Pyridyl Benzamides Research Articles

Quantitative Structure-Toxicity Relationship in Bioactive Molecules from a Conceptual DFT Perspective.

The preclinical drug discovery stage often requires a large amount of costly and time-consuming experiments using huge sets of chemical compounds. In the last few decades, this process has undergone significant improvements by the introduction of quantitative structure-activity relationship (QSAR) modelling that uses a certain percentage of experimental data to predict the biological activity/property of compounds with similar structural skeleton and/or containing a particular functional group(s). The use of machine learning tools along with it has made life even easier for pharmaceutical researchers. Here, we discuss the toxicity of certain sets of bioactive compounds towards Pimephales promelas and Tetrahymena pyriformis in terms of the global conceptual density functional theory (CDFT)-based descriptor, electrophilicity index (ω). We have compared the results with those obtained by using the commonly used hydrophobicity parameter, logP (where P is the n-octanol/water partition coefficient), considering the greater ease of computing the ω descriptor. The Human African trypanosomiasis (HAT) curing activity of 32 pyridyl benzamide derivatives is also studied against Tryphanosoma brucei. In this review article, we summarize these multiple linear regression (MLR)-based QSAR studies in terms of electrophilicity (ω, ω2) and hydrophobicity (logP, (logP)2) parameters.

The Synthesis of N-(Pyridin-2-yl)-Benzamides from Aminopyridine and Trans-Beta-Nitrostyrene by Fe2Ni-BDC Bimetallic Metal–Organic Frameworks

A bimetallic metal–organic framework material, which was generated by bridging iron (III) cations and nickel (II) cations with 1,4-Benzenedicarboxylic anions (Fe2Ni-BDC), was synthesized by a solvothermal approach using nickel (II) nitrate hexahydrate and iron (III) chloride hexahydrate as the mixed metal source and 1,4-Benzenedicarboxylic acid (H2BDC) as the organic ligand source. The structure of samples was determined by X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, and nitrogen physisorption measurements. The catalytic activity and recyclability of the Fe2Ni-BDC catalyst for the Michael addition amidation reaction of 2-aminopyridine and nitroolefins were estimated. The results illustrated that the Fe2Ni-BDC catalyst demonstrated good efficiency in the reaction under optimal conditions. Based on these results, a reaction mechanism was proposed. When the molar ratio of 2-aminopyridine and trans-β-nitrostyrene was 1:1, and the solvent was dichloromethane, the isolated yield of pyridyl benzamide reached 82%; at 80 °C over 24 h. The catalyst can be reused without a substantial reduction in catalytic activity with 77% yield after six times of reuse.

A new chemotype with promise against Trypanosoma cruzi

Pyridyl benzamide 2 is a potent inhibitor of Trypanosoma cruzi, but not other protozoan parasites, and had a selectivity-index of ≥10. The initial structure–activity relationship (SAR) indicates that benzamide and sulfonamide functional groups, and N-methylpiperazine and sterically unhindered 3-pyridyl substructures are required for high activity against T. cruzi. Compound 2 and its active analogs had low to moderate metabolic stabilities in human and mouse liver microsomes.

An In Silico QSAR Model Study Using Electrophilicity as a Possible Descriptor Against T. Brucei

Human African trypanosomiasis (HAT) is a vector-borne sleeping sickness parasitic disease spread through the bite of infected tsetse flies (Glossina genus), which is highly populated in rural Africa. The present study constructed quantitative structure-activity relationship (QSAR) models based on quantum chemical electronic descriptors to bring out the extent to which the electronic factor of the selected compounds affects the HAT activity. Theoretical prediction of toxicity (pIC50) of the series of heterocyclic scaffolds consisting 32 pyridyl benzamide derivatives towards HAT is investigated by considering all possible combinations of electrophilicity index (ω) and the square of electrophilicity index (ω2) as descriptors in the studied models along with other descriptors previously used by Masand et al. A multiple linear regression (MLR) analysis is conducted to develop the models. Further, in order to obtain the variable selection on the overall data set having diverse functional groups, the analysis using sum of ranking differences methodology with ties is carried out.

