Central Pyridine Ring Research Articles

Shining a light on Co(terpyridine)2 complexes: Unravelling the impact of ligand substitution at the 4’-position on optical and electrochemical properties through experimental and theoretical investigations

The present work involves synthesis, characterisation and study of absorption, emission and electrochemical properties of cobalt(III) bis-terpyridine complexes with varying substituent at the 4’-position of the central pyridine ring of terpyridine moiety. The work clearly demonstrates the modulation of the light harvesting window with changing the substituent viz. phenyl, naphthalenyl and thienyltriphenylamine. The naphthalenylterpyridine based cobalt complex shows considerable room temperature luminescence. Cyclic voltammetry data of the complexes reveal a reversible CoIII/II based redox feature. DFT based structure optimisations for all the complexes were performed at the B3LYP level using 6-31G (d,p) and LANL2DZ basis sets. TD-DFT based theoretical calculations were performed with the optimised structures to simulate the experimental absorption spectrum for all the complexes and hence the electronic transitions for the observed absorption peaks were assigned.

Does the Central Nitrogen Atom Make a Difference? A Comparison of Non‐Coordinating Pyridine and Benzene Spacers in Multitopic Ligands

AbstractIn metal coordination compounds of the divergent ligands 4,2′:6′,4“‐terpyridine and 3,2′:6′,3”‐terpyridine and their 4′‐functionalized derivatives, the central pyridine ring of the 4,2′:6′,4“‐terpyridine and 3,2′:6′,3”‐terpyridine domains is non‐coordinated. We present an overview of data from the Cambridge Structural Database to assess whether there are structural similarities between the coordination compounds of 4,2′:6′,4“‐tpy and 1,3‐di(pyridin‐4‐yl)benzene, and between 3,2′:6′,3”‐tpy and 1,3‐di(pyridin‐3‐yl)benzene. Based upon structurally characterized compounds, it emerges that the coordination chemistry of ligands including one or more 4,2′:6′,4“‐terpyridine or 3,2′:6′,3”‐terpyridine metal‐binding domains is more abundantly exemplified than that of corresponding ligands based upon 1,3‐di(pyridin‐4‐yl)benzene and 1,3‐di(pyridin‐3‐yl)benzene. We provide an overview of metallamacrocycles and cages, 1D‐coordination polymers and 2D‐ and 3D‐networks.

Effect of substituents on the 1O2 production and biological activity of (N^N^N)Pt(py) complexes.

Twelve (N^N^N)platinum pyridyl complexes, (N^N^N)Pt(pyF), were synthesised and investigated for their singlet oxygen generation and potential biological activities. They exhibited 1IL and 1MLCT absorption transitions at approximately 325 and 360 nm, identified through TD-DFT calculations. Luminescence was observed only in the L1-derived compounds in solution, with a dual emission with the main contribution of phosphorescence under deaerated conditions. Room temperature phosphorescence was detected in all solid-state cases. Electron-withdrawing substituents at specific positions (R1 and X) and the number of fluorine atoms in R2 were found to enhance the photosensitizing capabilities of these compounds. Biological assessments, including cytotoxicity and photocytotoxicity, were conducted to evaluate their potential as chemotherapeutic agents and photosensitizers. Complexes with chloro substitution in the N^N^N tridentate ligand of the central pyridine ring exhibited promising chemotherapeutic properties. Ancillary pyridine ring substitution became significant under irradiation conditions, with fluoromethylated substituents enhancing cytotoxicity. Complex 2-CF3 was the most efficient singlet oxygen producer and a highly effective photosensitizer. CHF2-substituted complexes also showed improved photosensitizing activity. DNA binding studies indicated moderate interactions with DNA, offering insights into potential biological applications.

