Optimization of the Antiviral Potency and Lipophilicity of Halogenated 2,6‐Diarylpyridinamines as a Novel Class of HIV‐1 NNRTIS

Nineteen new halogenated diarylpyridinamine (DAPA) analogues modified at the phenoxy C‐ring were synthesized and evaluated for anti‐HIV activity and certain drug‐like properties. Ten compounds showed high anti‐HIV activity (EC₅₀<10 nM ). In particular, (E)‐6‐(2′′‐bromo‐4′′‐cyanovinyl‐6′′‐methoxy)phenoxy‐N²‐(4′‐cyanophenyl)pyridin‐2,3‐diamine ( 8 c ) displayed low‐nanomolar antiviral potency (3–7 nM ) against wild‐type and drug‐resistant viral strains bearing the E138K or K101E mutations, which are associated with resistance to rilvipirine ( 1 b ). Compound 8 c exhibited much lower resistance fold changes (RFC: 1.1–2.1) than 1 b (RFC: 11.8–13.0). Compound 8 c also exhibited better metabolic stability (in vitro half‐life) than 1 b in human liver microsomes, possessed low lipophilicity (clog D: 3.29; measured log P: 3.31), and had desirable lipophilic efficiency indices (LE>0.3, LLE>5, LELP<10). With balanced potency and drug‐like properties, 8 c merits further development as an anti‐HIV drug candidate.     

Design of gem‐Difluoro‐bis‐Tetrahydrofuran as P2 Ligand for HIV‐1 Protease Inhibitors to Improve Brain Penetration: Synthesis,X‐ray Studies,and Biological Evaluation

The structure‐based design, synthesis, biological evaluation, and X‐ray structural studies of fluorine‐containing HIV‐1 protease inhibitors are described. The synthesis of both enantiomers of the gem‐difluoro‐bis‐THF ligands was carried out in a stereoselective manner using a Reformatskii–Claisen reaction as the key step. Optically active ligands were converted into protease inhibitors. Two of these inhibitors, (3R,3aS,6aS)‐4,4‐difluorohexahydrofuro[2,3‐b]furan‐3‐yl(2S,3R)‐3‐hydroxy‐4‐((N‐isobutyl‐4‐methoxyphenyl)sulfonamido)‐1‐phenylbutan‐2‐yl) carbamate ( 3 ) and (3R,3aS,6aS)‐4,4‐difluorohexahydrofuro[2,3‐b]furan‐3‐yl(2S,3R)‐3‐hydroxy‐4‐((N‐isobutyl‐4‐aminophenyl)sulfonamido)phenylbutan‐2‐yl) carbamate ( 4 ), exhibited HIV‐1 protease inhibitory K_i values in the picomolar range. Both 3 and 4 showed very potent antiviral activity, with respective EC₅₀ values of 0.8 and 3.1 nM against the laboratory strain HIV‐1_LAI. The two inhibitors exhibited better lipophilicity profiles than darunavir, and also showed much improved blood–brain barrier permeability in an in vitro model. A high‐resolution X‐ray structure of inhibitor 4 in complex with HIV‐1 protease was determined, revealing that the fluorinated ligand makes extensive interactions with the S2 subsite of HIV‐1 protease, including hydrogen bonding interactions with the protease backbone atoms. Moreover, both fluorine atoms on the bis‐THF ligand formed strong interactions with the flap Gly 48 carbonyl oxygen atom.     

6,7‐Dimethoxy‐2‐{2‐[4‐(1H‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinolines as Superior Reversal Agents for P‐Glycoprotein‐Mediated Multidrug Resistance

P‐glycoprotein (P‐gp)‐mediated multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy. Based on our previous study, 17 novel compounds with the 6,7‐dimethoxy‐2‐{2‐[4‐(1H‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinoline scaffold were designed and synthesized. Among them, 2‐[(1‐{4‐[2‐(6,7‐dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)ethyl]phenyl}‐1H‐1,2,3‐triazol‐4‐yl)methoxy]‐N‐(p‐tolyl)benzamide (compound 7 h ) was identified as a potent modulator of P‐gp‐mediated MDR, with high potency (EC₅₀=127.5±9.1 nM ), low cytotoxicity (TI>784.3), and long duration (>24 h) in reversing doxorubicin (DOX) resistance in K562/A02 cells. Compound 7 h also enhanced the effects of other MDR‐related cytotoxic agents (paclitaxel, vinblastine, and daunorubicin), increased the accumulation of DOX and blocked P‐gp‐mediated rhodamine 123 efflux function in K562/A02 MDR cells. Moreover, 7 h did not have any effect on cytochrome (CYP3A4) activity. These results indicate that 7 h is a relatively safe modulator of P‐gp‐mediated MDR that has good potential for further development.     

