Pyridine Amide Research Articles

Construction of white light “On-Off-On” supramolecular materials for relay detection of Fe3+ and H2PO4−

White light materials are of great interest due to their wide potential applications in lighting devices, displays and probes. Herein, a novel bis-component white light-emitting supramolecular polymer gel TBG was facilely constructed from tripodal pyridine amides and tripodal imidazole by host–guest self-assembly process. Interestingly, the TBG exhibits strong aggregation-induced emission and can be used for highly efficient and sensitive fluorescence detection of ions (Fe3+ and H2PO4−) via the fluorescence “On-Off-On” pathway. The limits of lowest detection limits (LODs) for Fe3+ and H2PO4− were calculated to be 10.08 nM and 21.87 nM, respectively. Meanwhile, the xerogel of TBG could adsorb and separate Fe3+ from aqueous solutions, and the adsorption rate reached 99 %. In addition, a thin film based on the TBG could be used as a convenient test kit for the fluorescence detection of Fe3+ and H2PO4−.

Degradation-Risk-Inspired Optimization of the Antifungal Oxazolinyl Aniline Lead by a Fusion of Triazole with Nicotinamide.

The discovery of readily available and easily modifiable new models is a crucial and practical solution for agrochemical innovation. Antifungal function-oriented fusion of triazole with the prevalidated lead (R)-LE001 affords a novel framework with a broad and enhanced antifungal spectrum. Characterized by the easy accessibility and adjustability of [1,2,4]triazolo[4,3-a]pyridine, modular fine-tuning provided a set of unprecedented leads (e.g., Z23, Z25, Z26, etc.) with superior antifungal potentials than the positive control boscalid. Candidate Z23 exhibited a more promising antifungal activity against Sclerotinia sclerotiorum, Botrytis cinerea, and Phytophthora capsici with EC50 values of 0.7, 0.6, and 0.5 μM, respectively. This candidate could effectively control boscalid-resistant B. cinerea strains and also exhibit good vivo efficacy in controlling gray mold. Noteworthily, both the SDH-inhibition and the efficiency against Oomycete P. capsici are quite distinct from that of the positive control boscalid. A molecular docking simulation also differentiates Z23 from boscalid. These findings highlight the potential of [1,2,4]triazolo[4,3-a]pyridine amide as a novel antifungal model.

Amide cyclodextrin that recognises monophosphate anions in harmony with water molecules.

Anion recognition in water by synthetic host molecules is a popular and challenging topic. It has been considered difficult because the water molecules compete for the recognition units. In this study, we have successfully created a novel macrocycle that achieves precise recognition through multipoint hydrogen bonding in harmony with water molecules. Specifically, an N-methylpyridinium amide β-cyclodextrin (β-CD) derivative 1(OTf)7 was synthesized, whose amide groups are directly attached to each pyranose ring. The pyridinium amide CD encapsulated a monophosphate anion in water, but it did not show interactions with sulfonates or carboxylates, thus a remarkable selectivity was demonstrated. Two monophosphates with different substituents, phenyl phosphate (PhOPO3 2-) and adamantyl phosphate (AdOPO3 2-), exhibited interesting contrasting pictures in the inclusion process, which were revealed by a combination of NOESY experiments, ITC measurements, and MD simulations. PhOPO3 2- was positioned slightly "upper" (closer to the pyridinium amide side) in 17+ with the oxygen atom of the phosphate ester R-O-P involved in the hydrogen bonds with the amide N-H, and configurational entropy plays a key role in the inclusion. Meanwhile, AdOPO3 2- was positioned "lower" (closer to the methoxy rim of CD) with the terminal -PO3 2- forming hydrogen bonds with the amides, and the hydrophobic effect is a major contributing driving force of the inclusion. The molecular design presented herein to achieve the precise recognition in water and clarification of the detailed mechanisms including the hydration phenomenon greatly contribute to the development of functional molecules that work in aqueous environments.