Tuning aminopolycarboxylate chelators for efficient complexation of trivalent actinides

The complexation of trivalent lanthanides and minor actinides (Am3+, Cm3+, and Cf3+) by the acyclic aminopolycarboxylate chelators 6,6′-((ethane-1,2-diylbis–((carboxymethyl)azanediyl))bis–(methylene))dipicolinic acid (H4octapa) and 6,6'-((((4-(1-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)pyridine-2,6-diyl)bis–(methylene))bis–((carboxymethyl)azanediyl))bis–(methylene)) dipicolinic acid (H4pypa-peg) were studied using potentiometry, spectroscopy, competitive complexation liquid–liquid extraction, and ab initio molecular dynamics simulations. Two studied reagents are strong multidentate chelators, well-suited for applications seeking radiometal coordination for in-vivo delivery and f-element isolation. The previously reported H4octapa forms a compact coordination packet, while H4pypa-peg is less sterically constrained due to the presence of central pyridine ring. The solubility of H4octapa is limited in a non-complexing high ionic strength perchlorate media. However, the introduction of a polyethylene glycol group in H4pypa-peg increased the solubility without influencing its ability to complex the lanthanides and minor actinides in solution.

New 2-alkoxycyanopyridine derivatives as inhibitors of EGFR, HER2, and DHFR: Synthesis, anticancer evaluation, and molecular modeling studies

New series of substituted 2-alkoxycyanopyridine derivatives were synthesized and evaluated for their in vitro and in vivo anticancer activities. Comparing the evaluated activities against cancer cell lines to the broad-spectrum anticancer doxorubicin, and the kinase inhibitor sorafenib, compounds 3a, 4b, 4c, 7a, and 8d demonstrated superior anticancer efficacy with elevated safety profiles and selectivity indices, particularly against MCF7 breast cancer. For exploration of their mechanism of action, assays for inhibition of EGFR, HER2 kinase, and DHFR were performed. The promising synthesized compounds exhibited potent dual kinase EGFR/HER2 inhibitory activity with IC50values of 0.248/0.156 μM for 4b and 0.138/0.092 μM for 4c. Additionally, with IC50 values of 0.138 and 0.193 M, respectively, 4b and 4c had the greatest DHFR inhibitory activity that was comparable to methotrexate. In the MCF7 breast cancer cell line, they caused arrest at the S phase of the cell cycle and exhibited apoptosis induction activity. With restored caspase-3 immunoexpression, the anti-breast cancer assay performed in vivo of 4b and 4c demonstrated a substantial decrease in tumor volume. Results from molecular modeling were in agreement with biological assays proving the importance of the 3-caynopyridine, two substituted phenyl rings attached to central pyridine ring, and propoxy side chain moieties for binding with the receptors. As 4c works by inhibiting both EGFR/HER2 kinase, DHFR enzymes, in addition to cellular apoptosis, it could be viewed as a model of compounds possessing a multi-targeting anticancer activity. Collectively, compounds 4b and 4c might represent prototypes for further development as anticancer molecules.

Blue-emitting monochlorothiophenyl-pyridine-carbonitriles: Synthesis, structural analysis, and fluorescence properties

Three new pyridine-carbonitrile derivatives, namely, 6-(5-chlorothiophen-3-yl)-2-methyl-4-p-tolylpyridine-3-carbonitrile (1), 6-(5-chlorothiophen-3-yl)-4-(4-fluorophenyl)-2-methylpyridine-3-carbonitrile (2), and 6-(5-chlorothiophen-3-yl)-2-methyl-4-(naphthalen-4-yl)pyridine-3-carbonitrile (3), have been synthesized. The compounds were characterized using IR, 1H and 13C NMR, and HRMAS. The structures were confirmed by X-ray structural analysis for all three derivatives. The molecular structure consists of the central pyridine ring bearing four substituents: a monochlorothiophene ring, a methyl group, a carbonitrile group and an aryl group. The crystal structure is dominated by aryl-aryl offset-face-to-face π···π stacking interactions. In addition, C—H···Cl [in (1)], C—H···N/F [in (2)], and C—H···N [in (3)] interactions are found as shape-complementary motifs. All interactions consolidate crystal supramolecularity. Photophysical measurements show fluorescence properties for derivatives (1)–(3). The derivatives were found to possess a blue emission in the range of λ = 366–390 nm. These findings can be useful for designing new compounds with improved properties for various applications, including optoelectronics, materials science, and chemical sensing.

