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In the present work, the two imidazopyridine derivatives namely ethyl 6,8-dibromoimidazo [1,2-a] pyridine-2-carboxylate (ES-IMD) and (5-methylimidazo [1,2-a] pyridine-2-yl) methanol (OL-IMD) were presented as powerful anti-polarizing agent for steel surface in aggressive system related to the obtained results in experimental and computational methods. 1H NMR and mass spectrometry (MS) were used to confirm the structures of resynthesized molecule. We assessed the effectiveness of OL-IMD and ES-IMD inhibitors in safeguarding mild steel from corrosion in a 1 M hydrochloric acid environment. We adopted an integrated experimental and computational approach to evaluate the inhibition efficiency and mechanism of OL-IMD and ES-IMD, utilizing gravimetric method, polarization curves and electrochemical impedance spectroscopy. Quantum chemical calculations and molecular dynamics simulations provided atomic-level insights into adsorption behaviour. Scanning electron microscopy characterized surface morphology. Findings revealed that OL-IMD and ES-IMD compounds performed as mixed-type inhibitors. At the greatest inhibitor concentration (10−3 M), the polarization curves gave inhibition efficiency values of 98.91% (ES-IMD) and 95.42% (OL-IMD). Thermodynamic activation parameters indicated a spontaneous adsorption process of OL-IMD and ES-IMD on the steel surface, which effectively increased the energy barrier for the corrosion process. The EIS parameters demonstrated that when inhibitor concentration raised, the double-layer capacitance (C dl) dropped which suggested that the dielectric constant was decreasing. The results reveal a substantial correlation produced by the three analysed approaches EIS, PDP, and WL. Thermodynamic activation parameters indicated a spontaneous adsorption process of OL-IMD and ES-IMD on the steel surface, which effectively increased the energy barrier for the corrosion process. Furthermore, the calculated ΔG ads values for the considered compounds were -47.39 (kJ/mol) and 49.26 (kJ/mol) for OL-IMD and ES-IMD respectively, proving the chemical nature of the adsorption. Furthermore, SEM surface studies displayed a homogeneous surface while the tested inhibitors were present, but a damaged surface in the blank solution. The theoretical models closely aligned with the experimental data, presented an excellent overview of the investigated inhibitors' reactivity against mild steel confirming the validity of the findings. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Development of a class of bicyclic inhibitors of the Plasmodium falciparum cyclic GMP-dependent protein kinase (Pf PKG), starting from known compounds with activity against a related parasite PKG orthologue, is reported. Examination of key sub-structural elements led to new compounds with good levels of inhibitory activity against the recombinant kinase and in vitro activity against the parasite. Key examples were shown to possess encouraging in vitro ADME properties, and computational analysis provided valuable insight into the origins of the observed activity profiles. [ABSTRACT FROM AUTHOR]

• New imidazopyridine analogues were designed for anti-TB activity. • I2 and I7 exhibited MIC of 3.12 and 4.16 μg/mL against MTBH 37 Rv strain. • I2 and I7 was found to be more active than standard drug streptomycin. • Molecular docking data were in accordance with the anti-TB results. • Single crystal X-ray and computational photo physical studies were carried out. With the intent to discover new anti-TB compounds, new imidazopyridine analogues were synthesized through Schiff-base reaction. The newly developed imidazopyridines (I1-I8) were characterized using spectroscopic and elemental analysis. In addition the structure of compound I3 was elucidated by the single crystal X-ray diffraction technique. The global chemical reactivity descriptor parameter was calculated using theoretically DFT-B3LYP-6–31G(d) basis set which estimated HOMO-LUMO value and results are discussed. All the newly synthesized compounds were screened for their in vitro anti-tubercular activity, while the most active compounds were subjected to a cytotoxicity assay on Vero cell lines. Most of the tested compounds exhibited significant anti-TB activity with MIC in the range 3.12 – 12.5 μg/mL. Among the synthesized, compound I2 and I7 were found to be more active than the standard anti-TB drug streptomycin and comparable activity to pyrazinamide. A cytotoxicity study on Vero-cell lines confirmed the nontoxic nature of compound I2 and I7 indicating good safety profile. The molecular docking studies on PDB IB: 4ED4 enzyme of Mycobacterium tuberculosis was conducted to investigate mechanisms of anti-TB activity. The compounds displayed excellent hydrogen binding interactions and docking scores against MTB, which were in accordance with the results and further supported its credibility. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Benzimidazole linked with imidazo[1,2- a ]pyridine molecules were synthesized by microwave irradiation. • Fluorescent properties of the molecules were determined in different solvents, aqueous media, and different acids. • 6a shows pH-sensitive fluorescence change. An approach for the synthesis of benzimidazole linked with imidazopyridine through a greener and highly efficient method is proposed herein. The approach involves the use of green, safe, and easy-to-use solvents: EtOH & H 2 O, which overthrows the already reported procedures using catalysts (Cu, Au, Zr, etc) and oxidizing agents. The efficiency of method was evaluated based on synthesis of derivatives (6a-h) containing versatile substituents. Synthesized compounds were investigated for their fluorescent properties in different solvents, aqueous medium, and different acids. 6a shows enhanced fluorescence in neutral to basic conditions and characterized by 1D & 2D NMR spectra. 6a could find application as pH-sensitive probes for the diagnosis of alkaline conditions. [ABSTRACT FROM AUTHOR]