Development of a Small Molecule Hydrogen Evolution Catalyst

Based on prior work done by Diane K. Smith et al on redox responsive 3 hydrogen bond array dimers, a fundamental investigation on the nature of proton coupled electron transfer (PCET) was done by surveying a series of new electroactive “host” H-bond dimers. In these dimers, electron transfer should induce proton transfer across a H-bond, increasing the overall strength of hydrogen bond binding the “guest” and “host”. In particular, the goal was to investigate how electrochemical behavior and binding strength changes as the relative acidity of the electro-inactive “guest” changes in a 2-hydrogen bond array. For this task, amido pyridinium derivatives will be used as the redox active "hosts" and a series of different carboxylic acid, 2-hydroxypyridine, and amide derivatives as the electro-inactive "guests". Unexpectedly, in the presence of carboxylic acids, the amido pyridinium acts as a hydrogen evolution catalyst. During guest host cyclic voltammogram (CV) titrations, there was a large anodic shift of 500 mV and a catalytic increase in current, which is characteristic of an EC mechanism (figure 2). A series of investigations into this mechanism were done following the initial discovery, including scan rate and concentration dependence CV’s, spectro-electrochemical studies, bulk electrolysis, DEMS, and DFT calculations. These studies allowed us to propose the mechanism below (figure 1) for hydrogen evolution. This presentation will detail our efforts to characterize this hydrogen evolution catalyst, the relevance of small molecule hydrogen evolution catalyst, and how we intend to modify it for synthetic purposes.Figure 1 (left image): Reduction of pyridinium amide with and without guests and proposed mechanism of hydrogen evolutionFigure 2 (right image): CV of pyridinium amide in the presence of dodecanoic acid Figure 1

Design, Synthesis, and In Vitro, In Silico and In Cellulo Evaluation of New Pyrimidine and Pyridine Amide and Carbamate Derivatives as Multi-Functional Cholinesterase Inhibitors

Alzheimer disease is an age-linked neurodegenerative disorder representing one of the greatest medical care challenges of our century. Several drugs are useful in ameliorating the symptoms, even if none could stop or reverse disease progression. The standard approach is represented by the cholinesterase inhibitors (ChEIs) that restore the levels of acetylcholine (ACh) by inhibiting the acetylcholinesterase (AChE). Still, their limited efficacy has prompted researchers to develop new ChEIs that could also reduce the oxidative stress by exhibiting antioxidant properties and by chelating the main metals involved in the disease. Recently, we developed some derivatives constituted by a 2-amino-pyrimidine or a 2-amino-pyridine moiety connected to various aromatic groups by a flexible amino-alkyl linker as new dual inhibitors of AChE and butyrylcholinesterase (BChE). Following our previous studies, in this work we explored the role of the flexible linker by replacing the amino group with an amide or a carbamic group. The most potent compounds showed higher selectivity against BChE in respect to AChE, proving also to possess a weak anti-aggregating activity toward Aβ42 and tau and to be able to chelate Cu2+ and Fe3+ ions. Molecular docking and molecular dynamic studies proposed possible binding modes with the enzymes. It is noteworthy that these compounds were predicted as BBB-permeable and showed low cytotoxicity on the human brain cell line.

New fluorinated poly(pyridine amide)s derived from 2,6-bis(4-iodophenyl)-4-(4-trifluoromethylphenyl)pyridine by C–N coupling reaction

2,6-Bis(4-iodophenyl)-4-(4-trifluoromethylphenyl)pyridine, as a new aromatic diiodide compound, was synthesized through a one-pot protocol by the sequential diazotization-iodination of 2,6-bis(4-aminophenyl)-4-(4-trifluoromethylphenyl)pyridine with KI/NaNO2/ p-TsOH in acetonitrile at room temperature. A number of new aromatic fluorinated poly(pyridine amide)s containing 2,6-diphenyl-4-(4-trifluoromethylphenyl)pyridine units were prepared via a Pd(PPh3)2Cl2 catalyzed carbonylation polymerization of this diiodide, diamines and carbon monoxide in DMAc in the presence of PPh3 and 1,8-diazabicyclo[5,4,0]-7-undecene. These new polyamides with inherent viscosities of 0.63–0.72 dL/g were amorphous and easily soluble in amide type aprotic solvents such as NMP, DMAc, DMF and dimethyl sulfoxide at room temperature. Thermal analysis data up to 800°C in nitrogen showed their high thermal behavior with 5% weight loss temperature of 428–498°C and char yield of 62–69%. Their limiting oxygen index of 42.3–45.1 showed that the resulting poly(pyridine amide)s could be classified as “self-extinguishing polymers”. Also, their thin films exhibited high optical transparency with a cut-off wavelength of 324–373 nm.

Design, synthesis and anti-mycobacterial evaluation of imidazo[1,2-a]pyridine analogues.