Highly emissive tridentate fluorophores based on bis-imidazo[1,2-α]pyridine for deep-blue photoluminescence with CIE y ≤ 0.08

Imidazo[1,2-α]pyridine-based multifunctional derivatives have been widely utilized in pharmaceuticals, chemical sensing, bioimaging, optoelectronics, and other fields. Through incorporation of different substituents at the C4 position of central pyridine ring, nine tridentate imidazo[1,2-α]pyridine derivatives 4a-i have been synthesized and fully characterized. The influence of substituents on the luminescence of 4a-i was systematically investigated by spectroscopic methods, which was in accordance with density functional theory calculations and electrochemical measurement. In CH2Cl2, all compounds exhibited strong near-UV to deep-blue emission and retained CIE y coordinates ≤0.08, with maximum emission band located at 378–450 nm and photoluminescence quantum yields in the range of 15%–94%. Meanwhile, compound 4f exhibited a positive acidochromism in CH2Cl2 upon addition of TFA, accompanied with the dual change of colorimetric and fluorometric determination, indicating its potential application for the development of pH sensor. Moreover, the high decomposition temperatures of 4a-i ranging from 289 °C to 450 °C indicated that these compounds showed good thermal stability. On the basis of their excellent photophysical and thermal properties, the electroluminescence performance of 4f were further evaluated with a maximum EQE of 3.14% and CIE coordinate (0.16, 0.08), which could be utilized as promising novel blue organic light-emitting material.

In Silico Studies of Novel Vemurafenib Derivatives as BRAF Kinase Inhibitors

BRAF inhibitors have improved the treatment of advanced or metastatic melanoma in patients that harbor a BRAFT1799A mutation. Because of new insights into the role of aberrant glycosylation in drug resistance, we designed and studied three novel vemurafenib derivatives possessing pentose-associated aliphatic ligands—methyl-, ethyl-, and isopropyl-ketopentose moieties—as potent BRAFV600E kinase inhibitors. The geometries of these derivatives were optimized using the density functional theory method. Molecular dynamic simulations were performed to find interactions between the ligands and BRAFV600E kinase. Virtual screening was performed to assess the fate of derivatives and their systemic toxicity, genotoxicity, and carcinogenicity. The computational mapping of the studied ligand–BRAFV600E complexes indicated that the central pyrrole and pyridine rings of derivatives were located within the hydrophobic ATP-binding site of the BRAFV600E protein kinase, while the pentose ring and alkyl chains were mainly included in hydrogen bonding interactions. The isopropyl-ketopentose derivative was found to bind the BRAFV600E oncoprotein with more favorable energy interaction than vemurafenib. ADME-TOX in silico studies showed that the derivatives possessed some desirable pharmacokinetic and toxicologic properties. The present results open a new avenue to study the carbohydrate derivatives of vemurafenib as potent BRAFV600E kinase inhibitors to treat melanoma.

5-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-[[6-(trifluoromethyl)pyridin-3-yl]methyl]pyridin-2-amine Dihydrochloride Dihydrate

The dihydrochloride salt of pexidartinib was synthesized and the crystal structure of its dihydrate was determined from single crystal data. The asymmetric unit consists of one formula unit. In the pexidartinib molecule, the N atom of the central pyridine ring and the pyridine-N atom of the pyrrolopyridine group are both protonated. The pexidartinib molecule forms N–H···O and N–H···Cl interactions with neighboring water molecules and chloride ions, respectively. Water/chloride (O–H···Cl) and water/water (O–H···O) interactions are also observed. Collectively, these intermolecular interactions result in a complex H-bonded framework structure.