• Several oxadiazole-based thiourea derivatives containing imidazopyridine moiety were synthesized. • Also, all derivatives were tested to determine their ability to inhibit α-amylase, α-glucosidase and 2- diphenyl-1-picrylhydrazyl (DDPH) and 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging enzymes. • A molecular docking simulation of the most potent derivatives was performed to determine whether they are able to bind to the active site of targeted enzymes. A series of new imidazopyridine based oxadiazole derivatives (5a-l) were designed and synthesized. Their structures were confirmed by spectral data and then subjected to in vitro assessment including α-glucosidase, α-amylase inhibitory, and 2- diphenyl-1-picrylhydrazyl (DDPH) and 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activities. The inhibitory activity results revealed that all the synthesized analogs displayed significant α-glucosidase and α-amylase inhibition with IC 50 values of 0.90 ± 0.10 to 18.10 ± 0.20 µM (for α-glucosidase) and 1.10 ± 0.10 to 19.70 ± 0.20 µM (for α-amylase) respectively as compared to standard acarbose with IC 50 values of 11.50 ± 0.30 µM (α-glucosidase) and 12.20 ± 0.30 µM (for α-amylase).The synthesized analogs also showed significant DPPH and ABTS radical scavenging activities with IC 50 values in the range of 1.05 ± 0.05 to 4.56 ± 3.12 µM (for DDPH) and 1.15 ± 0.05 to 4.89 ± 2.89 µ M (for ABTS) respectively, incomparison to standard ascorbic acid with IC 50 = 1.83 ± 1.32 µM (for DDPH) and 1.84 ± 1.16 µM (for ABTS) respectively. After crucial analysis of varying substitution effects on inhibitory (α-glucosidase &α-amylase) and radical scavenging (DPPH & ABTS) potentials respectively, the structure-activity relationship (SAR) was established. Through the in silico molecular docking analysis, the ability of the synthesized analogs to inhibit α-glucosidase and α -amylase was also examined.There was a good correlation between in vitro and in silico studies for synthesized analogs 5i and 5d Further studies are required to determine whether these potent analogs could be a potential treatment for diabetes disease. [ABSTRACT FROM AUTHOR]

[Display omitted] • The charge transfer mechanism controls the mild steel corrosion process. • The inhibitory power of the two investigated imidazopyridine derivatives decreases with a rise in temperature. • The studied inhibitors adsorb on the mild steel surface in accordance with the Langmuir's isotherm model. • Quantum chemical calculations support experimental findings. In this study, two inhibitors namely 6-Chloro −2-phenylimidazo[1,2-a]pyridine (Pyr1) and 6-Chloro-2-(4- Chlorophenyl)imidazo[1,2-a]pyridine (Pyr2) were used to investigate their inhibition ability toward mild steel corrosion in 1 M HCl using electrochemical techniques and quantum approaches. The two inhibitors show corrosion inhibition efficiency of 98.35% and 97.57% for Pyr2 and Pyr1 respectively at the optimum concentration 10-3 M. This is due to the features of the substituent group and the effect of its emplacement in the phenyl ring. The electrochemical measurements reveal that both anodic and cathodic current are affected by these organic compounds so they are classified as mixed-type inhibitors with predominance cathodic character. The inhibited solution was analysed using UV spectrometer, which indicates a tendency to develop a complex between inhibitors and ferrous ions. The computational approaches were performed in order to examine the correlation between inhibition efficiency and molecular structure of the inhibitors Pyr1 and Pyr2. [ABSTRACT FROM AUTHOR]

