residue were identified and Delta E(nm)(double dagger) has been derived using them. The lowest Delta E(nm)(double dagger) values were used in addition to Q(min) (highest negative charge), Delta H(f)(0) (heat of formation), E(T) (total energy), and E(E) (electronic energy). Multiple linear regression analysis was employed to correlate the variation of relative binding affinity values. The analyses show that Delta E(nm)(double dagger) values in combination with other descriptors provide significant correlation with relative binding affinity values. The result underscores that carbonyl oxygen of the receptor is important for interaction with estrogen derivatives. This model could be utilized to predict the binding affinity of a new compound of this series.

Pd-catalyzed C-C bond-forming reactions of thymidine mesitylene sulfonate.

Facile synthesis of C-4 aryl pyrimidinone nucleoside analogues from an easily prepared O4-arylsulfonate derivative of thymidine is reported. Two O4-arylsulfonylthymidine precursors, (4-methylphenyl)sulfonyl and (2,4,6-trimethylphenyl)sulfonyl, were prepared and analyzed for their stabilities. Of the two, the latter possessed suitable stability as well as reactivity for Pd-catalyzed C-C bond-forming reactions with a variety of arylboronic acids. These reactions at the C-4 position are nontrivial in comparison with similar reactions at the C-5 position of pyrimidine nucleosides, with hydrolysis of the arylsulfonate precursor being a competing reaction in some cases. There are pronounced solvent influences in these reactions, but successful reactions can be attained by careful control of conditions. Many reactions proceeded efficiently at room temperature, and electron-deficient arylboronic acids can also be cross-coupled under suitable conditions. Desilylation of these products was also nontrivial, and various conditions were tested. Finally, antiviral screening was performed with the C-4 aryl pyrimidinone nucleoside analogues, but none possessed any interesting activity. The study represents the first successful synthesis of C-4 aryl pyrimidinone nucleoside analogues by cross-coupling of arylboronic acids with an arylsulfonate derived from a pyrimidine nucleoside, as well as antiviral testing of this new class of compounds.

Morpholin-2-one derivatives as novel selective T-type Ca2+ channel blockers.

Morpholin-2-one-5-carboxamide derivatives were prepared by using the one-pot Ugi multicomponent reaction and evaluated for blocking effects on T- and N-type Ca(2+) channels. Among them, compound 5i produced the highest potency (IC(50)=0.45+/-0.02 microM), while compounds 5d, 5f, 5k, 5n, 5o, and 6m produced relatively high potency as well as selectivity on T-type Ca(2+) channels. These novel scaffolds showed potent and selective T-type Ca(2+) channel blocking activities.

Indium-mediated one-pot three-component reaction of aromatic amines, enol ethers, and allylic bromides.

[reaction: see text] A new and efficient indium-mediated one-pot three-component reaction for the synthesis of N-aryl-substituted homoallylamines from aromatic amines, enol ethers, and allylic bromides in THF at room temperature is described.

Stereoselective syntheses of rolliniastatin 1, rollimembrin, and membranacin.

A radical cyclization of beta-alkoxyvinyl sulfoxides-Pummerer rearrangement-allylation protocol was successfully applied to the synthesis of the threo/cis/threo/cis/erythro bis-oxolane moiety in rolliniastatin 1 (1), rollimembrin (2), and membranacin (3).

Stereoselection in radical cyclization of beta-alkoxyvinyl sulfoxides: synthesis of tetrahydrofuranyl allyl carbinols.

[reaction: see text] Tetrahydrofuranyl allyl carbinols may be prepared stereoselectively via radical cyclization of beta-alkoxyvinyl sulfoxides, Pummerer rearrangement, and reaction with allylstannane.

3,4-Dihydroquinazoline derivatives as novel selective T-type Ca2+ channel blockers.

For LVA T-type Ca2+ channel blockers, 3,4-dihydroquinazoline derivatives as new scaffolds were prepared and evaluated for the inhibitory activity against two members of the recombinant T-type Ca2+ channel family. Among them, 8a (KYS05001, IC50=0.9 microM) was nearly equipotent with mibefradil (IC50=0.84 microM) and inhibited LVA T-type Ca2+ channel with greater efficacy than HVA Ca2+ channel.

Indium-mediated reductive elimination of halohydrins.

Olefin formation has been successfully carried out by reductive elimination reactions of halohydrins with Pd(PPh(3))(4)/In/InCl(3) in aqueous media.

An efficient synthesis of 2,5-diketopiperazine derivatives by the Ugi four-center three-component reaction.

A facile synthetic approach to 2,5-diketopiperazines 4 by the Ugi four-center three-component reaction using commercially available dipeptides as a bifunctional component, aldehydes, and isocyanides was described.