Hainanxylogranolides A–F: New Limonoids isolated from the seeds of Hainan mangrove plant Xylocarpus granatum

Six new limonoids, named hainanxylogranolides A–F (1–6), together with nineteen known ones (7–25) were isolated from the seeds of a Hainan mangrove Xylocarpus granatum. The structures of the new compounds were established by extensive NMR spectroscopic data combined with the DFT and TDDFT calculated electronic circular dichroism spectra. Hainanxylogranolide A (1) is the aromatic B-ring limonoid containing a central pyridine ring and a C-17 substituted γ(21)-hydroxybutenolide moiety. Hainanxylogranolide B (2) belongs to the small group of mexicanolides containing a C3–O–C8 bridge, whereas hainanxylogranolides C and D (3 and 4) are mexicanolides comprising a C1–O–C8 bridge. Compounds 9 and 25 posed obvious inhibition effect on the tube formation of HUVECs. There are only about 25% tube-like structures were observed at the concentration of 40.0 μM of compound 25. The antiviral activities of the isolates against herpes simplex virus-1 (HSV-1) and severe fever with thrombocytopenia syndrome virus (SFTSV) were tested in vitro. Compound 23 exhibited moderate anti-SFTSV activity with the IC50 value of 29.58 ± 0.73 μM. This is the first report of anti-angiogenic effect and anti-SFTSV activity of limonoids from the genus Xylocarpus.

Addressing Atropisomerism in the Development of Sotorasib, a Covalent Inhibitor of KRAS G12C: Structural, Analytical, and Synthetic Considerations.

ConspectusNearly a century after its first description, configurationally stable axial chirality remains a rare feature in marketed drugs. In the development of the KRASG12C inhibitor sotorasib (LUMAKRAS/LUMYKRAS), an axially chiral biaryl moiety proved a critical structural element in engaging a “cryptic” protein binding pocket and enhancing inhibitor potency. Restricted rotation about this axis of chirality gave rise to configurationally stable atropisomers that demonstrated a 10-fold difference in potency. The decision to develop sotorasib as a single-atropisomer drug gave rise to a range of analytical and synthetic challenges, whose resolution we review here.Assessing the configurational stability of differentially substituted biaryl units in early inhibitor candidates represented the first challenge to be overcome, as differing atropisomer stability profiles called for differing development strategies (e.g., as rapidly equilibrating rotamers vs as single atropisomers). We relied on a range of NMR, HPLC, and computational methods to assess atropisomer stability. Here, we describe the various variable-temperature NMR, time-course NMR, and chiral HPLC approaches used to assess the configurational stability of axially chiral bonds displaying a range of rotational barriers.As optimal engagement of the “cryptic” pocket of KRASG12C was ultimately achieved with a configurationally stable atropisomeric linkage, the second challenge to be overcome entailed preparing the preferred (M)-atropisomer of sotorasib on industrial scale. This synthetic challenge centered on the large-scale synthesis of an atropisomerically pure building block comprising the central azaquinazolinone and pyridine rings of sotorasib. We examined a range of strategies to prepare this compound as a single atropisomer: asymmetric catalysis, chiral chromatographic purification, and classical resolution. Although chiral liquid and simulated moving bed chromatography provided expedient access to initial multikilo supplies of this key intermediate, a classical resolution process was ultimately developed that proved significantly more efficient on metric-ton scale. To avoid discarding half of the material from this resolution, this process was subsequently refined to enable thermal recycling of the undesired atropisomer, providing an even more efficient commercial process that proved both robust and green.While the preparation of sotorasib as a single atropisomer significantly increased both the analytical and synthetic complexity of its development, the axially chiral biaryl linkage that gave rise to the atropisomerism of sotorasib proved a key design element in optimizing sotorasib’s binding to KRASG12C. It is hoped that this review will help in outlining the range of analytical techniques and synthetic strategies that can be brought to bear in addressing the challenges posed by such axially chiral compounds and that this account may provide helpful guidelines for future efforts aimed at the development of such single atropisomer, axially chiral pharmaceutical agents.