An efficient iron-catalyzed intermolecular aminooxygenation of 2-aminopyridines with a wide range of ynals has been developed. 3-Aroylimidazo[1,2- a ]pyridines containing various functional groups are synthesized under the standard conditions. The transformation is conducted in simple conditions and forms products in good yields. [ABSTRACT FROM AUTHOR]

Ulcer is a serious disease that is caused due to different bacteria and over usage of various NSAIDs which caused to reduce the defensive system of stomach. Therefore, some novel series are needed to overcome these issues. Oxazole - based imidazopyridine scaffolds (4a-p) were designed and synthesized by two step reaction protocol and then subjected to urease inhibition profile (in vitro). All the newly afforded analogs (4a-p) were found potent and demonstrated moderate to significant inhibition profile. Particularly, the analogs 4i (IC 50 = 5.68 ± 1.66 μM) , 4o (IC 50 = 7.11 ± 1.24 μM) , 4 g (IC 50 = 9.41 ± 1.19 μM) and 4 h (IC 50 = 10.45 ± 2.57 μM) were identified to be more potent than standard thiourea drug (IC 50 = 21.37 ± 1.76 μM). Additionally, the variety of spectroscopic tools such as 1H NMR, 13C NMR and HREI-MS analysis were employed to confirm the precise structures of all the newly afforded analogs. The structure–activity relationship (SAR) studies showed that analogs possess the substitution either capable of furnishing strong HB like –OH or had strong EW nature such as -CF 3 & –NO 2 groups displayed superior inhibitory potentials than the standard thiourea drug. A good PLI (protein–ligand interaction) profile was shown by most active analogs when subjected to molecular study against corresponding target with key significant interactions such as pi-pi stacking, pi-pi T shaped and hydrogen bonding. [ABSTRACT FROM AUTHOR]

Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6 , through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1 . Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients. [ABSTRACT FROM AUTHOR]

The inhibition of aldosterone synthase (CYP11B2) may be an effective treatment of hypertension and heart failure, among other ailments. Previously reported benzimidazole CYP11B2 inhibitors led the way for bioisosteric imidazopyridines that are both potent and selective over CYP11B1. [ABSTRACT FROM AUTHOR]

1,3-Disubstituted-imidazopyridines were designed for developing inhibitors against HIF-1 transcriptional activity. Designed compounds were rapidly synthesized from a key aromatic scaffold via microwave-assisted Suzuki-Miyaura coupling/C H direct arylation sequence. Evaluation of ability to inhibit the hypoxia induced transcriptional activity of HIF-1 revealed that the compound 2i and 3a retained the same level of the inhibitory activity comparing with that of known inhibitor, YC-1 ( 1 ). Identified, readily accessible 1-aryl-3-furanyl/thienyl-imidazopyridine templates should be useful for future drug development. [ABSTRACT FROM AUTHOR]

A practical strategy for the preparation of imidazopyridine derivatives from ortho -haloaminopyridines utilizing a two-step C–N coupling/cyclization reaction sequence has been developed. This procedure provides rapid and efficient access to many medicinally interesting imidazopyridine compounds and related imidazopyrazine/purine heterocycles. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) remains one of the most threatening diseases in the world and the need for development of new therapies is dire. Herein we describe the rationale for the design and subsequent syntheses and studies of conjugates between pBTZ and both the imidazopyridine and cephalosporin scaffolds. Overall some compounds exhibited notable anti-TB activity in the range of 2–0.2 μM in the Microplate Alamar Blue (MABA) Assay. [ABSTRACT FROM AUTHOR]

Alterations in PI3K/AKT signaling are known to be implicated with tumorigenesis. The PI3 kinases family of lipid kinases has been an attractive therapeutic target for cancer treatment. Imidazopyridine compound 1 , a potent, selective, and orally available pan-PI3K inhibitor, identified by scaffold morphing of a benzothiazole hit, was further optimized in order to achieve efficacy in a PTEN-deleted A2780 ovarian cancer mouse xenograft model. With a hypothesis that a planar conformation between the core and the 6-heteroaryl ring will allow for the accommodation of larger 5′-substituents in a hydrophobic area under P-loop, SAR efforts focused on 5′-alkoxy heteroaryl rings at the 6-position of imidazopyridine and imidazopyridazine cores that have the same dihedral angle of zero degrees. 6′-Alkoxy 5′-aminopyrazines in the imidazopyridine series were identified as the most potent compounds in the A2780 cell line. Compound 14 with 1,1,1-trifluoroisopropoxy group at 6′-position demonstrated excellent potency and selectivity, good oral exposure in rats and in vivo efficacy in A2780 tumor-bearing mouse. Also, we disclose the X-ray co-crystal structure of one enantiomer of compound 14 in PI3Kα, confirming that the trifluoromethyl group fits nicely in the hydrophobic hot spot under P-loop. [ABSTRACT FROM AUTHOR]

