Stereoselective Photoredox-Catalyzed Chlorotrifluoromethylation of Alkynes: Synthesis of Tetrasubstituted Alkenes

A new photoredox-catalyzed chlorotrifluoromethylation reaction of internal arylalkynes under mild conditions using visible light has been developed. The reactions proceed with high levels of regio- and stereoselectivity and utilize commercially available CF₃SO₂Cl as both the CF₃ and Cl source. In the mechanistic pathway for this process, generation of the CF₃ radical and chloride ion occurs by Ir­(ppy)₃-photocatalyzed reductive decomposition of CF₃SO₂Cl. The synthetically important trifluoromethyl-substituted vinyl chlorides produced in this process can be readily transformed to 1,1-bis-arylalkenes by using Suzuki coupling

3‑Aryl-1,2,4-oxadiazole Derivatives Active Against Human Rhinovirus

The human rhinovirus (hRV) is the causative agent of the common cold that often aggravates respiratory complications in patients with asthma or chronic obstructive pulmonary disease. The high rate of mutations and variety of serotypes are limiting the development of anti-hRV drugs, which emphasizes the need for the discovery of novel lead compounds. Previously, we identified antiviral compound <b>1</b> that we used here as the starting material for developing a novel compound series with high efficacy against hRV-A and -B. Improved metabolic stability was achieved by substituting an ester moiety with a 1,2,4-oxadiazole group. Specifically, compound <b>3k</b> exhibited a high efficacy against hRV-B14, hRV-A21, and hRV-A71, with EC₅₀ values of 66.0, 22.0, and 3.7 nM, respectively, and a relevant hepatic stability (59.6 and 40.7% compound remaining after 30 min in rat and human liver microsomes, respectively). An <i>in vivo</i> study demonstrated that <b>3k</b> possessed a desirable pharmacokinetic profile with low systemic clearance (0.158 L·h^–1·kg^–1) and modest oral bioavailability (27.8%). Hence, <b>3k</b> appears to be an interesting candidate for the development of antiviral lead compounds

Vicinal Difunctionalization of Alkenes: Chlorotrifluoromethylation with CF₃SO₂Cl by Photoredox Catalysis

Photoredox-catalyzed vicinal chlorotrifluoromethylation of alkene is described. In the presence of Ru­(Phen)₃Cl₂, CF₃SO₂Cl was used as a source for the CF₃ radical and chloride ion under visible light irradiation. Various terminal and internal alkenes were transformed to their vicinal chlorotrifluoromethylated derivatives. Biologically active compounds were applied under the condition to obtain desired products, suggesting that the method could be feasible for late-stage modification in drug discovery

Identification, Synthesis, and Evaluation of New Neuraminidase Inhibitors

High-throughput screening was performed on ∼6800 compounds to identify <b>KR-72039</b> as an inhibitor of H1N1 and H5N1 neuraminidases (NAs). Structure–activity relationship studies led to <b>3e</b>, which inhibited H5N1 NA with an IC₅₀ of 2.8 μM and blocked viral replication. Docking analysis shows that compounds bind to loop-430 around the NA active site. Compound <b>3l</b> additionally inhibited H7N9 NA, making it a dual inhibitor of N1- and N2-type NAs

A Novel Series of Highly Potent Small Molecule Inhibitors of Rhinovirus Replication

Human rhinoviruses (hRVs) are the main causative pathogen for common colds and are associated with the exacerbation of asthma. The wide variety in hRV serotypes has complicated the development of rhinovirus replication inhibitors. In the current investigation, we developed a novel series of benzothiophene derivatives and their analogues (<b>6</b>–<b>8</b>) that potently inhibit the replication of both hRV-A and hRV-B strains. Compound <b>6g</b> inhibited the replication of hRV-B14, A21, and A71, with respective EC₅₀ values of 0.083, 0.078, and 0.015 μM. The results of a time-of-addition study against hRV-B14 and hRV-A16 and resistant mutation analysis on hRV-B14 implied that <b>6g</b> acts at the early stage of the viral replication process, interacting with viral capsid protein. A molecular docking study suggested that <b>6g</b> has a capsid-binding mode similar to that of pleconaril. Finally, derivatives of <b>6</b> also displayed significant inhibition against poliovirus 3 (PV3) replication, implying their potential inhibitory activities against other enterovirus species

Chromogenic Tubular Polydiacetylenes from Topochemical Polymerization of Self-Assembled Macrocyclic Diacetylenes