Structure activity relationships leading to the identification of the indirect activator of AMPK, R419

Using an in-cell AMPK activation assay, we have developed structure–activity relationships around a hit pyridine dicarboxamide 5 that resulted in 40 (R419). A particular focus was to retain the on-target potency while also improving microsomal stability and reducing off-target activities, including hERG inhibition. We were able to show that removing a tertiary amino group from the piperazine unit of hit compound 5 improved microsomal stability while hERG inhibition was improved by modifying the substitution of the central core pyridine ring. The SAR resulted in 40, which continues to maintain on-target potency. Compound 40 was able to activate AMPK in vivo after oral administration and showed efficacy in animal models investigating activation of AMPK as a therapy for glucose control (both db/db and DIO mouse models).

Molecular docking study of xylogranatins binding to glycogen synthase kinase-3β

ObjectiveThe mangrove tree Xylocarpus granatum J. Koenig (X. granatum) is a medicinal plant used to treat various diseases in several Asian countries. Many bioactive natural products have been isolated from the plants, particularly several groups of limonoids, including 18 xylogranatins (Xyl-A to R), all of which bear a furyl-δ-lactone core commonly found in limonoids. Based on a structural analogy with the limonoids obacunone and gedunin, we hypothesized that xylogranatins could target the enzyme glycogen synthase kinase-3β (GSK-3β), a major target for the treatment of neurodegenerative pathologies, viral infections, and cancers. MethodsWe investigated the binding of the 18 xylogranatins to GSK-3β using molecular docking in comparison with two known reference GSK-3β ATP-competitive inhibitors, LY2090314 and AR-A014418. For each compound bound to GSK-3β, the empirical energy of interaction (ΔE) was calculated and compared to that obtained with known GSK-3β inhibitors and limonoid triterpenes that target this enzyme. ResultsFive compounds were identified as potential GSK-3β binders, Xyl-A, –C, -J, –N, and –O, for which the calculated empirical ΔE was equivalent to that calculated using the best reference molecule AR-A014418. The best ligand is Xyl-C, which is known to have marked anticancer properties. Binding of Xyl-C to the ATP-binding pocket of GSK-3β positions the furyl-δ-lactone unit deep into the binding-site cavity. Other xylogranatin derivatives bearing a central pyridine ring or a compact polycyclic structure are much less adapted for GSK-3β binding. Structure-binding relationships are discussed. ConclusionGSK-3β may contribute to the anticancer effects of X. granatum extract. This study paves the way for the identification of other furyl-δ-lactone-containing limonoids as GSK-3β modulators.

Synthesis, characterization and investigation of photophysical and biological properties of Cu(II) and Zn(II) complexes of benzimidazole ligands

In this work, two benzimidazole ligands (L1 and L2) containing a central pyridine ring that have two alkylated (pentyl for L1 and hexyl for L2) benzimidazole units at the second and sixth positions were synthesized. Mononuclear Cu(II) and Zn(II) complexes with the general formulae of [ML(X)2] (where M: Cu(II) or Zn(II), L: L1 or L2 and X: NO3− or NCS−) were synthesized, and their structures were characterized by the spectroscopic and analytical methods. Moreover, Cu(II) complexes [CuL1(Bipy)](ClO4)2 and [CuL2(Bipy)](ClO4)2 (where Bipy: 2,2′‐bipyridine) were also prepared. The solid structures of complexes [CuL1(NCS)2, [CuL1(Bipy)](ClO4)2 and [CuL2(NO3)(EtOH)]NO3 were determined by single crystal X‐ray diffraction studies. The DNA binding properties of the ligands and their metal complexes were investigated by the spectrophotometric titrations. The compounds showed considerable DNA binding affinities. The structural variations and coordination geometry around the metal centre were found to affect the binding properties.

Wang-OSO3H catalyzed green synthesis of 2-arylamino-3-cyanopyridine derivatives under ultrasound: Their assessment as potential inhibitors of SIRT1