Derivatives of imidazopyridine are used in medicinal chemistry due to their biological and pharmaceutical properties. This review article presents imidazopyridine pharmacological activity as antiinflammatory, anticancer, antiviral, antiosteoporotic, antiparasitic, and antihypertensive agents by studying its various synthesized derivatives. Some of compounds with imidazopyridine skeleton are used in psychiatry and autoimmune disorders. The presented data suggest that IR and Raman spectra measurements are a good methods for identification and characterization of the compounds containing imidazopyridine core. Two stretching vibrations: ν as ( Φ ) and ν s ( Φ ) are of a diagnostic importance. The appearance of these bands in the IR and Raman spectra of some plants, tissues and pharmaceuticals confirms the presence of imidazopyridine skeleton in these substances. [ABSTRACT FROM AUTHOR]

Starting from our previously identified novel c-Met kinase inhibitors bearing 1 H -imidazo[4,5- h ][1,6]naphthyridin-2(3 H )-one scaffold, a global structural exploration was conducted to furnish an optimal binding motif for further development, directed by the enzyme inhibitory mechanism. First round SAR study picked two imidazonaphthyridinone frameworks with 1,8- and 3,5-disubstitution pattern as class I and class II c-Met kinase inhibitors, respectively. Further structural optimization on type II inhibitors by truncation of the imidazonaphthyridinone core and incorporation of an N -phenyl cyclopropane-1,1-dicarboxamide pharmacophore led to the discovery of novel imidazopyridine-based c-Met kinase inhibitors, displaying nanomolar enzyme inhibitory activity and improved Met kinase selectivity. More significantly, the new chemotype c-Met kinase inhibitors effectively inhibited Met phosphorylation and its downstream signaling as well as the proliferation of Met-dependent EBC-1 human lung cancer cells at submicromolar concentrations. [ABSTRACT FROM AUTHOR]

Metastatic prostate cancer (mPCa) relapses after a short period of androgen deprivation therapy and becomes the castration-resistant prostate cancer (CR PCa); to which the treatment is limited. Hence, it is imperative to identify novel therapeutic agents towards this patient population. In the present study, antiproliferative activities of novel imidazopyridines were compared. Among three derivatives, PHE, AMD and AMN, examined, AMD showed the highest inhibitory activity on LNCaP C-81 cell proliferation, following dose- and time-dependent manner. Additionally, AMD exhibited significant antiproliferative effect against a panel of PCa cells, but not normal prostate epithelial cells. Further, when compared to AMD, its derivative DME showed higher inhibitory activities on PCa cell proliferation, clonogenic potential and in vitro tumorigenicity. The inhibitory activity was apparently in part due to the induction of apoptosis. Mechanistic studies indicate that AMD and DME treatments inhibited both AR and PI3K/Akt signaling. The results suggest that better understanding of inhibitory mechanisms of AMD and DME could help design novel therapeutic agents for improving the treatment of CR PCa. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we report the identification of potent benzimidazoles as PDE10A inhibitors. We first identified imidazopyridine 1 as a high-throughput screening hit compound from an in-house library. Next, optimization of the imidazopyridine moiety to improve inhibitory activity gave imidazopyridinone 10b. Following further structure–activity relationship development by reducing lipophilicity and introducing substituents, we acquired 35, which exhibited both improved metabolic stability and reduced CYP3A4 time-dependent inhibition. [Copyright &y& Elsevier]

Abstract: A series of imidazopyridine derivatives have been synthesized efficiently via intramolecular cyclization in excellent yields using Al3+-exchanged on K10 montmorillonite clay (Al3+-K10 clay) as a reusable heterogeneous catalyst. To the best of our knowledge, this is the first report to utilize Al3+-K10 as a catalyst for imidazopyridine synthesis. Many functional groups are tolerated during the synthesis of targeted compounds. The catalyst is reused at least five times with a slight decrease in the yield. This catalyst is environmentally benign, cost-effective, and also provides other advantages such as nontoxicity, operational/experimental simplicity, and mild reaction conditions. [Copyright &y& Elsevier]

Abstract: This Letter details the synthesis and evaluation of imidazo[4,5-b]pyridines as inhibitors of B-Raf kinase. These compounds bind in a DFG-in, αC-helix out conformation of B-Raf, which is a binding mode associated with significant kinase selectivity. Structure–activity relationship studies involved optimization of the ATP-cleft binding region of these molecules, and led to compound 23, an inhibitor with excellent enzyme/cell potency, and kinase selectivity. [Copyright &y& Elsevier]