Tubular materials formed by self-assembly of small organic molecules find great utility in chemical and material science. Conventional tubular structures often lack stability because noncovalent molecular interactions are responsible for their conformational integrities. Herein we report the development of covalently linked chromogenic organic nanotubes which are prepared by using topochemical polymerization of self-assembled macrocyclic diacetylenes (MCDAs). Crystal structures of five MCDAs having different diameters were elucidated, and four of these substances were transformed to tubular polydiacetylenes (PDA) by UV-induced polymerization. Surprisingly, MCDA-1 was found to self-assemble in stacks with a tilt angle of 62.1°, which significantly deviates from the optimal value for polymerization of 45°. This observation suggests that geometric parameters derived using linear diacetylene (DA) models might not be strictly applicable to polymerization of MCDA systems. Blue-phase PDAs obtained by polymerization of MCDA-1 and MCDA-3 have different thermochromic and solvatochromic properties, which enable them to be utilized for colorimetric differentiation of aromatic solvents including isomeric xylenes. The observations made and information obtained in this study should enhance the understanding and design of stimulus-responsive rigid organic nanotubes

Stimulus-Responsive Azobenzene Supramolecules: Fibers, Gels, and Hollow Spheres

Novel, stimulus-responsive supramolecular structures in the form of fibers, gels, and spheres, derived from an azobenzene-containing benzenetricarboxamide derivative, are described. Self-assembly of tris­(4-((<i>E</i>)-phenyldiazenyl)­phenyl)­benzene-1,3,5-tricarboxamide (<b>Azo-1</b>) in aqueous organic solvent systems results in solvent dependent generation of microfibers (aq DMSO), gels (aq DMF), and hollow spheres (aq THF). The results of a single crystal X-ray diffraction analysis of <b>Azo-1</b> (crystallized from a mixture of DMSO and H₂O) reveal that it possesses supramolecular columnar packing along the <i>b</i> axis. Data obtained from FTIR analysis and density functional theory (DFT) calculation suggest that multiple hydrogen bonding modes exist in the <b>Azo-1</b> fibers. UV irradiation of the microfibers, formed in aq DMSO, causes complete melting while regeneration of new fibers occurs upon visible light irradiation. In addition to this photoinduced and reversible phase transition, the <b>Azo-1</b> supramolecules display a reversible, fiber-to-sphere morphological transition upon exposure to pure DMSO or aq THF. The role played by amide hydrogen bonds in the morphological changes occurring in <b>Azo-1</b> is demonstrated by the behavior of the analogous, ester-containing tris­(4-((<i>E</i>)-phenyldiazenyl)­phenyl)­benzene-1,3,5-tricarboxylate (<b>Azo-2</b>) and by the hydrogen abstraction in the presence of fluoride anions

Stimulus-Responsive Azobenzene Supramolecules: Fibers, Gels, and Hollow Spheres

Novel, stimulus-responsive supramolecular structures in the form of fibers, gels, and spheres, derived from an azobenzene-containing benzenetricarboxamide derivative, are described. Self-assembly of tris­(4-((<i>E</i>)-phenyldiazenyl)­phenyl)­benzene-1,3,5-tricarboxamide (<b>Azo-1</b>) in aqueous organic solvent systems results in solvent dependent generation of microfibers (aq DMSO), gels (aq DMF), and hollow spheres (aq THF). The results of a single crystal X-ray diffraction analysis of <b>Azo-1</b> (crystallized from a mixture of DMSO and H₂O) reveal that it possesses supramolecular columnar packing along the <i>b</i> axis. Data obtained from FTIR analysis and density functional theory (DFT) calculation suggest that multiple hydrogen bonding modes exist in the <b>Azo-1</b> fibers. UV irradiation of the microfibers, formed in aq DMSO, causes complete melting while regeneration of new fibers occurs upon visible light irradiation. In addition to this photoinduced and reversible phase transition, the <b>Azo-1</b> supramolecules display a reversible, fiber-to-sphere morphological transition upon exposure to pure DMSO or aq THF. The role played by amide hydrogen bonds in the morphological changes occurring in <b>Azo-1</b> is demonstrated by the behavior of the analogous, ester-containing tris­(4-((<i>E</i>)-phenyldiazenyl)­phenyl)­benzene-1,3,5-tricarboxylate (<b>Azo-2</b>) and by the hydrogen abstraction in the presence of fluoride anions