Tuning of Terahertz Resonances of Pyridyl Benzamide Derivatives by Electronegative Atom Substitution

N-(pyridin-2-yl) benzamide (Ph2AP)-based organic molecules with prominent terahertz (THz) signatures (less than 5 THz) have been synthesized. The THz resonances are tuned by substituting the most electronegative atom, fluorine, at ortho (2F-Ph2AP), meta (3F-Ph2AP), and para (4F-Ph2AP) positions in a Ph2AP molecule. Substitution of fluorine helps in varying the charge distribution of the atoms forming hydrogen bond and hence strength of the hydrogen bond is varied which helps in tuning the THz resonances. The tuning of lower THz resonances of 2F-Ph2AP, 3F-Ph2AP, and 4F-Ph2AP has been explained in terms of compliance constant (relaxed force constant). Four-molecule cluster simulations have been carried out using Gaussian09 software to calculate the compliance constant of the hydrogen bonds. Crystal structure simulations of the above molecules using CRYSTAL14 software have been carried out to understand the origin of THz resonances. It has been observed that THz resonances are shifted to higher frequencies with stronger hydrogen bonds. The study shows that 3F-Ph2AP and 4F-Ph2AP have higher hydrogen bond strength and hence the THz resonances originating due to stretching of intermolecular hydrogen bonds have been shifted to higher frequencies compared to 2F-Ph2AP. The methodology presented here will help in designing novel organic molecules by substituting various electronegative atoms in order to achieve prominent THz resonances.

Ce(iii)-catalyzed highly efficient synthesis of pyridyl benzamides from aminopyridines and nitroolefins without external oxidants.

An efficient synthesis of a variety of pyridyl benzamides from 2-aminopyridines and nitroolefins is described. This rare-earth-metal-catalyzed reaction provides the corresponding products with broad substrate scope in moderate to excellent yields, in the absence of additives and external oxidants. Water is used as the source of the carbonyl oxygen atom in pyridyl benzamides. Furthermore, 2-substituted oxazolo[4,5-b]pyridines are formed in good yields under the standard conditions when 2-aminopyridin-3-ols are used as the substrates.

Quantitative structure–activity relationships (QSARs) and pharmacophore modeling for human African trypanosomiasis (HAT) activity of pyridyl benzamides and 3-(oxazolo[4,5-b]pyridin-2-yl)anilides

In the present work, quantitative structure–activity relationship and pharmacophore modeling analysis were performed for human African trypanosomiasis healing activity of pyridyl benzamides (dataset-1) and 3-(oxazolo[4,5-b]pyridin-2-yl)anilides (dataset-2). For quantitative structure–activity relationship analysis, a pool of descriptors (mono-dimensional to three-dimensional) was generated, followed by descriptor reduction using objective and subjective feature selection. Multiple splitting was employed for the generation of multiple quantitative structure–activity relationship models to get maximum information about the descriptors that have correlation with the HAT activity of pyridyl benzamides and 3-(oxazolo[4,5-b]pyridin-2-yl)anilides. The genetic algorithm-multilinear regression quantitative structure–activity relationship models have excellent statistical robustness with good external predictive ability. The pharmacophore model and quantitative structure–activity relationship analyses furnished complementary and consensus results to each other.

Pyridyl Benzamides as a Novel Class of Potent Inhibitors for the Kinetoplastid Trypanosoma brucei

A whole-organism screen of approximately 87000 compounds against Trypanosoma brucei brucei identified a number of promising compounds for medicinal chemistry optimization. One of these classes of compounds we termed the pyridyl benzamides. While the initial hit had an IC50 of 12μM, it was small enough to be attractive for further optimization, and we utilized three parallel approaches to develop the structure-activity relationships. We determined that the physicochemical properties for this class are generally favorable with particular positions identified that appear to block metabolism when substituted and others that modulate solubility. Our most active compound is 79, which has an IC50 of 0.045 μM against the human pathogenic strain Trypanosoma brucei rhodesiense and is more than 4000 times less active against the mammalian L6 cell line.

Complexes of lanthanide perchlorates with 2- N-(pyridyl)benzamide

New complexes of lanthanide perchlorates with 2- N-(pyridyl) benzamide (PyBA) of the type Ln(PyBA) 3(ClO 4) 3 where Ln  Y and LaYb have been synthesised and characterised by analyses, conductance, IR, 13C NMR (for diamagnetic complexes only) and electronic spectra. The molar conductance and IR data point to the ionic nature of the perchlorate groups in the complexes. IR data along with the 13C NMR data unequivocally proves that the coordination of the ligand to the metal ions taken place in a bidentate fashion through the oxygen of the benzamide group and the nitrogen of the heterocyclic ring. From a comparison of the visible electronic spectral shapes of the Nd 3+, Ho 3+ and Er 3+ complexes with those reported in the literature, a 6-coordinate geometry around the metal ion has been assigned in all the complexes.