Based on the molecular hybridization strategy, thirty-four imidazo[1,2-a]pyridine amides (IPAs) and imidazo[1,2-a]pyridine sulfonamides (IPSs) were designed and synthesized. The structures of the target compounds were characterized using 1H NMR, 13C NMR, LCMS, and elemental analyses. The synthesized compounds were evaluated in vitro for anti-tubercular activity using the microplate Alamar Blue assay against Mycobacterium tuberculosis H37Rv strain and the MIC was determined. The evaluated compounds exhibited MIC in the range 0.05-≤100 μg mL-1. Among these derivatives, IPA-6 (MIC 0.05 μg mL-1), IPA-9 (MIC 0.4 μg mL-1), and IPS-1 (MIC 0.4 μg mL-1) displayed excellent anti-TB activity, whereas compounds IPA-5, IPA-7 and IPS-16 showed good anti-TB activity (MIC 0.8-3.12 μg mL-1). The most active compounds with MIC of <3.125 μg mL-1 were screened against human embryonic kidney cells to check their cytotoxicity to normal cells. It was observed that these compounds were nontoxic (SI value ≥66). The ADMET characteristics of the final compounds were also predicted in silico. Further, using the Glide module of Schrodinger software, a molecular docking study of IPA-6 was carried out to estimate the binding pattern at the active site of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis (PDB 4TZK). Finally, molecular dynamics simulations were performed for 100 ns to elucidate the stability, conformation, and intermolecular interactions of the co-crystal ligand and significantly active compound IPA-6 on the selected target protein. IPA-6, the most active compound, was found to be 125 times more potent than the standard drug ethambutol (MIC 6.25 μg mL-1).

The Impact of Halogen Substituents on the Synthesis and Structure of Co-Crystals of Pyridine Amides.

Strategies for co-crystal synthesis tend to employ either hydrogen- or halogen-bonds between different molecules. However, when both interactions are present, the structural influence that they may exert on the resulting assembly is difficult to predict a priori. To shed some light on this supramolecular challenge, we attempted to co-crystallize ten aliphatic dicarboxylic acids (co-formers) with three groups of target molecules; N-(pyridin-2-yl)picolinamides (2Pyr-X), N-(pyridin-2-yl)nicotinamides (3Pyr-X), N-(pyridin-2-yl)isonicotinamides (4Pyr-X); X=Cl/ Br/ I. The structural outcomes were compared with co-crystals prepared from the non-halogenated targets. As expected, none of the reactions with 2Pyr-X produced co-crystals due to the presence of a very stable intramolecular N-H···N hydrogen bond. In the 3Pyr series, all six structures obtained showed the same synthons, –COOH···N(py) and –COOH···N(py)-NH, that were found in the non-halogenated parent 3Pyr and were additionally accompanied by structure directing X···O(OH) interactions (X=Br/I). The co-crystals of the unhalogenated parent 4Pyr co-crystals assembled via intermolecular –COOH···N(py) and –COOH···N(py)-NH synthons. Three of the analogues 4Pyr-X co-crystals displayed only COOH···N(py) and –COOH···N(py)-NH interactions. The three co-crystals of 4Pyr-X with fumaric acid (for which no analogues structures with 4Pyr are known) formed –COOH···N(py)-NH and –NH···O=C hydrogen bonds and showed no structure-directing halogen bonds. In three co-crystals of 4Pyr-I in which –COOH···N(py)-NH hydrogen bond was present, a halogen-bond based –I···N(py) synthon replaced the –COOH···N(py) motif observed in the parent structures. The structural influence of the halogen atoms increased in the order of Cl < Br < I, as the size of σ-holes increased. Finally, it is noteworthy that isostructurality among structures of the homomeric targets was not translated to structural similarities between their respective co-crystals.

First Principle Analysis on Pyridine Amide Derivatives’ Adsorption Behavior on the Pt (111) Surface

The reactivity and adsorption behavior of three pyridine amide additives (Nicotinamide, Pyridine-2-formamide and Pyridine-4-formamide) on the Pt (111) surface was studied by First principle methods. The quantum chemical calculations of molecular reactivity show that the frontier orbitals of the three additives are distributed around the pyridine ring, oxygen atom of carbonyl and nitrogen atom of amino, and the nucleophilic and electrophilic active centers are located on the nitrogen atoms of pyridine ring, oxygen atom of carbonyl and nitrogen atom of amino. All three molecules were adsorbed with the chemical adsorption on the Pt (111) surface, and the order of adsorption was Nicotinamide &gt; Pyridine-2-formamide &gt; Pyridine-4-formamide. The C and N atoms of three derivatives forms C-Pt and N-Pt bonds with the Pt atoms of the Pt (111) surface, which makes derivatives stably adsorb on the Pt surface and form a protective film. The protective film inhibits the diffusion of atoms to the surface of the growth center, so as to inhibit the formation of dendrite and obtain a smooth aluminum deposition layer.

