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ChemMedChem Apr 2022Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the antagonists of melanin...
Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the antagonists of melanin concentrating hormone receptor 1 (MCHR1). The design, synthesis, and biological studies of novel MCHR1 antagonists based on benzofuro-pyridine and pyrazino-indole scaffold was performed. We confirmed that fine-tuning lipophilicity and basic pK by modifying the benzyl group and introducing different substituents on the aliphatic nitrogen sidechain decreases both hERG inhibition and metabolic clearance. We have succeeded to develop excellent in vitro parameters in the case of compounds 17 (4-[(5-chloropyridin-2-yl)methoxy]-1-[4-(2-hydroxyethyl)-8-oxa-4-azatricyclo[7.4.0.0 , ]trideca-1(13),2(7),9,11-tetraen-11-yl]-1,2-dihydropyridin-2-one monohydrochloride) and 23 g (4-[(5-chloropyridin-2-yl)methoxy]-1-(1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)pyridin-2(1H)-one monohydrochloride), which can be considered as valuable tools for further pharmacological investigation.
Topics: Humans; Obesity; Pyridines; Receptors, Somatostatin; Structure-Activity Relationship
PubMed: 35041296
DOI: 10.1002/cmdc.202100707 -
Acta Parasitologica Mar 2023The imidazo[1,2-a] pyridines have huge applications in medicinal chemistry with potent activity against wide spectrum of infectious agents. The efficacy of...
BACKGROUND AND PURPOSE
The imidazo[1,2-a] pyridines have huge applications in medicinal chemistry with potent activity against wide spectrum of infectious agents. The efficacy of imidazo[1,2-a]pyridine on the in vitro growth of different piroplasms, including Babesia bovis, B. bigemina, B. divergens, B. caballi, and Theileria equi, was investigated in this study.
METHODS
The anti-piroplasm efficacy of imidazo[1,2-a] pyridines was assessed using a fluorescence-based SYBR Green I assay. Furthermore, efficacy of imidazo[1,2-a]pyridine against piroplasms following discontinuation of treatment was also assessed using a viability assay. In vitro cultures of B. bovis and T. equi were used to assess the imidazo[1,2-a]pyridine and diminazene aceturate (DA) interaction.
RESULTS
In vitro, imidazo[1,2-a]pyridine inhibited the growth of B. bovis, B. bigemina, B. caballi, and T. equi in a dose-dependent manner. The highest inhibitory effects of imidazo[1,2-a]pyridine were detected on the growth of B. caballi with IC value of 0.47 ± 0.07. Interestingly, the efficacy of imidazo[1,2-a]pyridine was higher against B. bigemina (IC: 1.37 ± 0.15) compared to the positive-control DA (IC: 2.29 ± 0.06). The viability test findings indicate that imidazo[1,2-a]pyridine had a long-lasting inhibitory effect on bovine Babesia parasites in vitro growth up to 4 days after treatment. Notably, when coupled with DA at 0.75 or 0.50 IC, a high concentration (0.75 IC) of imidazo[1,2-a]pyridine produced additive suppression of B. bovis growth which suggest that imidazo[1,2-a]pyridine/DA could be a promising combination therapy for the treatment of B. bovis.
CONCLUSION
The obtained encouraging findings pave the way for in vitro and in vivo efficacy trials of imidazo[1,2-a]pyridine derivatives against several piroplasmids.
Topics: Animals; Cattle; Babesia; Theileria; Pyridines; Babesiosis; Theileriasis
PubMed: 36637693
DOI: 10.1007/s11686-022-00655-w -
Archiv Der Pharmazie Oct 2021Novel inhibitors are needed to tackle tuberculosis. Herein, we report the 3-aryl-substituted imidazo[1,2-a]pyridines as potent antituberculosis agents. A small library...
Novel inhibitors are needed to tackle tuberculosis. Herein, we report the 3-aryl-substituted imidazo[1,2-a]pyridines as potent antituberculosis agents. A small library of 3-aryl-substituted imidazo[1,2-a]pyridines was synthesized using direct arylation, followed by nitro reduction and finally Pd-catalyzed C-N coupling reactions. The compounds thus obtained were evaluated against Mycobacterium tuberculosis H37Rv. Compound 26 was identified as an antituberculosis lead with a minimum inhibitory concentration of 2.3 μg/ml against M. tuberculosis H37Rv. This compound showed a selectivity index of 35. The docking of 26 in the active site of the M. tuberculosis cytochrome bc1 complex cytochrome b subunit (Mtb QcrB) revealed key π-π interactions of compound 26 with the Tyr389 and Trp312 residues of Mtb QcrB.