Abstract: A single step access to fused imidazopyridine involving [bmIm]OH promoted click cyclocondensation of N-methylisatin with 2-aminopyridine has been achieved. The title heterocyclic scaffolds were obtained in excellent yield with high purity. [bmIm]OH was found to be more attractive as it plays the role of solvent, base, and catalyst. [Copyright &y& Elsevier]

Abstract: PI3 kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. The PI3 Kinase pathway is often de-regulated in cancer through PI3Kα overexpression, gene amplification, mutations and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment. Herein we describe how the potency of a benzothiazole fragment hit was quickly improved based on structural information and how this early chemotype was further optimized through scaffold hopping. This effort led to the identification of a series of 2-acetamido-5-heteroaryl imidazopyridines showing potent in vitro activity against all class I PI3Ks and attractive pharmacokinetic properties. [Copyright &y& Elsevier]

Abstract: In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with novel structures, we have employed a scaffold hopping strategy to explore the chemically diversed space of bioactive compounds. The original arylazolylthioacetanilide platform was replaced with different imidazopyridinyl- thioacetanilide scaffolds to yield the optimal pharmacophore moieties in order to generate novel NNRTIs with desirable potency. Some of the new compounds proved able to inhibit HIV-1 replication in the low micromolar range. In particular, compound 5b16 displayed the most potent anti-HIV-1 activity (EC50 =0.21±0.06μM), inhibiting HIV-1 IIIB replication in MT-4 cells more effectively than dideoxycytidine (EC50 =1.4±0.1μM) and similarly with nevirapine (EC50 =0.20±0.10μM). Preliminary structure–activity relationship (SAR) of the newly synthesized congeners is discussed, and molecular modeling study is performed to rationalize the SAR conclusions. [Copyright &y& Elsevier]

Abstract: mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series. [Copyright &y& Elsevier]

Abstract: Design, synthesis and biological evaluation of the imidazopyridine analogs as novel GSK3β inhibitors for treatment of type 2 diabetes mellitus are described. Most of the analogs exhibited excellent inhibitory activities (IC50<44nM) against glycogen synthase kinase 3β (GSK3β). The structure–activity relationship (SAR) of the imidazopyridine analogs and the binding mode of analog 23 in the catalytic domain of GSK3β, based on our X-ray crystallography study, are described. In particular, analog 28, which was selected as a potential drug candidate for treatment of type 2 diabetes mellitus, exhibited excellent GSK3β inhibition, pharmacokinetic profiles and blood glucose lowering effect in mouse. [Copyright &y& Elsevier]

Abstract: Small heteroaromatic rings are valuable monomers in drug discovery that can enable rapid access to novel and desirable chemical space. Installation of a synthetic handle on a heteroaromatic core may be difficult if steric and electronic factors are not in alignment with the desired transformation. Described are practical routes for the construction of 5-bromo-6-methyl imidazopyrazine (1) as well as 5-bromo and 5-chloro-6-methyl imidazopyridines (2a and 2b), which were developed using electron density surface maps encoded with ionization potential to guide synthetic strategy. [Copyright &y& Elsevier]

Abstract: The molecular structures, vibrational energy levels and potential energy distribution of 4-methyl-imidazo[4,5-c]pyridine (4MIPc) and 7-methyl-imidazo[4,5-c]pyridine (7MIPc) are derived from the quantum chemical calculations and compared to the experimental results obtained from the X-ray diffraction (XRD), IR and Raman studies. The B3LYP/6-311G(2d,2p) quantum model and PED contributions have been applied for the assignment of the vibrational modes. 4MIPc crystallizes in an orthorhombic structure, space group Pna21 and Z =4 and 7MIPc crystallizes in a triclinic structure, space group P−1 and Z =4. The almost planar conformation of the molecules and presence of the N–H⋯N hydrogen bonds formed with the pyridine and imidazole nitrogen atoms was found to be characteristic for the studied systems. The presence of hydrogen bonds is also confirmed by the results of IR studies. [Copyright &y& Elsevier]