Homology modeling and molecular docking simulation of some novel imidazo[1,2-a]pyridine-3-carboxamide (IPA) series as inhibitors of Mycobacterium tuberculosis

BackgroundTuberculosis (TB) remains a serious global health challenge that is caused by Mycobacterium tuberculosis and has killed numerous people. This necessitated the urgent need for the hunt and development of more potent drugs against the fast-emerging extensively drug-resistant (XDR) and multiple-drug-resistant (MDR) M. tuberculosis strains. Mycobacterium tuberculosis cytochrome b subunit of the cytochrome bc1 complex (QcrB) was recognized as a potential drug target in M. tuberculosis (25618/H37Rv) for imidazo[1,2-a]pyridine-3-carboxamides whose crystal strucuture is not yet reported in the Protein Data Bank (PDB). The concept of homology modeling as a powerful and useful computational method can be applied, since the M. tuberculosis QcrB protein sequence data are available. ResultsThe homology model of QcrB protein in M. tuberculosis was built from the X-ray structure of QcrB in M. smegmatis as a template using the Swiss-Model online workspace. The modeled protein was assessed, validated, and prepared for the molecular docking simulation of 35 ligands of N-(2-phenoxy)ethyl imidazo[1,2-a] pyridine-3-carboxamide (IPA) to analyze their theoretical binding affinities and modes. The docking results showed that the binding affinity values ranged from − 6.5 to − 10.1 kcal/mol which confirms their resilience potency when compared with 6.0kcal/mol of isoniazid standard drug. However, ligands 2, 7, 22, 26, and 35 scored higher binding affinity values of − 9.60, − 9.80, − 10.10, − 10.00, and − 10.00 kcal/mol, and are respectively considered as the best ligands among others with better binding modes in the active site of the modeled QcrB protein. ConclusionThe information derived in this research revealed some potential hits and paved a route for structure-based drug discovery of new hypothetical imidazo pyridine amide analogs as anti-tubercular drug candidates.

Highly sensible chemosensor for Cu2+ and Hg2+ based on anthracene anchored Calix[4]arene pyridine amide receptor

Highly sensible chemosensor for Cu2+ and Hg2+ based on anthracene anchored Calix[4]arene pyridine amide receptor

Effect of Heterocyclic Ring on LnIII Coordination, Luminescence and Extraction of Diamides of 2,2'-Bipyridyl-6,6'-Dicarboxylic Acid.

We have synthesized and examined several complexes of lanthanides with diamides of 2,2′-bipyridyl-6,6′-dicarboxylic acid bearing various hetaryl-based side chains for the elucidation of the effect of the heterocycle on the structure and properties of the ligands. The multigram scale methods for the preparation of various N-alkyl-hetaryls and their diamides were developed. The solid state structure of 6-methyl-2-pyridylamide of 2,2′-bipyridyl-6,6′-dicarboxylic acid possesses a flat structure where the conformation is completely different from that previously observed for N-alkylated 2,2′-bipyridyl-6,6′-dicarboxamides and 2,6-pyridinedicarboxamides. The complexes of new ligands were synthesized and NMR and X-Ray studied their structure in solution and solid state. The results demonstrate that complexes possess the same structures both in solid state and in solution. Stability constants of the complexes were less when comparing with dimethyl-substituted diamides, but higher than for unsubstituted dianilide. Contrarily, the extraction ability of 2-pyridyl-diamide is significantly lower than for corresponding anilide. Specific interaction of extractant with solvent molecules, which is not available for electron-sink pyridine amides, can explain this. The luminescence of new Eu complexes was significantly higher than for all previously 2,2′-bipyridyl-6,6′-dicarboxamides and QY reaches 18%. Asymmetry ratios of Eu complexes were 25% higher when compared other complexes with 2,2′-bipyridyl-6,6′-dicarboxamides, which indicates large deviation from the inversion center.

Design, Synthesis, and Biological Evaluation of Pyridineamide Derivatives Containing a 1,2,3-Triazole Fragment as Type II c-Met Inhibitors.