Topics: Antitubercular Agents; Microbial Sensitivity Tests; Molecular Docking Simulation; Mycobacterium tuberculosis; Pyridines; Structure-Activity Relationship
PubMed: 34185337
DOI: 10.1002/ardp.202000419 -
BioMed Research International 2023Multidrug-resistant (MDR) pathogens have created a fatal problem for human health and antimicrobial treatment. Among the currently available antibiotics, many are... (Review)
Review
Multidrug-resistant (MDR) pathogens have created a fatal problem for human health and antimicrobial treatment. Among the currently available antibiotics, many are inactive against MDR pathogens. In this context, heterocyclic compounds/drugs play a vital role. Thus, it is very much essential to explore new research to combat the issue. Of the available nitrogen-bearing heterocyclic compounds/drugs, pyridine derivatives are of special interest due to their solubility. Encouragingly, some of the newly synthesized pyridine compounds/drugs are found to inhibit multidrug-resistant (MRSA). Pyridine scaffold bearing poor basicity generally improves water solubility in pharmaceutically potential molecules and has led to the discovery of numerous broad-spectrum therapeutic agents. Keeping these in mind, we have reviewed the chemistry, recent synthetic techniques, and bacterial preventative activity of pyridine derivatives since 2015. This will facilitate the development of pyridine-based novel antibiotic/drug design in the near future as a versatile scaffold with limited side effects for the next-generation therapeutics.
Topics: Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Anti-Bacterial Agents; Anti-Infective Agents; Pyridines
PubMed: 37250749
DOI: 10.1155/2023/9967591 -
Organic Letters Jun 2023This study presents a DNA-compatible synthesis of diverse 5-arylimidazo[1,2-]pyridin-3-amine derivatives using the Suzuki-Miyaura reaction, followed by a...
This study presents a DNA-compatible synthesis of diverse 5-arylimidazo[1,2-]pyridin-3-amine derivatives using the Suzuki-Miyaura reaction, followed by a Groebke-Blackburn-Bienaymé (GBB) reaction. The GBB reaction demonstrates a wide substrate scope, mild one-pot reaction conditions, and compatibility with subsequent enzymatic ligation, highlighting its potential in DNA-encoded library technology.
Topics: Amines; Cyclization; DNA; Gene Library; Pyridines
PubMed: 37310879
DOI: 10.1021/acs.orglett.3c01366 -
Chemistry, An Asian Journal Apr 2022New examples of nonaromatic fused expanded porphyrins containing both pyridine and crown ether moiety as a part of macrocyclic framework were synthesized by condensing...
New examples of nonaromatic fused expanded porphyrins containing both pyridine and crown ether moiety as a part of macrocyclic framework were synthesized by condensing pyridine based pentapyrrane with polyether-based diol in CH Cl in the presence of one equivalent of BF ⋅ OEt under inert conditions followed by oxidation with DDQ in open air. The condensation was expected to form pyridine-containing crowned expanded porphyrins but resulted in the formation of fused crowned expanded porphyrins due to intramolecular fusion of two pyrrole nitrogens with two adjacent inverted thiophene carbons as revealed by X-ray crystallography obtained for one of the macrocycle. HRMS and NMR studies supported the formation of fused crowned pyridine containing expanded porphyrins, and the macrocycles showed simple, well-resolved NMR spectra where all resonances were identified easily by 2D NMR spectroscopy. The macrocycles exhibited typical nonaromatic absorption features and showed one broad band with peak maxima at 535 nm and one or two shoulder bands in the higher energy region. The protonation studies resulted in clear colour change from purple to blue and absorption bands experienced bathochromic shifts with a broad band at 662 nm which was extended up to 800 nm. The electrochemical studies revealed that the macrocycles were easier to oxidize but difficult to reduce. DFT studies indicated that the macrocycle attains a very puckered and distorted 'U' shaped structure owing to the flexibility of the crown ether chain and TD-DFT studies corroborated experimental results. The preliminary studies indicated that the macrocycles could be used as colorimetric optical sensor for the detection of Cu ion.
Topics: Crown Ethers; Molecular Conformation; Porphyrins; Pyridines
PubMed: 35244342
DOI: 10.1002/asia.202101425 -
ChemMedChem Mar 2021Starting from the N-hydroxy-3-(4-(2-phenylbutanoyl)amino)phenyl)acrylamide (5 b) previously described by us as a HDAC inhibitor, we prepared four aza-analogues, 6-8,...