Abstract: New antimicrobial agents, imidazo[1,2-a]pyridine and imidazo[2,1-b][1,3]benzothiazole, have been synthesized. Their antimicrobial activities were conducted against various Gram-positive, Gram-negative bacteria and fungi. Compounds 6c, 7a, 10b, 11a, 12b, 14a, 14b, 15a and 15b, exerted strong inhibition of the investigated bacterial and fungal strains compared to control antibiotics amoxicillin and cefixime and the antifungal agent fluconazole. Results from this study showed that the nature of the substituents on the armed aryl groups determines the extent of the activity of the fused imidazopyridine and/or imidazobenzothiazole derivatives. Preliminary structure–activity observations revealed that bromo-fluoro substituents enhanced the antimicrobial activity significantly compared to other substituents. [Copyright &y& Elsevier]

Abstract: New antimicrobial agents [imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine] have been synthesized. Their antimicrobial activities were conducted against various Gram-positive and Gram-negative bacteria including Staphylococcus aureus. Compounds 5d, 7a, 10a, 11a and 12a proved to efficiently inhibit the growth of all the Gram-positive and Gram-negative strains investigated. Results of this study showed that the nature of the substituents on the armed phenyl groups determined the extent of the activity of the fused imidazopyridine and/or imidazopyrimidine derivatives. Preliminary structure–activity observations revealed that groups with positive sigma and positive bi values (e.g. 5d, 6c, 12a, 12d) were significantly more active compared to other bioisosteres (e.g. 5b). Furthermore, increasing the molar refractivity of the substitution pattern (e.g. 5b, 6b and 6d) sharply decreased the antibacterial activity. [ABSTRACT FROM AUTHOR]

Abstract: A novel series of adenosine A2A receptor antagonists was identified by high-throughput screening of an encoded combinatorial compound collection. The initial hits were optimized for A2A binding affinity, A1 selectivity, and in vitro microsomal stability generating orally available 2-aminoimidazo[4,5-b]pyridine-based A2A antagonist leads. [ABSTRACT FROM AUTHOR]

Abstract: The treatment of 2-bromo-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (1) with pyridine, 2-methylpyridine or 4-methylpyridine afforded their corresponding pyridinum bromides 3a–c. The latter salts reacted with activated acetylene to give the corresponding indolizine derivatives 6a–c. Imidazo[1,2-a]pyridine 9a,b, quinoxaline 15, imidazo[1,2-b][1,2,4]triazole 18 and imidazo[1,2-a]benzimidazole 21 derivatives were prepared from 1 as a starting material. The investigation of the derivative influence on the carcinogen metabolizing enzymes and in the tumor initiation process revealed that 3a–c were strong inducers of epoxide hydrolase (mEH), and that 3a was an inducer of glutathione S-transferases (GSTs) and glutathione (GSH) and a potent scavenger of ROOe:glyph name="rad" /> and inhibited the induced DNA damage, while 3b was a scavenger of ROOderate inhibitor of DNA damage. Additionally, 6a–c significantly induced quinine reductase (QR) activity, whereas 6b induced GSTs, and 6c elevated GSH content, while both of 6b and 6c scavenged OHbited the DNA damage. On the other hand, 9a possessed a moderate scavenging activity of ROObitory effect on the induced DNA damage, while 18 was a strong inducer of QR activity, scavenger of OHibitor of the DNA damage and 2 was a significant inhibitor of cytochrome P-450 1A (Cyp1A) and was an inducer of GSTs, and GSH, and a moderate inhibitor of the DNA damage. [Copyright &y& Elsevier]

4-Phenylsulfonyl tetrafluoropyridine was reacted with various N- aryl amidines to give the corresponding imidazopyridine systems via an intramolecular nucleophilic aromatic substitution process whilst pentafluoropyridine gave N ′-(perfluoropyridin-4-yl)- N- phenylbenzimidamide and 2,3,5,6-tetrafluoro- N- phenylpyridin-4-amine by a competing elimination reaction. [ABSTRACT FROM AUTHOR]

Abstract: Synthesis of several novel imidazopyridine-5,6,7,8-tetrahydro-8-quinolinamine derivatives with potent activity against HIV are described. Synthetic approaches allowing for variation of the substitution pattern are outlined and resulting changes in antiviral activity and pharmacokinetics are highlighted. Several compounds with low nanomolar anti-HIV activity and oral bioavailability are described. [Copyright &y& Elsevier]

Abstract: A novel class of imidazopyridine derivatives was designed as PLK1 inhibitors. Extensive SAR studies supported by molecular modeling afforded a highly potent and selective compound 36. Compound 36 demonstrated good antitumor efficacy in xenograft nude rat model. [Copyright &y& Elsevier]

