2-Pyridone-Directed CuII-Catalyzed General Method of C(sp2)-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 N-substituted 2-pyridones as an N,O-directing group for selective C(sp2)-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. Density functional theory (DFT) calculations support the mechanism, including acetate-supported concerted metalation deprotonation (CMD) steps and the unique role of dimethyl sulfoxide (DMSO) solvent. The facile synthesis of pharmaceutically important sulfonamides and other compounds highlights the method's potential in chemistry and medicinal chemistry.

Copper(II)-Mediated, Site-Selective C(sp2)-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 N-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. Combined with potent antimalarial activity of compound 1 (Pf3D7 IC50  = 29 nM) with meager in vitro intrinsic clearance, moderate plasma-protein binding, and acceptable permeability, compound 1 displayed sustained exposure and high oral bioavailability in mice and can thus have the potential as next generation PI4K inhibitor for in vivo 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 = -13.168 kcal/mol) of the bound ligand PAT-494 scored better than its R-enantiomer (Gscore = -9.562 kcal/mol) which corroborated with the reported observation and analysis of the results suggested the scope of manipulation of the hydantoin substructure in PAT-494. Accordingly, the docking-based screening of a focused library of 10 compounds resulted in compound 1 as a better candidate for pharmacological studies. Compound 1 was synthesized from L-tryptophan and evaluated against ATX enzymatic activities with an IC50 of 7.6 and 24.6 nM in biochemical and functional assays, respectively. Further, ADME-PK studies divulged compound 1 as non-cytotoxic (19.02% cell growth inhibition at 20 µM in human embryonic kidney cells), metabolically stable against human liver microsomes (CLint  = 15.6 µl/min/mg; T1/2  = 113.2 min) with solubility of 4.82 µM and orally bioavailable, demonstrating its potential to be used for in vivo experiments.

Organocatalytic synthesis of (Het)biaryl scaffolds via photoinduced intra/intermolecular C(sp2)-H arylation by 2-pyridone derivatives.

A unique N,O-bidentate ligand 6-oxo-1,6-dihydro-pyridone-2-carboxylic acid dimethylamide (L1) catalyzed direct C(sp2)-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. Furthermore, the synthetic applicability of this unified approach has been showcased via the construction of biologically relevant 4-quinolone, tricyclic lactam and sultam derivatives.

Palladium-catalyzed directed synthesis of ortho-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. In this context, herein, we divulge our results relating to Pd(ii)-catalyzed deuterium incorporation (>97%) at the γ C(sp2)-position of pyridone-containing phenylacetic acid derivatives, where 3-amino-1-methyl-1H-pyridin-2-one (AMP) not only acts as an efficient N,O-directing group, but it also constitutes a part of the target molecules of medicinal importance. Our methodology, which has been optimized based on the effects of temperature, catalyst, time, and substrate scope, shows advantages over existing protocols, with non-selectivity or meager deuteration or the use of an expensive metal (catalytic or super stoichiometric) and a deuterated solvent, reported previously for the deuteration of phenylacetic acid and its derivatives. Moreover, towards our aim of synthesizing deuterium-labeled biologically relevant compounds, the gram scale synthesis of a deuterated analogue of biphenyl acetic acid (3), known to have activity against epileptic seizures, has also been successfully accomplished in high yields and with excellent isotope enrichment via implementing this protocol.

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. Among the various catalysts screened, the catalyst 1 is indeed efficient for stereoselective 1,4-conjugated Michael additions (dr: >97:3, ee up to >99.9%) resulting in high chemical yields (up to 95%) in a very short reaction time (1 h) at room temperature. This methodology provides a robust, green, and convenient protocol and can thus be an important addition to the arsenal of the asymmetric Michael addition reaction. Upon successful implementation, the present strategy also led to the formation of an optically active octahydroindole, the key component found in many natural products.

8-Aminoimidazo[1,2-a]pyridine (AIP) directed Pd(II) catalysis: site-selective ortho-C(sp2)-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-a]pyridine (AIP) directed selective ß-C(sp2)-H arylation.

Palladium catalyzed arylation of the inert ß-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 ß-site selectivity and tolerates a broad spectrum of functional groups.