A series of 4-(pyridin-4-yloxy)benzamide derivatives containing a 1,2,3-triazole fragment were designed, synthesized, and their inhibitory activity against A549, HeLa, and MCF-7 cancer cell lines was evaluated. Most compounds exhibited moderate to potent antitumor activity against the three cell lines. Among them, the promising compound B26 showed stronger inhibitory activity than Golvatinib, with IC50 values of 3.22, 4.33, and 5.82 μM against A549, HeLa, and MCF-7 cell lines, respectively. The structure–activity relationships (SARs) demonstrated that the modification of the terminal benzene ring with a single electron-withdrawing substituent (fluorine atom) and the introduction of a pyridine amide chain with a strong hydrophilic group (morpholine) to the hinge region greatly improved the antitumor activity. Meanwhile, the optimal compound B26 showed potent biological activity in some pharmacological experiments in vitro, such as cell morphology study, dose-dependent test, kinase activity assay, and cell cycle experiment. Finally, the molecular docking simulation was performed to further explore the binding mode of compound B26 with c-Met.

Synthesis and Anticancer Activity of Novel Hetero Ring Fused Pyridine Amide Derivatives

A series of novel hetero ring fused pyridine amide derivatives were prepared starting from ethyl furo[2,3-b]pyridine-2-carboxylate (3) on reaction with ammonia to afford furo[2,3-b]pyridine-2-carboxamide (4), compound 4 on reaction with trifluoroacetic acid to give compound 5, which on reaction with bromoethyl acetate followed by hydrazine hydrate to give compound 7. Compound 7 when reacted with different substituted aromatic aldehydes to give Schiff base compounds (8a-l). Similarly, compound 6a when reacted with diverse substituted aliphatic amines to give amide derivatives (9a-h). All the synthesized compounds 8a-l and 9a-h were screened for anticancer activity against four cancer cell lines such as A549-lung cancer (CCL-185); DU145-prostate cancer (HTB-81); SiHa-squamous cell carcinoma (HTB-35); MCF-7-breast cancer (HTB-22); HEK-29-human embryonic kidney cells (CRL-1573). Compounds 9e and 9f are found to have promising anticancer activity at micro molar concentration and found to be non-toxic on normal cell line.

Experimental and Theoretical Evaluation of the Structure and Properties of New Stannyl Complexes of Pyridine Amide Ligands

Aims: Penta and tetra coordinated stannyl derivatives of N, N'-Bis(2-pyridyl)pyridine-2,6-dicarboxamide (H2L) and N-(pyridine-2-yl)picolinamide (HL1) have been synthesized. The structure of the complexes has been well established by Sn119 NMR and computational studies (GAUSSIAN 03 suit of programs). MESP and NBO studies have been carried out to understand different binding modes and properties of the complexes as well as ligands. The relative bond strengths have been estimated using the Wiberg bond index analysis.&#x0D; Study Design: Experimental and computational.&#x0D; Place and Duration of Study: Department of Chemistry, University of Rajasthan, Jaipur, 2014.&#x0D; Methodology: The structure of the complexes has been analyzed by IR and NMR. Computational studies (GAUSSIAN 03 suit of programs) have been used to elucidate the structure of the newly synthesized complexes.&#x0D; Results: 119Sn NMR showed a pentacoordinate range for diamide complexes indicating coordination through the nitrogen of central pyridine ring in addition to amide nitrogens and tetracoordinate range for monoamide complexes confirming the formation of the products. The bonding properties have been confirmed by the computational calculations.&#x0D; Conclusion: A series of dialkyl/diphenyl and trialkyl/triphenyl derivatives of organo tin complexes containing amide functionality have been synthesized and their structural characterizations performed by different spectral techniques and computational analysis.

Macrocyclic anthracene-anchored calix[4]arene as a sensitive and selective fluorescent chemosensor for ytterbium ions

ABSTRACTA novel anthracene anchored cone calix[4]arene pyridine amide receptor C4PA was synthesized and characterized by combination of spectroscopic and spectrophotometric techniques. Ion binding properties of C4PA towards a series of metal cations were investigated by UV and fluorescence spectra. A remarkable increase for receptor C4PA in fluorescence intensity in the presence of trace amounts of Yb3+ was observed. C4PA showed “turn on” type fluorescence response toward Yb3+ with high selectivity and C4PA also retained its selectivity toward Yb3+ in the presence of most competing metal ions.

Chemogenomic Profiling of the Fungal Pathogen Candida albicans.