Abstract: A new series of DPP-4 inhibitors derived from piperidine-fused benzimidazoles and imidazopyridines is described. Optimization of this class of DPP-4 inhibitors led to the discovery of imidazopyridine 34. The potency, selectivity, cross-species DMPK profiles, and in vivo efficacy of 34 is reported. [Copyright &y& Elsevier]

Discovery of novel and potent lead molecules for the specific therapeutic targets by de novo drug design is still in infancy. Here, we disclose the unprecedented development of imidazopyri(mi)dine-based tumor pyruvate kinase M2 (PKM2) modulators by subsequent link and grow strategy. The most potent modulator 15n acts as a PKM2 activator with an AC 50 of 90 nM, with considerable cancer cell-selectivity and membrane-permeability. NMR metabolomics studies also revealed that treatment with 15n results in diminution in lactate concentrations in MCF-7 cells. 15n binds to a previously reported site at PKM2 adjacent to the interface of two monomers. In molecular dynamics (MD) simulation studies, it was observed that 15n stabilizes the PKM2 at the dimeric interface, assisting in the formation of a biologically active tetramer conformation. 15n was also screened on MCF-7 breast cancer cell lines grown on 3-D scaffolds, and the results exhibited better anticancer potential compared to control, paving the way for future clinical studies. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: The synthesis and antibacterial activities of three chemotypes of DNA supercoiling inhibitors based on imidazolo[1,2-a]pyridine and [1,2,4]triazolo[1,5-a]pyridine scaffolds that target the ATPase subunits of DNA gyrase and topoisomerase IV (GyrB/ParE) is reported. The most potent scaffold was selected for optimization leading to a series with potent Gram-positive antibacterial activity and a low resistance frequency. [Copyright &y& Elsevier]

Drug-induced phototoxic skin responses have been recognized as undesirable side effects, and as we previously proposed the determination of reactive oxygen species (ROS) from photo-irradiated compounds can be effective for the prediction of phototoxic potential. In this investigation, we evaluated the photosensitizing properties of imidazopyridine derivative, a novel 5-HT4 partial agonist, using ROS assay and several analytical/biochemical techniques. Exposure of the compound to simulated sunlight resulted in the significant production of singlet oxygen, which is indicative of its phototoxic potential. In practice, an imidazopyridine derivative under UVA/B light exposure also showed significant photodegradation and even photobiochemical events; peroxidation of fatty acid and genetic damage after DNA-binding, which are considered as causative agents for phototoxic dermatitis. Interestingly, both photodegradation and lipoperoxidation were dramatically attenuated by the addition of radical scavengers, especially singlet oxygen quenchers, suggesting the possible involvement of ROS generation in the phototoxic pathways. In the 3T3 neutral red uptake phototoxicity test, imidazopyridine derivative also showed the phototoxic effect on 3T3 mouse fibroblast cells. These results suggest the phototoxic risk of newly synthesized imidazopyridine derivative and also verify the usefulness of ROS assay for phototoxicity prediction. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:4307–4318, 2008 [ABSTRACT FROM AUTHOR]

Abstract: We describe a novel series of imidazopyridine substituted phenylalanines which are potent VLA-4 antagonists. A wide variety of substituents are tolerated as replacements for the pendant 3-pyridyl ring. A clear structure–activity relationship was identified around the substitution of the 3-amino-cyclobut-2-enone portion of the molecule. [Copyright &y& Elsevier]

Abstract: Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Recently, we reported the synthesis and biological activity of potent imidazo[1,2-a]pyridine anticoccidial agents. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we report the synthesis and anticoccidial activity of a second set of such compounds, focusing on derivatization of the amine side chain at the imidazopyridine 7-position. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development. [Copyright &y& Elsevier]

Abstract: A potent IRAK-4 inhibitor was identified through routine project cross screening. The binding mode was inferred using a combination of in silico docking into an IRAK-4 homology model, surrogate crystal structure analysis and chemical analogue SAR. [Copyright &y& Elsevier]