New approaches / strategies to develop potential anticancer agents are necessary not only to address the increasing incidences of cancer worldwide but also to overcome the multifaceted problem of drug resistance. SIRT1, the most widely studied among all the sirtuins plays an important role in cancer and is considered as a promising pharmacological target for this disease. A new framework based on 2-arylamino-3-cyanopyridine was designed and assessed in silico for the identification of new and potential inhibitors of SIRT1. Initially, docking of a series of representative molecules in silico not only indicated their encouraging interactions with SIRT1 but also suggested their potential selectivity towards this protein over SIRT2. The study also suggested that H-bonding with residues ASN346 and ALA262 and other interactions with residues PHE273, PHE297, ILE411, ILE347, HIS363, GLN345 etc were common for several of these molecules. Thus, a library of molecules based on the designed framework was constructed for further pharmacological studies. These molecules were accessed conveniently via the ultrasound assisted 4-component reaction of appropriate ketone, aldehyde, aromatic amine and malononitrile in aqueous media under open air. The sulphonic acid-functionalized Wang resin (Wang-OSO3H) was explored as a polymeric and recoverable acidic catalyst for this purpose. The catalyst was recovered and recycled for a number of times without significant loss of its catalytic activity. A range of 2-arylamino-3-cyanopyridine derivatives were prepared in good (82–91%) yields using this green reaction. In vitro evaluation of these pyridine derivatives against SIRT1 revealed encouraging inhibitory activities (> 50% inhibition) thereby corroborating the outcome of docking studies. Indeed, the compounds 5a, 5g and 5j identified as most promising in the in silico docking studies were also found to be the most active pyridine derivatives in this in vitro assay. The Structure-Activity-Relationship (SAR) study revealed that an aryl group at C-4 position of the central pyridine ring was preferred over the heteroaryl or alkyl moiety whereas an unsubstituted benzene ring was favored over a substituted one at the C-6 position. Similarly, an unsubstituted phenyl group appeared to be better than the substituted one for the arylamino moiety at C-2 position. The reason for lower activity for a particular molecule was also investigated via in silico studies. Overall, according to the in silico as well as in vitro studies the pyridine derivatives 5a, 5g and 5j appeared as most potent among the compounds tested that were found to be several fold more potent than the known pyridine based inhibitor nicotinamide.

Discovery of a 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amine derivative as a novel DNA intercalating topoisomerase IIα poison

Several anticancer agents have been developed and innovative approaches have been made toward cancer type-specific medicines for cancer treatment. As a continuous effort to develop potential chemotherapeutic agents, a novel series of 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amines containing amino groups, hydroxyphenyl and fluorine functionalities were designed and synthesized. The compounds were evaluated for topo IIα inhibitory and cytotoxicity against HCT15, and HeLa human cancer cell lines. Among synthesized thirty compounds, the majority exhibited strong topo IIα inhibition and anti-proliferation against HCT15 colorectal adenocarcinoma cell line. The structure-activity relationship study revealed that compounds with –CF3 and –OCF3 substituents at 4- position and 3′ or 4′-hydroxyphenyl at 2-position attached to the central pyridine ring displayed potent topo IIα and anti-proliferative activity in colorectal and cervix cancer cell line. In vitro studies provided the evidence that compounds 16, 19, 22, and 28 possess excellent topo IIα inhibition and antiproliferative activity. For a better understanding, topo IIα cleavage complex, EtBr displacement, KI quenching assays and molecular docking of compound 19 was performed and the results revealed the mode of action as a DNA intercalative topo IIα poison inhibitor. The results obtained from this study provide insight into the DNA binding mechanism of 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amines and alteration in topo IIα inhibitory and antiproliferative activity with modifications in the rigid structure.

4-Flourophenyl-substituted 5H-indeno[1,2-b]pyridinols with enhanced topoisomerase IIα inhibitory activity: Synthesis, biological evaluation, and structure–activity relationships