1‐Arylsulfonyl‐5‐(N‐hydroxyacrylamide)indolines Histone Deacetylase Inhibitors Are Potent Cytokine Release Suppressors

A series of 1‐arylsulfonyl‐5‐(N‐hydroxyacrylamide)indolines ( 7 – 15 ) has been developed; the compounds exhibited potent histone deacetylase (HDAC) inhibitory activities. Notably, almost all of this series exhibited better HDAC‐inhibitory and antiproliferative activities than 3‐(1‐benzenesulfonyl‐1H‐indol‐5‐yl)‐N‐hydroxyacrylamide ( 6 ), as reported in a previous study. Among these compounds, 3‐[1‐(4‐methoxybenzenesulfonyl)‐2,3‐dihydro‐1H‐indol‐5‐yl]‐N‐hydroxyacrylamide ( 9 ) showed a two‐ to tenfold increase in activity compared to SAHA ( 1 ) in the suppression of lipopolysaccharide‐induced cytokine production. Compound 9 also caused a marked reduction in carrageenan‐induced acute inflammation in a rat model. Taken together, these data indicated that 1‐arylsulfonyl‐5‐(N‐hydroxyacrylamide)indolines HDAC inhibitors exhibit potent anti‐inflammatory activity.     

Pharmacophore‐Based Design of Novel Oxadiazoles as Selective Sphingosine‐1‐phosphate (S1P) Receptor Agonists with in vivo Efficacy

Sphingosine‐1‐phosphate (S1P) receptor agonists have shown promise as therapeutic agents for multiple sclerosis (MS) due to their regulatory roles within the immune, central nervous system, and cardiovascular system. Here, the design and optimization of novel [1,2,4]oxadiazole derivatives as selective S1P receptor agonists are described. The structure–activity relationship exploration was carried out on the three dominant segments of the series: modification of the polar head group (P), replacement of the oxadiazole linker (L) with different five‐membered heterocycles, and the use of diverse 2,2′‐disubstituted biphenyl moieties as the hydrophobic tail (H). All three segments have a significant impact on potency, S1P receptor subtype selectivity, physicochemical properties, and in vitro absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of the compounds. From these optimization studies, a selective S1P₁ agonist, N‐methyl‐N‐(4‐{5‐[2‐methyl‐2′‐(trifluoromethyl)biphenyl‐4‐yl]‐1,2,4‐oxadiazol‐3‐yl}benzyl)glycine ( 45 ), and a dual S1P_1,5 agonist, N‐methyl‐N‐(3‐{5‐[2′‐methyl‐2‐(trifluoromethyl)biphenyl‐4‐yl]‐1,2,4‐oxadiazol‐3‐yl}benzyl)glycine ( 49 ), emerged as frontrunners. These compounds distribute predominantly in lymph nodes and brain over plasma and induce long lasting decreases in lymphocyte count after oral administration. When evaluated head‐to‐head in an experimental autoimmune encephalomyelitis mouse model, together with the marketed drug fingolimod, a pan‐S1P receptor agonist, S1P_1,5 agonist 49 demonstrated comparable efficacy while S1P₁‐selective agonist 45 was less potent. Compound 49 is not a prodrug, and its improved property profile should translate into a safer treatment of relapsing forms of MS.     

Fluorophore‐Labeled Cyclooxygenase‐2 Inhibitors for the Imaging of Cyclooxygenase‐2 Overexpression in Cancer: Synthesis and Biological Studies

A group of cyclooxygenase‐2 (COX‐2)‐specific fluorescent cancer biomarkers were synthesized by linking the anti‐inflammatory drugs ibuprofen, (S)‐naproxen, and celecoxib to the 7‐nitrobenzofurazan (NBD) fluorophore. In vitro COX‐1/COX‐2 inhibition studies indicated that all of these fluorescent conjugates are COX‐2 inhibitors (IC₅₀ range: 0.19–23.0 μM ) with an appreciable COX‐2 selectivity index (SI≥4.3–444). In this study the celecoxib–NBD conjugate N‐(2‐((7‐nitrobenzo[c][1,2,5]oxadiazol‐4‐yl)amino)ethyl)‐4‐(5‐(p‐tolyl)‐3‐(trifluoromethyl)‐1H‐pyrazol‐1‐yl)benzenesulfonamide ( 14 ), which displayed the highest COX‐2 inhibitory potency and selectivity (COX‐2 IC₅₀=0.19 μM ; SI=443.6), was identified as an impending COX‐2‐specific biomarker for the fluorescence imaging of cancer using a COX‐2‐expressing human colon cancer cell line (HCA‐7).     