Starting from the N-hydroxy-3-(4-(2-phenylbutanoyl)amino)phenyl)acrylamide (5 b) previously described by us as a HDAC inhibitor, we prepared four aza-analogues, 6-8, 9 b, as regioisomers containing the pyridine nucleus. Preliminary screening against mHDAC1 highlighted the N-hydroxy-5-(2-(2-phenylbutanoyl)amino)pyridyl)acrylamide (9 b) as the most potent inhibitor. Thus, we further developed both pyridylacrylic- and nicotinic-based hydroxamates (9 a, 9 c-f, and 11 a-f) and 2'-aminoanilides (10 a-f and 12 a-f), related to 9 b, to be tested against HDACs. Among them, the nicotinic hydroxamate 11 d displayed sub-nanomolar potency (IC : 0.5 nM) and selectivity up to 34 000 times that of HDAC4 and from 100 to 1300 times that of all the other tested HDAC isoforms. The 2'-aminoanilides were class I-selective HDAC inhibitors, generally more potent against HDAC3, with the nicotinic anilide 12 d being the most effective (IC =0.113 μM). When tested in U937 leukemia cells, the hydroxamates 9 e, 11 c, and 11 d blocked over 80 % of cells in G2/M phase, whereas the anilides did not alter cell-cycle progress. In the same cell line, the hydroxamate 11 c and the anilide 10 b induced about 30 % apoptosis, and the anilide 12 c displayed about 40 % cytodifferentiation. Finally, the most potent compounds in leukemia cells 9 b, 11 c, 10 b, 10 e, and 12 c were also tested in K562, HCT116, and A549 cancer cells, displaying antiproliferative IC values at single-digit to sub-micromolar level.
Topics: Anilides; Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Isoenzymes; Molecular Structure; Pyridines; Recombinant Proteins; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 33220015
DOI: 10.1002/cmdc.202000854 -
Molecules (Basel, Switzerland) Dec 2020The subject of the work was the synthesis of new derivatives of1-pyrrolo[3,4-c]pyridine-1,3(2)-dione with potential analgesic and sedative activity. Eight compounds...
The subject of the work was the synthesis of new derivatives of1-pyrrolo[3,4-c]pyridine-1,3(2)-dione with potential analgesic and sedative activity. Eight compounds werereceived. The analgesic activity of the new compounds was confirmed in the "hot plate" test and in the "writhing" test. All tested imides - were more active in the "writhing" test than aspirin, and two of them, and , were similar to morphine. In addition, all of the new imides inhibited the locomotor activity in mice to a statistically significant extent, and two of them also prolonged the duration of thiopental sleep.On the basis of the results obtained for the previously synthesized imides and the results presented in this paper, an attempt was madeto determine the relationship between thechemical structure of imides and their analgesic and sedativeproperties.
Topics: Analgesics; Animals; Hypnotics and Sedatives; Locomotion; Male; Mice; Pyridines; Pyrroles; Structure-Activity Relationship
PubMed: 33322767
DOI: 10.3390/molecules25245883 -
Natural Product Research Aug 2022Two undescribed disubstituted pyridine derivatives irpexidines A and B ( and ) and two undescribed alkylfuran derivatives irpexins K and L ( and ) were isolated from...
Two undescribed disubstituted pyridine derivatives irpexidines A and B ( and ) and two undescribed alkylfuran derivatives irpexins K and L ( and ) were isolated from fermentation broth of . Their structures were established by extensive spectroscopic methods. The pyridine derivatives from this fungus were reported for the first time. The new compounds were evaluated for their cytotoxicity against Hela cancer cell and inhibitory activity on NO production.
Topics: Fungi; Furans; Polyporales; Pyridines
PubMed: 33599175
DOI: 10.1080/14786419.2021.1889544 -
Chemical Record (New York, N.Y.) Sep 2022Multiply aryl/alkyl-substituted pyridines are some of the untapped synthetic targets because of the challenge in regioselectively introducing less polar aryl/alkyl... (Review)
Review
Multiply aryl/alkyl-substituted pyridines are some of the untapped synthetic targets because of the challenge in regioselectively introducing less polar aryl/alkyl groups at the desired positions in the pyridine framework. Interestingly, the importance of this family of compounds has increased annually, particularly in biological and materials engineering applications. The syntheses of such pyridines have been extensively reported, but there is a lack of comprehensive review articles. Hence, this review discusses recent advances by grouping reaction patterns that generally deliver tri-, tetra-, and penta-aryl/alkyl pyridines.
Topics: Pyridines
PubMed: 35701177
DOI: 10.1002/tcr.202200099