ABSTRACTThere is currently a small number of classes of antifungal drugs, and these drugs are known to target a very limited set of cellular functions. We derived a set of approximately 900 nonessential, transactivator-defective disruption strains from the tetracycline-regulated GRACE collection of strains of the fungal pathogen Candida albicans. This strain set was screened against classic antifungal drugs to identify gene inactivations that conferred either enhanced sensitivity or increased resistance to the compounds. We examined two azoles, fluconazole and posaconazole; two echinocandins, caspofungin and anidulafungin; and a polyene, amphotericin B. Overall, the chemogenomic profiles within drug classes were highly similar, but there was little overlap between classes, suggesting that the different drug classes interacted with discrete networks of genes in C. albicans. We also tested two pyridine amides, designated GPI-LY7 and GPI-C107; these drugs gave very similar profiles that were distinct from those of the echinocandins, azoles, or polyenes, supporting the idea that they target a distinct cellular function. Intriguingly, in cases where these gene sets can be compared to genetic disruptions conferring drug sensitivity in other fungi, we find very little correspondence in genes. Thus, even though the drug targets are the same in the different species, the specific genetic profiles that can lead to drug sensitivity are distinct. This implies that chemogenomic screens of one organism may be poorly predictive of the profiles found in other organisms and that drug sensitivity and resistance profiles can differ significantly among organisms even when the apparent target of the drug is the same.

Supramolecular Synthons in Bumetanide Cocrystals and Ternary Products

A novel design strategy for cocrystals of the diuretic sulfonamide drug bumetanide (BUM) with carboxamides is reported based on reliable supramolecular synthons. Binary cocrystals of BUM with pyridine carboxamides, pyridones, and cytosine were obtained by solvent-assisted grinding followed by solution crystallization. All cocrystal structures exhibit hydrogen bonding of the coformer with the carboxylic acid group of BUM via heterosynthons which replace the acid homodimer in the drug crystal structure. Pyridones are inserted as N–H···O dimers which are in turn bonded to the acid group of BUM, while the pyridine amide coformers interact via the acid–amide heterosynthon. Cocrystal polymorphs were obtained for bumetanide–isonicotinamide cocrystal structure with the sulfonamide–pyridine and sulfonamide–acid synthons. Careful crystal packing analysis of BUM structure and nine new binary adducts gave an idea for the design ternary cocrystals, and subsequently four new ternary crystalline products were crystalliz...

Four new amide derivatives of pyridinecarboxylic acids. Synthesis, structure and spectroscopic characterization

This study treats about four new pyridine amide derivatives obtained by a simple and inexpensive method of synthesis which consisted in amide coupling of pyridine-2-carboxylic acid and pyridine-4-carboxylic acid chlorides and aromatic amines: methyl 2-amino-3-methylbenzoate (Ea), methyl 3-amino-2-methylbenzoate (Eb), methyl 3-amino-4-methylbenzoate (Ec). All products of synthesis: L1, L2, L3, L4 were analyzed in detail by FT-IR, 1H, 13C, COSY 2D, HSQC, HMBC NMR spectroscopy, elemental, TGA and X-ray analysis. The excitation and emission spectra for obtained amides were also registered. An exact examination of results confirmed receiving four amide compounds with higher potential ability to metal ion coordination than the substrates alone.

Molecular Modeling Studies of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors through Receptor-Based 3D-QSAR and Molecular Dynamics Simulations.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a potential target for the treatment of numerous human disorders, such as diabetes, obesity, and metabolic syndrome. In this work, molecular modeling studies combining molecular docking, 3D-QSAR, MESP, MD simulations and free energy calculations were performed on pyridine amides and 1,2,4-triazolopyridines as 11β-HSD1 inhibitors to explore structure-activity relationships and structural requirement for the inhibitory activity. 3D-QSAR models, including CoMFA and CoMSIA, were developed from the conformations obtained by docking strategy. The derived pharmacophoric features were further supported by MESP and Mulliken charge analyses using density functional theory. In addition, MD simulations and free energy calculations were employed to determine the detailed binding process and to compare the binding modes of inhibitors with different bioactivities. The binding free energies calculated by MM/PBSA showed a good correlation with the experimental biological activities. Free energy analyses and per-residue energy decomposition indicated the van der Waals interaction would be the major driving force for the interactions between an inhibitor and 11β-HSD1. These unified results may provide that hydrogen bond interactions with Ser170 and Tyr183 are favorable for enhancing activity. Thr124, Ser170, Tyr177, Tyr183, Val227, and Val231 are the key amino acid residues in the binding pocket. The obtained results are expected to be valuable for the rational design of novel potent 11β-HSD1 inhibitors.