Abstract: Selective inhibitors of the replication of the classical swine fever virus (CSFV) may have the potential to control the spread of the infection in an epidemic situation. We here report that 5-[(4-bromophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (BPIP) is a highly potent inhibitor of the in vitro replication of CSFV. The compound resulted in a dose-dependent antiviral effect in PK15 cells with a 50% effective concentration (EC50) for the inhibition of CSFV Alfort187 (subgroup 1.1) of 1.6±0.4μM and for CSFV Wingene (subgroup 2.3) 0.8±0.2μM. Drug-resistant virus was selected by serial passage of the virus in increasing drug-concentration. The BPIP-resistant virus (EC50: 24±4.0μM) proved cross-resistant with VP32947 [3-[((2-dipropylamino)ethyl)thio]-5H-1,2,4-triazino[5,6-b]indole], an unrelated earlier reported selective inhibitor of pestivirus replication. BPIP-resistant CSFV carried a T259S mutation in NS5B, encoding the RNA-dependent RNA-polymerase (RdRp). This mutation is located near F224, a residue known to play a crucial role in the antiviral activity of BPIP against bovine viral diarrhoea virus (BVDV). The T259S mutation was introduced in a computational model of the BVDV RdRp. Molecular docking of BPIP in the BVDV polymerase suggests that T259S may have a negative impact on the stacking interaction between the imidazo[4,5-c]pyridine ring system of BPIP and F224. [Copyright &y& Elsevier]

Abstract: Herein we report investigations into the p38α MAP kinase activity of trisubstituted imidazoles that led to the identification of compounds possessing highly potent in vivo activity. The SAR of a novel series of imidazopyridines is demonstrated as well, resulting in compounds possessing cellular potency and enhanced in vivo activity in the rat collagen-induced arthritis model of chronic inflammation. [Copyright &y& Elsevier]

Abstract: Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we present the synthesis and biological activity of imidazo[1,2-a]pyridine anticoccidial agents. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development. [Copyright &y& Elsevier]

Abstract: Diaryl imidazo[1,2-a]pyridine derivatives, such as 6a and 7i, have been synthesized and found to be potent inhibitors of parasite PKG activity. The most potent compounds are the 7-isopropylaminomethyl analog 6a and 2-isopropylamino analog 7i. These compounds are also fully active in in vivo assay as anticoccidial agents at 25ppm in feed. [Copyright &y& Elsevier]

Abstract: The dynamic NMR analysis of 2, a subunit of a new class of cyclic-dependent kinase inhibitors, reveals that the compound exists as two conformational isomers, Z and E, in acetone, as a consequence of the restricted rotation about the imidazopyridine–carbonyl bond. The less hindered Z-rotamer is the most abundant conformer (85:15 Z/E at 233K) and the free energy of activation of the interconversion is 13.2kcalmol−1. The rotamer ratio and the interconversion barrier are similar in other solvents, such as CD3OD and CDCl3. [Copyright &y& Elsevier]

Abstract: Casein kinase 1 (CK1) is a family of multifunctional Ser/Thr protein kinases that are ubiquitous in eukaryotic cells. Recent studies have demonstrated the existence of, and role for, CK1 in protozoan parasites such as Leishmania, Plasmodium and Trypanosoma. The value of protein kinases as potential drug targets in protozoa is evidenced by the successful exploitation of cyclic guanosine monophosphate-dependent protein kinase (PKG) with selective tri-substituted pyrrole and imidazopyridine inhibitors. These compounds exhibit in vivo efficacy against Eimeria tenella in chickens and Toxoplasma gondii in mice. We now report that both of these protein kinase inhibitor classes inhibit the growth of Leishmania major promastigotes and Trypanosoma brucei bloodstream forms in vitro. Genome informatics predicts that neither of these trypanosomatids codes for a PKG orthologue. Biochemical studies have led to the unexpected discovery that an isoform of CK1 represents the primary target of the pyrrole and imidazopyridine kinase inhibitors in these organisms. CK1 from extracts of L. major promastigotes co-fractionated with [3H]imidazopyridine binding activity. Further purification of CK1 activity from L. major and characterization via liquid chromatography coupled tandem mass spectrometry identified CK1 isoform 2 as the specific parasite protein inhibited by imidazopyridines. L. major CK1 isoform 2 expressed as a recombinant protein in Escherichia coli displayed biochemical and inhibition characteristics similar to those of the purified native enzyme. The results described here warrant further evaluation of the activity of these kinase inhibitors against mammalian stage Leishmania parasites in vitro and in animal models of infection, as well as studies to genetically validate CK1 as a therapeutic target in trypanosomatid parasites. [Copyright &y& Elsevier]

Abstract: Compounds 10a (IC50 110pM) and 21 (IC50 40pM) are the most potent inhibitors of Eimeria tenella cGMP-dependent protein kinase activity reported to date and are efficacious in the in vivo antiparasitic assay when administered to chickens at 12.5 and 6.25ppm levels in the feed. However, both compounds are positive in the Ames microbial mutagenesis assay which precludes them from further development as antiprotozoal agents in the absence of negative lifetime rodent carcinogenicity studies. [Copyright &y& Elsevier]