Synthesis and Biological Evaluation of Imidazo[2,1‐b][1,3,4]thiadiazole‐Linked Oxindoles as Potent Tubulin Polymerization Inhibitors

A series of imidazo[2,1‐b][1,3,4]thiadiazole‐linked oxindoles composed of an A, B, C and D ring system were synthesized and investigated for anti‐proliferative activity in various human cancer cell lines; test compounds were variously substituted at rings C and D. Among them, compounds 7 ((E)‐5‐fluoro‐3‐((6‐p‐tolyl‐2‐(3,4,5‐trimethoxyphenyl)‐imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one), 11 ((E)‐3‐((6‐p‐tolyl‐2‐(3,4,5‐trimethoxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one), and 15 ((E)‐6‐chloro‐3‐((6‐phenyl‐2‐(3,4,5‐trimethoxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one) exhibited potent anti‐proliferative activity. Treatment with these three compounds resulted in accumulation of cells in G₂/M phase, inhibition of tubulin assembly, and increased cyclin‐B1 protein levels. Compound 7 displayed potent cytotoxicity, with an IC₅₀ range of 1.1–1.6 μM , and inhibited tubulin polymerization with an IC₅₀ value (0.15 μM ) lower than that of combretastatin A‐4 (1.16 μM ). Docking studies reveal that compounds 7 and 11 bind with αAsn101, βThr179, and βCys241 in the colchicine binding site of tubulin.     

Organosoluble and light‐colored fluorinated polyimides based on 1,1‐bis[4‐(4‐amino‐2‐trifluoromethylphenoxy)phenyl]‐1‐phenylethane and various aromatic dianhydrides

To investigate the CF₃ group affecting the coloration and solubility of polyimides (PI), a novel fluorinated diamine 1,1‐bis[4‐(4‐amino‐2‐ trifluoromethylphenoxy)phenyl]‐1‐phenylethane (2) was prepared from 1,1‐ bis(4‐hydrophenyl)‐1‐phenylethan and 2‐chloro‐5‐nitrobenzotrifluoride. A series of light‐colored and soluble PI 5 were synthesized from 2 and various aromatic dianhydrides 3a–f using a standard two‐stage process with thermal 5a– f(H) and chemical 5a–f(C) imidization of poly(amic acid). The 5 series had inherent viscosities ranging from 0.55 to 0.98 dL/g. Most of 5a–f(H) were soluble in amide‐type solvents, such as N‐methyl‐2‐pyrrolidone (NMP), N,N‐ dimethylacetamide (DMAc), and N,N‐dimethylformamide (DMF), and even soluble in less polar solvents, such as m‐Cresol, Py, Dioxane, THF, and CH₂Cl₂, and the 5(C) series was soluble in all solvents. The GPC data of the 5a–f(C) indicated that the Mn and Mw values were in the range of 5.5–8.7 × 10⁴ and 8.5–10.6 × 10⁴, respectively, and the polydispersity index (PDI) Mw /Mn values were 1.2–1.5. The PI 5 series had excellent mechanical properties. The glass transition temperatures of the 5 series were in the range of 232–276°C, and the 10% weight loss temperatures were at 505–548 °C in nitrogen and 508–532 °C in air, respectively. They left more than 56% char yield at 800°C in nitrogen. These films had cutoff wavelengths between 356.5–411.5 nm, the b* values ranged from 5.0–71.1, the dielectric constants, were 3.11–3.43 (1MHz) and the moisture absorptions were in the range of 011–0.40%. Comparing 5 containing the analogous PI 6 series based on 1,1‐bis[4‐(4‐aminophenoxy)phenyl]‐1‐ phenylethane (BAPPE), the 5 series with the CF₃ group showed lower color intensity, dielectric constants, and better solubility. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 96: 2399–2412, 2005     

The Catalytic Asymmetric Addition of Diethylzinc to N‐(Diphenylphosphinoyl) Imines Catalyzed by Cu(OTf)2‐Chiral N‐(Binaphthyl‐2‐yl)thiophosphoramide Ligands

Chiral N‐(binaphthyl‐2‐yl)thiophosphoramide L7 [O,O‐diethyl 2′‐(ethylamino)‐1,1′‐binaphthyl‐2‐ylamidothiophosphate] prepared from the reaction of diethyl chlorothiophosphate with (R)‐(+)‐N‐ethyl‐1,1′‐binaphthyl‐2,2′‐diamine was used as a catalytic chiral ligand in the first Cu(OTf)₂‐promoted catalytic asymmetric addition of diethylzinc to N‐(diphenylphosphinoyl) imines in which ~85% ee can be realized.     

