Effect of an Autotaxin Inhibitor, 2-(4-Chlorophenyl)-7-methyl-8-pentylimidazo[1,2-] Pyrimidin-5(8)-one (CBT-295), on Bile Duct Ligation-Induced Chronic Liver Disease and Associated Hepatic Encephalopathy in Rats.

The role of autotaxin (ATX)-lysophosphatidic acid (LPA) is yet to be explored in the context of liver cirrhosis and associated encephalopathy. Our objective of this study was to evaluate the role of an ATX inhibitor in biliary cirrhosis and associated hepatic encephalopathy in rats. The preliminary investigation revealed significant impairment in liver function, which eventually led to the development of hepatic encephalopathy.

Copper(II)-catalyzed, site-selective C(sp)-H amination using 8-aminoimidazo[1,2-]pyridine (8-AIP) as a directing group.

An efficient copper(II)-catalyzed regioselective C(sp)-H amination of arenes/heteroarenes has been developed with the assistance of 8-AIP (8-aminoimidazo[1,2-]pyridine) as an efficacious 6,5-fused bicyclic removable chelating auxiliary. This operationally simple approach is scalable, has a broad substrate scope, and is highly compatible with functional groups. Furthermore, post-diversification of the synthesized derivatives demonstrates the methodology's synthetic adaptability.

2-Pyridone-Directed Cu-Catalyzed General Method of C(sp)-H Activation for C-S, C-Se, and C-N Cross-Coupling: Easy Access to Aryl Thioethers, Selenide Ethers, and Sulfonamides and DFT Study.

We have demonstrated -substituted 2-pyridones as an ,-directing group for selective C(sp)-H-activated thiolation, selenylation, and sulfonamidation of ortho C-H bonds of benzamides. This method utilizes a cost-effective Cu(II)-salt catalyst instead of precious metal catalysts, achieving high yields, including gram-scale synthesis and excellent functional group tolerance. We applied this protocol to access 30 different compounds with high yields, demonstrating thiolation of fluorine-substituted benzamides as well.

Copper(II)-Mediated, Site-Selective C(sp)-H Sulfonamidation of 1-Naphthylamines.

An operationally simple and efficient protocol for copper(II)-mediated, picolinamido-directed C8-H sulfonamidation of 1-naphthylamine derivatives with various sulfonamides has been developed. Remarkably, this cross-dehydrogenative C-H/H-N coupling reaction exhibits a broad substrate scope with excellent functional group tolerance, is scalable, and enables an expeditious route to a library of unsymmetrical -arylated sulfonamides in good to excellent yields with exclusive site selectivity.

Identification of 5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine as novel orally bioavailable and metabolically stable antimalarial compound for further exploration.

Malaria continues to be a significant public health problem threatened by the emergence and spread of resistance to artemisinin-based combination therapies and marked half a million deaths in 2016. A new imidazopyridine chemotype has been envisaged through scaffold-hopping approach combined with docking studies for putative-binding interactions with Plasmodium falciparum phosphatidylinositol-4-kinase (PfPI4K) target. The docking results steered to the synthesis of compound 1 [5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine] followed by the in vitro screening for antiplasmodial activity and ADME-PK studies.

Structure-based discovery of (S)-2-amino-6-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione as low nanomolar, orally bioavailable autotaxin inhibitor.

Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure-based design, synthesis, and biological investigations revealing a potent and orally bioavailable ATX inhibitor 1. During the molecular docking and scoring studies within the ATX enzyme (PDB-ID: 4ZGA), the S-enantiomer (Gscore = -13.

Organocatalytic synthesis of (Het)biaryl scaffolds photoinduced intra/intermolecular C(sp)-H arylation by 2-pyridone derivatives.

A unique ,-bidentate ligand 6-oxo-1,6-dihydro-pyridone-2-carboxylic acid dimethylamide (L1) catalyzed direct C(sp)-H (intra/intermolecular) arylation of unactivated arenes has been developed to expedite access to (Het)biaryl scaffolds under UV-irradiation at room temperature. The protocol tolerated diverse functional groups and substitution patterns, affording the target products in moderate to excellent yields. Mechanistic investigations were also carried out to better understand the reaction pathway.