A series of fluorinated and hydroxylated 2,4-diphenyl indenopyridinols were designed and synthesized using l-proline-catalyzed and microwave-assisted synthetic methods for the development of new anticancer agents. Adriamycin and etoposide were used as reference compounds for the evaluation of topo IIα inhibitory and anti-proliferative activity of the synthesized compounds. Exploring the structure–activity relationships of 36 prepared compounds and biological results, most of the compounds with ortho- and para-fluorophenyl at 4-position of indenopyridinol ring displayed strong topo IIα inhibition. In addition, the majority of the ortho- and meta-fluorophenyl substituted compounds 1–24 displayed strong anti-proliferative activity against DU145 prostate cancer cell line compared to the positive controls. Interestingly, compound 4 possessing ortho-phenolic and ortho-fluorophenyl group at 2- and 4-position, respectively of the central pyridine ring showed high anti-proliferative activity (IC50 = 0.82 μM) against T47D human breast cancer cell line, while para-phenolic and para-fluorophenyl substituted compound 36 exhibited potent topo IIα inhibitory activity with 94.7% and 88.6% inhibition at 100 μM and 20 μM concentration, respectively. A systematic comparison between the results of this study and the previous study indicated that minor changes in the position of functional groups in the structure affect the topo IIα inhibitory activity and anti-proliferative activity of the compounds. The findings from this study will provide valuable information to the researchers working on the medicinal chemistry of topoisomerase IIα-targeted anticancer agents.

Crystal structure and Hirshfeld surface analysis of (Z)-2-amino-4-(2,6-di-chloro-phen-yl)-5-(1-hy-droxy-ethyl-idene)-6-oxo-1-phenyl-1,4,5,6-tetra-hydro-pyridine-3-carbo-nitrile.

The mol-ecular conformation of the title compound, C20H15Cl2N3O2, is stabilized by an intra-molecular O-H⋯O hydrogen bond, forming an S(6) ring motif. The central pyridine ring is almost planar [maximum deviation = 0.074 (3) Å]. It subtends dihedral angles of 86.10 (15) and 87.17 (14)°, respectively, with the phenyl and di-chloro-phenyl rings, which are at an angle of 21.28 (15)° to each other. The =C(-OH)CH3 group is coplanar. In the crystal, mol-ecules are linked by inter-molecular N-H⋯N and C-H⋯N hydrogen bonds, and N-H⋯π and C-H⋯π inter-actions, forming a three-dimensional network. The most important contributions to the crystal packing are from H⋯H (33.1%), C⋯H/H⋯C (22.5%), Cl⋯H/H⋯Cl (14.1%), O⋯H/H⋯O (11.9%) and N⋯H/H⋯N (9.7%) inter-actions.

Application of Vinamidinium Salt Chemistry for a Palladium Free Synthesis of Anti-Malarial MMV048: A "Bottom-Up" Approach.

MMV390048 (1) is a clinical compound under investigation for antimalarial activity. A new synthetic route was developed which couples two aromatic fragments while forming the central pyridine ring over two steps. This sequence takes advantage of raw materials used in the existing etoricoxib supply chain and eliminates the need for palladium catalysts, which were projected to be major cost-drivers.

Supramolecular association and quantification of intermolecular interactions of 4′-functionalized 2,2′:6′,2″-terpyridines: Experimental observation and theoretical studies

Three versatile 4′-substituted 2,2′:6′,2″-terpyridine compounds (1–3) having different substitutions (4-ethoxyphenyl, 4-methoxyphenyl and pyridyl) at 4′-position of the central pyridine ring have been synthesized and structurally characterized. Three representative crystal structures have been determined through single crystal X-ray diffraction analysis. X-ray crystallography revels that the structures are stabilized through C–H···π and π–π stacking interactions. In the solid-state, the supramolecular assemblies of the title compounds have been explored in detail. Compounds (1) and (3) exhibits both C–H···π and π–π interactions in building supramolecular assemblies whereas compound (2) exhibit π–π interaction only. All the intermolecular interactions that are involved within the structures are quantified through Hirshfeld surface analyses. The weak noncovalent interactions that played significant role in building supramolecular assemblies are further characterized by Bader's theory of ‘atoms-in-molecules’ (AIM). Finally, the supramolecular networks are characterized by theoretical ‘Noncovalent Interaction’ (NCI) plot index.The supramolecular solid-state frameworks of three 4′-functionalized 2,2′:6′,2″-terpyridine derivatives have been quantified which are further characterized theoretically by the Bader's theory of ‘atoms-in-molecules’(AIM) and ‘noncovalent interaction’ (NCI) plot index.