Synthesis and Biological Evaluation of 1‐Methyl‐1H‐indole–Pyrazoline Hybrids as Potential Tubulin Polymerization Inhibitors

A series of 1‐methyl‐1H‐indole–pyrazoline hybrids were designed, synthesized, and biologically evaluated as potential tubulin polymerization inhibitors. Among them, compound e19 [5‐(5‐bromo‐1‐methyl‐1H‐indol‐3‐yl)‐3‐(3,4,5‐trimethoxyphenyl)‐4,5‐dihydro‐1H‐pyrazole‐1‐carboxamide] showed the most potent inhibitory effect on tubulin assembly (IC₅₀=2.12 μm ) and in vitro growth inhibitory activity against a panel of four human cancer cell lines (IC₅₀ values of 0.21–0.31 μm ). Further studies confirmed that compound e19 can induce HeLa cell apoptosis, cause cell‐cycle arrest in G₂/M phase, and disrupt the cellular microtubule network. These studies, along with molecular docking and 3D‐QSAR modeling, provide an important basis for further optimization of compound e19 as a potential anticancer agent.     

Synthesis and photovoltaic device studies of azo‐linked low‐bandgap polymers

We report the synthesis of a series of new polymers containing azo linkage as a part of the main chain. The monomer 1,2‐bis(7‐bromo‐9,9‐dioctyl‐9H ‐fluoren‐2‐yl)diazene was synthesized using a precursor approach which avoids non‐selective bromination and was copolymerized with various donor or acceptor units. The homopolymer poly[1,2‐bis(9,9‐dioctyl‐9H ‐fluoren‐2‐yl)diazene] ( P1 ) as well as the copolymers poly[1‐(9,9‐dioctyl‐9H ‐fluoren‐2‐yl)‐2‐(9,9,9′,9′‐tetraoctyl‐9H ,9′H ‐[2,2′‐bifluoren]‐7‐yl)diazene] ( P2 ), poly[1‐(9,9‐dioctyl‐7‐(4‐octylthiophen‐2‐yl)‐9H ‐fluoren‐2‐yl)‐2‐(9,9‐dioctyl‐9H ‐fluoren‐2‐yl)diazene] ( P3 ) and poly[4‐(7‐((9,9‐dioctyl‐9H ‐fluoren‐2‐yl)diazenyl)‐9,9‐dioctyl‐9H ‐fluoren‐2‐yl)benzo[c ][1,2,5]thiadiazole] ( P4 ) were synthesized by Suzuki polymerization. The copolymers poly[1‐(7‐(4,4‐dioctyl‐4H ‐cyclopenta[1,2‐b :5,4‐b ′]dithiophen‐2‐yl)‐9,9‐dioctyl‐9H ‐fluoren‐2‐yl)‐2‐(9,9‐dioctyl‐9H ‐fluoren‐2‐yl)diazene] ( P5 ) and poly[4‐(5‐(7‐((9,9‐dioctyl‐9H ‐fluoren‐2‐yl)diazenyl)‐9,9‐dioctyl‐9H ‐fluoren‐2‐yl)‐4‐octylthiophen‐2‐yl)‐7‐(4‐octylthiophen‐2‐yl)benzo[c ][1,2,5]thiadiazole] ( P6 ) were synthesized by direct arylation polymerization reaction. Polymers synthesized using the direct arylation method show good molecular weight, with absorption maxima in the range 500 to 532 nm. P5 and P6 possess low optical bandgaps of 1.81 and 1.86 eV, respectively. A power conversion efficiency of 0.53% with open circuit voltage of 0.53 V, short circuit current density of 3.1 mA cm^?2 and fill factor of 29% has been achieved with C71‐PCBM as acceptor in bulk heterojunction solar cells fabricated with P5 as donor. © 2016 Society of Chemical Industry     