Palladium-catalyzed directed synthesis of -deuterated phenylacetic acid and analogues.

The synthesis of deuterium-labeled organic compounds is of increased interest, especially after the approval of deutetrabenazine by the Food and Drug Administration in 2014. The selective incorporation of deuterium in the place of hydrogen not only represents uniqueness in terms of a novel chemical class, but it also can improve the pharmacokinetic profiles of drug molecules while retaining potency and other parameters; thus, hydrogen-deuterium (H/D) exchange methods have been proven to be powerful additions in different areas of chemical science. In that regard, metal-catalyzed deuterium labeling via C-H activation mediated by a unique inbuilt directing group (DG) can play a significant role in the synthesis of novel deuterated chemical entities.

Asymmetric 1,4-Michael Addition in Aqueous Medium Using Hydrophobic Chiral Organocatalysts.

Organic transformations exclusively in water as an environmentally friendly and safe medium have drawn significant interest in the recent years. Moreover, transition metal-free synthesis of enantiopure molecules in water will have a great deal of attention as the system will mimic the natural enzymatic reactions. In this work, a new set of proline-derived hydrophobic organocatalysts have been synthesized and utilized for asymmetric Michael reactions in water as the sole reaction medium.

8-Aminoimidazo[1,2-]pyridine (AIP) directed Pd(II) catalysis: site-selective -C(sp)-H arylation in aqueous medium.

We demonstrate herein the first example of a palladium(ii) catalyzed regioselective ortho-C(sp2)-H arylation in aqueous medium (a sustainable solvent) utilizing 8-AIP (8-aminoimidazo[1,2-a]pyridine) as a promising and removable bidentate directing group/auxilliary. This newly developed protocol features a broad substrate scope with excellent functional group tolerance and enables an expeditious route to a library of unsymmetrical amides in good to excellent yields with exclusive site-selectivity.

Palladium catalyzed 8-aminoimidazo[1,2-]pyridine (AIP) directed selective β-C(sp)-H arylation.

Palladium catalyzed arylation of the inert β-C(sp2)-H bond of carboxylic acid derivatives is reported herein for the first time utilizing 8-aminoimidazo[1,2-a]pyridine (AIP) as an efficacious and new inbuilt 6,5-fused bicyclic removable directing group. This protocol is scalable, exhibits high levels of β-site selectivity and tolerates a broad spectrum of functional groups.

Synthesis of Functionalized Arylacetamido-2-pyridones through -C(sp)-H-Activated Installation of Olefins and Alkynes.

We have identified different N-substituted 2-pyridones as inbuilt directing groups for selective C-H-activated functionalization instead of deprotecting and/or throwing away the directing groups. A robust general method for external ligand-free Pd-catalyzed C(sp)-H olefination and alkynylation is established to access valuable phenylacetamido-2-pyridones. Diverse substrate scope has been demonstrated with different examples with high yield and gram-scale synthesis.

Additive-Free, Pd-Catalyzed 3-Amino-1-methyl-1-pyridin-2-one-Directed C(sp)-H Arylation and Methylation in Water.

Small molecules containing a 2-pyridone unit received much attention due to their significance in medicinal chemistry. In this regard, development of novel methodologies via metal-catalyzed carbon-carbon bond formation by chelation-assisted C-H activation will be an attractive method to achieve therapeutically important 2-pyridone analogues and arylated acid synthons. We report our studies on a Pd(II)-catalyzed coupling reaction between methyl, aryl, heteroaryl iodides, and sp carbons both at β- and γ-positions using 3-amino-1-methyl-1-pyridin-2-one as an efficient, built-in bidentate ,-directing group (DG) toward the synthesis of pyridone derivatives.

Pyrrolidine-Oxadiazolone Conjugates as Organocatalysts in Asymmetric Michael Reaction.