Synthesis of Functionalized Arylacetamido-2-pyridones through ortho-C(sp2)-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 PdII-catalyzed C(sp2)-H olefination and alkynylation is established to access valuable phenylacetamido-2-pyridones. Diverse substrate scope has been demonstrated with 48 different examples with high yield and gram-scale synthesis. Adequate tolerance of valuable functional groups was also observed, such as olefins possessing esters, sulfone, amide, cyanide, and ketones, aromatic residues containing fluorine, chlorine, bromine, NO2, methyl, dimethyl, and methoxy, as well as 2-pyridone-N-bearing methyl, cyclopropyl methyl, cyclopentyl methyl, benzyl, phenyl, acetate, and acetamide groups, which smoothly produced the respective desired products. We used triisopropyl silane-substituted alkynes for the alkynylation reaction, which can easily be converted to several functional groups including terminal alkyne, heterocycle through click reaction, and others. Implementing our protocol, we have also demonstrated late-stage olefination and alkynylation of 2-pyridone, containing the CB2 agonist-type molecule with excellent yield. Considering N-substituted 2-pyridone acts as a biologically-active structural unit, this general method has the significance in terms of late-stage functionalization to access new molecular entities which can be employed in medicinal chemistry research through diverse C-H activation.

Additive-Free, Pd-Catalyzed 3-Amino-1-methyl-1H-pyridin-2-one-Directed C(sp2)-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 sp2 carbons both at ß- and γ-positions using 3-amino-1-methyl-1H-pyridin-2-one as an efficient, built-in bidentate N,O-directing group (DG) toward the synthesis of pyridone derivatives. The effect of temperature, solvent, reagent equivalence, and substrate has been investigated for this DG-mediated late-stage functionalization reactions along with the crystal structure of a selected analogue. Moreover, this DG has been successfully applied for ortho-selective C(sp2)-H activation in aqueous medium in high yields to demonstrate the practicability of this present methodology.

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 PdII Catalysis: C(sp3)-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 PdII metallacycle for selective γ-C(sp3)-H activation and arylation of aromatic and aliphatic carboxylic acid derivatives. The versatility of the directing group is validated for remote arylation of ß-C(sp3)-H, ß-C(sp2)-H, and γ-C(sp2)-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. A thorough investigation was carried out to assess the quadruplex binding affinity by using various biophysical and biochemical studies and the binding mode was explained by using molecular modeling and dynamics studies. Results clearly indicate that DHCHL is a strong G-quadruplex stabilizer with affinity similar to that of the parent alkaloid CHL. Compounds ADC and DHCHL were also screened against different human cancer cell lines. Among the cancer cells, (±)-ADC and its enantiomers showed varied (15-48%) inhibition against human colorectal cell line HCT116 and breast cancer cell line MDA-MB-231 albeit low enantio-specificity in the inhibitory effect; whereas DHCHL showed 30% inhibition against A431 cell line only, suggesting the compounds are indeed cancer tissue specific.

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. Among these, a lead compound 6a bearing a 1H-benzimidazole motif showed comparable binding affinity to MCHR1 to the corresponding imidazopyridine derivative 1. Optimization of 6a afforded a series of potent thiophene derivatives (6q-u); however, most of these were found to cause time-dependent inhibition (TDI) of CYP3A4. As bioactivation of thiophenes to form sulfoxide or epoxide species was considered to be a major cause of CYP3A4 TDI, we introduced electron withdrawing groups on the thiophene and found that a CF3 group on the ring or a Cl adjacent to the sulfur atom helped prevent CYP3A4 TDI. Consequently, 4-[(5-chlorothiophen-2-yl)methoxy]-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (6s) was identified as a potent MCHR1 antagonist without the risk of CYP3A4 TDI, which exhibited a promising safety profile including low CYP3A4 inhibition and exerted significant antiobesity effects in diet-induced obese F344 rats.

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. It exhibited low potential for hERG inhibition and phospholipidosis induction as well as sufficient brain concentration to exert antiobesity effects in diet-induced obese rats.

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. In particular, 2'-O-modifications influence sugar pucker and third strand conformation, and have been important to the development of bioactive TFOs. Here we have analyzed the impact of 2'-O-hydroxyethyl (2'-HE) substitutions, in combination with other 2' modifications. We prepared modified TFOs conjugated to psoralen and measured targeting activity in a gene knockout assay in cultured hamster cells. We find that 2'-HE residues enhance the bioactivity of TFOs containing 2'-O-methyl (2'-OMe) modifications, but reduce the bioactivity of TFOs containing, in addition, 2'-O-aminoethyl (2'-AE) residues.