2‐Anilino‐3‐Aroylquinolines as Potent Tubulin Polymerization Inhibitors

Several 2‐anilino‐3‐aroylquinolines were designed, synthesized, and screened for their cytotoxic activity against five human cancer cell lines: HeLa, DU‐145, A549, MDA‐MB‐231, and MCF‐7. Their IC₅₀ values ranged from 0.77 to 23.6 μm . Among the series, compounds 7 f [(4‐fluorophenyl)(2‐((4‐fluorophenyl)amino)quinolin‐3‐yl)methanone] and 7 g [(4‐chlorophenyl)(2‐((4‐fluorophenyl)amino)quinolin‐3‐yl)methanone] showed remarkable antiproliferative activity against human lung cancer and prostate cancer cell lines. The IC₅₀ values for inhibiting tubulin polymerization were 2.24 and 2.10 μm for compounds 7 f and 7 g , respectively, and were much lower than that of the reference compound E7010 [N‐(2‐(4‐hydroxyphenylamino)pyridin‐3‐yl)‐4‐methoxybenzenesulfonamide]. Furthermore, flow cytometric analysis revealed that these compounds arrest the cell cycle at the G₂/M phase, leading to apoptosis. Apoptosis was also confirmed by mitochondrial membrane potential, Annexin V–FITC assay, and intracellular ROS generation. Immunohistochemistry, western blot, and tubulin polymerization assays showed that these compounds disrupt tubulin polymerization. Molecular docking studies revealed that these compounds bind efficiently to β‐tubulin at the colchicine binding site.     

Synthesis and characterization of optically active star‐shaped poly (N‐phenylmaleimide)s with a calixarene core

Two N‐phenylmaleimide derivatives bearing a chiral oxazoline group, N‐[o‐(4‐phenyl‐4,5‐dihydro‐1,3‐oxazol‐2‐yl)phenyl]maleimide [(R)‐PhOPMI] and N‐[o‐(4‐isopropyl‐4,5‐dihydro‐1,3‐oxazol‐2‐yl)phenyl]maleimide [(S)‐PrⁱOPMI], were polymerized using in situ generated calixarene‐based phenates as initiators to yield optically active polymers. The formation of star‐shaped architectures was strongly dependent on both polymerization conditions and calixarene moieties. In the case of polymerization conducted in toluene at 80–100 °C, the arm‐chain numbers achieved their respective maxima for the polymers with these multifunctional initiators. In contrast, the polymers obtained in polymerizations at lower temperature possessed fewer arm chains. The structure and chiroptical properties were investigated on the basis of ¹³C NMR, multiangular laser light scattering, gel permeation chromatography, and circular dichroism for the macromolecules with calixarene cores. Copyright © 2006 Society of Chemical Industry     

Synthese des 5‐[(Acetylhydrazono)‐(4‐chlorphenyl)‐methyl]thiophen‐2‐yl‐esters der Trifluormethansulfonsäure

The synthesis of 5‐[(acetylhydrazono)‐(4‐chlorophenyl)‐methyl]thiophen‐2‐yl ester of the trifluoromethanesulfonic acid ( 2a ) and its N‐methyl derivative 2b was attempted. Oxidation of 2‐thiophene boronic acid to 2‐hydroxythiophene and in situ reaction there of with triflic anhydride yielded the hitherto unknown thiophene‐2‐yl ester of the trifluormethanesulfonic acid ( 6 ) which was transformed under Friedel‐Crafts conditions into 5‐(4‐chlorobenzoyl)‐thiophene‐2‐yl ester of the trifluoromethanesulfonic acid ( 3 ). Reaction of 3 with acetyl hydrazine resulted in the formation of the title compound 2a , albeit in low yield. The conversion of N′‐[(5‐bromothiophen‐2‐yl)‐(4‐chlorophenyl)‐methylen]‐N‐methylhydrazide ( 4b ) via boronic acid into 5‐[(acetylmethylhydrazono)‐(4‐chlorophenyl)‐methyl]thiophen‐2‐yl ester of the trifluoromethanesulfonic acid ( 2b ) was not successful.     

Discovery of 7‐Aryl‐Substituted (1,5‐Naphthyridin‐4‐yl)ureas as Aurora Kinase Inhibitors

As part of our research projects to identify new chemical entities of biological interest, we developed a synthetic approach and the biological evaluation of (7‐aryl‐1,5‐naphthyridin‐4‐yl)ureas as a novel class of Aurora kinase inhibitors for the treatment of malignant diseases based on pathological cell proliferation. 1,5‐Naphthyridine derivatives showed excellent inhibitory activities toward Aurora kinases A and B, and the most active compound, 1‐cyclopropyl‐3‐[7‐(1‐methyl‐1H‐pyrazol‐4‐yl)‐1,5‐naphthyridin‐4‐yl]urea ( 49 ), displayed IC₅₀ values of 13 and 107 nM against Aurora kinases A and B, respectively. In addition, the selectivity toward a panel of seven cancer‐related protein kinases was highlighted. In vitro ADME properties were also determined in order to rationalize the difficulties in correlating antiproliferative activity with Aurora kinase inhibition. Finally, the good safety profile of these compounds imparts promising potential for their further development as anticancer agents.