Pyrrolidine-oxadiazolone based organocatalysts are envisaged, synthesized, and utilized for asymmetric Michael reactions. Results of the investigations suggest that some of the catalysts are indeed efficient for stereoselective 1,4-conjugated Michael additions (dr: >97:3, ee up to 99%) in high chemical yields (up to 97%) often in short reaction time. As an extension, one enantiopure Michael adduct has been utilized to synthesize optically active octahydroindole.

3-Amino-1-methyl-1 H-pyridin-2-one-Directed Pd Catalysis: C(sp)-H Activated Diverse Arylation Reaction.

A new bidentate directing group, 3-amino-1-methyl-1 H-pyridin-2-one, is introduced to achieve a powerful Pd metallacycle for selective γ-C(sp)-H activation and arylation of aromatic and aliphatic carboxylic acid derivatives. The versatility of the directing group is validated for remote arylation of β-C(sp)-H, β-C(sp)-H, and γ-C(sp)-H to achieve therapeutically important 2-pyridone analogues and arylated acid synthons. The traceless removal of the directing group to retrieve the directing element and carboxylic acids makes this method more interesting.

Dihydrochelerythrine and its derivatives: Synthesis and their application as potential G-quadruplex DNA stabilizing agents.

A convenient route was envisaged toward the synthesis of dihydrochelerythrine (DHCHL), 4 by intramolecular Suzuki coupling of 2-bromo-N-(2-bromobenzyl)-naphthalen-1-amine derivative 5 via in situ generated arylborane. This compound was converted to (±)-6-acetonyldihydrochelerythrine (ADC), 3 which was then resolved by chiral prep-HPLC. Efficiency of DHCHL for the stabilization of promoter quadruplex DNA structures and a comparison study with the parent natural alkaloid chelerythrine (CHL), 1 was performed.

Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel 1-(1H-benzimidazol-6-yl)pyridin-2(1H)-one derivatives and design to avoid CYP3A4 time-dependent inhibition.

Melanin-concentrating hormone (MCH) is an attractive target for antiobesity agents, and numerous drug discovery programs are dedicated to finding small-molecule MCH receptor 1 (MCHR1) antagonists. We recently reported novel pyridine-2(1H)-ones as aliphatic amine-free MCHR1 antagonists that structurally featured an imidazo[1,2-a]pyridine-based bicyclic motif. To investigate imidazopyridine variants with lower basicity and less potential to inhibit cytochrome P450 3A4 (CYP3A4), we designed pyridine-2(1H)-ones bearing various less basic bicyclic motifs.

Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure-Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives.

Aiming to discover melanin-concentrating hormone receptor 1 (MCHR1) antagonists with improved safety profiles, we hypothesized that the aliphatic amine employed in most antagonists reported to date could be removed if the bicyclic motif of the compound scaffold interacted with Asp123 and/or Tyr272 of MCHR1. We excluded aliphatic amines from our compound designs, with a cutoff value of pK(a) < 8, and explored aliphatic amine-free MCHR1 antagonists in a CNS-oriented chemical space limited by four descriptors (TPSA, ClogP, MW, and HBD count). Screening of novel bicyclic motifs with high intrinsic binding affinity for MCHR1 identified the imidazo[1,2-a]pyridine ring (represented in compounds 6a and 6b), and subsequent cyclization of the central aliphatic amide linkage led to the discovery of a potent, orally bioavailable MCHR1 antagonist 4-[(4-chlorobenzyl)oxy]-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one 10a.

Enhancement and inhibition by 2'-O-hydroxyethyl residues of gene targeting mediated by triple helix forming oligonucleotides.

Reagents that recognize and bind specific genomic sequences in living mammalian cells would have great potential for genetic manipulation, including gene knockout, strain construction, and gene therapy. Triple helix forming oligonucleotides (TFOs) bind specific sequences via the major groove, but pyrimidine motif TFOs are limited by their poor activity under physiological conditions. Base and sugar analogues that overcome many of these limitations have been described.