Design, synthesis, theoretical study, antioxidant, and anticholinesterase activities of new pyrazolo-fused phenanthrolines

Pyrazole-fused phenanthroline compounds were obtained through several synthetic routes. NMR, HRMS, and IR techniques were used to characterize and confirm the chemical structures. Crystal structures were obtained from compounds 3a, 5b, 5j, 5k, and 5n and analyzed using X-ray diffraction. Compounds were evaluated as acetyl (AChE) and butyrylcholinesterase (BChE) inhibitors, and the results showed a moderate activity. Compound 5c presented the best activity against AChE (IC50 = 53.29 μM) and compound 5l against BChE enzyme (IC50 = 119.3 μM). Furthermore, the ability of the synthetic compounds to scavenge cationic radicals DPPH and ABTS was evaluated. Compound 5e (EC50 = 26.71 μg mL−1) presented the best results in the DPPH assay, and compounds 5e, 5f and 5g (EC50 = 11.51, 3.10 and <3 μg mL−1, respectively) showed better ABTS cationic radical scavenging results. Finally, in silico analyses indicated that 71% of the compounds show good oral availability and are within the ranges established by the Lipinski criteria.

[1]  R. Chatterjee,et al.  Ionic Liquid‐Assisted Synthesis of 2‐Amino‐3‐cyano‐4 H ‐chromenes: A Sustainable Overview , 2021, Journal of Heterocyclic Chemistry.

[2]  Virender Kumar,et al.  Multicomponent synthesis, in vitro cytotoxic evaluation and molecular modelling studies of polyfunctionalized pyrazolo[3,4-b]pyridine derivatives against three human cancer cell lines , 2021, Synthetic Communications.

[3]  S. A. Ibrahim,et al.  Green routes for the synthesis of new pyrazole bearing biologically active imidiazolyl, pyridine and quinoxaline derivatives as promising antimicrobial and antioxidant agents , 2021, Journal of the Iranian Chemical Society.

[4]  J. Joseph,et al.  Design, synthesis, characterization, DNA binding, acetyl and butyryl cholinesterase activities of metal chelates with 1,10-Phenanthroline derivative , 2020, Inorganic Chemistry Communications.

[5]  M. Khoobi,et al.  A review: Biologically active 3,4-heterocycle-fused coumarins. , 2020, European journal of medicinal chemistry.

[6]  Mohamed S. Nafie,et al.  Discovery of novel pyrazolo[3,4-b]pyridine scaffold-based derivatives as potential PIM-1 kinase inhibitors in breast cancer MCF-7 cells. , 2020, Bioorganic & medicinal chemistry.

[7]  Shi-wu Chen,et al.  Synthesis and antioxidant activity of conjugates of hydroxytyrosol and coumarin. , 2020, Bioorganic chemistry.

[8]  H. M. Gençkal.  New heteroleptic Cu(II) complexes of chrysin with 2,2ꞌ–bipyridine and substituted 1,10–phenanthrolines: Synthesis, characterization, thermal stability and antioxidant activity , 2020 .

[9]  K. Fromm,et al.  Different coordination abilities of 1,7- and 4,7-phenanthroline in the reactions with copper(II) salts: Structural characterization and biological evaluation of the reaction products , 2019, Polyhedron.

[10]  Haibin Luo,et al.  Dual functional cholinesterase and PDE4D inhibitors for the treatment of Alzheimer's disease: Design, synthesis and evaluation of tacrine-pyrazolo[3,4-b]pyridine hybrids. , 2019, Bioorganic & medicinal chemistry letters.

[11]  M. Tiwari,et al.  A multifunctional therapeutic approach: Synthesis, biological evaluation, crystal structure and molecular docking of diversified 1H-pyrazolo[3,4-b]pyridine derivatives against Alzheimer's disease. , 2019, European journal of medicinal chemistry.

[12]  M. Shaaban,et al.  Synthesis of new pyrazoles and pyrozolo [3,4-b] pyridines as anti-inflammatory agents by inhibition of COX-2 enzyme. , 2019, Bioorganic chemistry.

[13]  D. Avcı,et al.  Synthesis, antioxidant activity and SAR study of novel spiro-isatin-based Schiff bases , 2019, Molecular Diversity.

[14]  K. Fromm,et al.  Mononuclear silver(I) complexes with 1,7-phenanthroline as potent inhibitors of Candida growth. , 2018, European journal of medicinal chemistry.

[15]  Suaib Luqman,et al.  Antiproliferative efficacy of curcumin mimics through microtubule destabilization. , 2018, European journal of medicinal chemistry.

[16]  C. Hureau,et al.  Oxidative stress as a biomarker for Alzheimer's disease. , 2018, Biomarkers in medicine.

[17]  M. Tomás,et al.  Oxidative stress and the amyloid beta peptide in Alzheimer’s disease , 2017, Redox biology.

[18]  D. Eisenberg,et al.  Neurodegeneration: Taming tangled tau , 2017, Nature.

[19]  C. Luchese,et al.  Antioxidant effect of quinoline derivatives containing or not selenium: Relationship with antinociceptive action quinolines are antioxidant and antinociceptive. , 2017, Anais da Academia Brasileira de Ciencias.

[20]  K. P. Kepp.  Alzheimer’s disease due to loss of function: A new synthesis of the available data , 2016, Progress in Neurobiology.

[21]  Marwa Sayed Salem,et al.  Novel Pyrazolo[3,4-b]pyridine Derivatives: Synthesis, Characterization, Antimicrobial and Antiproliferative Profile. , 2016, Biological & pharmaceutical bulletin.

[22]  M. Tobe,et al.  The chemistry and biological activity of heterocycle-fused quinolinone derivatives: A review. , 2015, European journal of medicinal chemistry.

[23]  K. Papadopoulos,et al.  Modified DPPH and ABTS Assays to Assess the Antioxidant Profile of Untreated Oils , 2015, Food Analytical Methods.

[24]  M. Diederich,et al.  Synthesis and bioactivity of novel amino-pyrazolopyridines. , 2014, European journal of medicinal chemistry.

[25]  A. Milelli,et al.  Oxidative stress in Alzheimer's disease: are we connecting the dots? , 2014, Journal of medicinal chemistry.

[26]  S. Batra,et al.  Synthesis of 3H-pyrazolo[3,4-c]isoquinolines and thieno[3,2-c]isoquinolines via cascade imination/intramolecular decarboxylative coupling. , 2013, Organic letters.

[27]  M. G. Savelieff,et al.  Untangling amyloid-β, tau, and metals in Alzheimer's disease. , 2013, ACS chemical biology.

[28]  M. Devereux,et al.  Deciphering the antimicrobial activity of phenanthroline chelators. , 2012, Current medicinal chemistry.

[29]  P. Dubey,et al.  L-Proline-Catalyzed Knoevenagel Condensation: A Facile, Green Synthesis of (E)-Ethyl 2-Cyano-3-(1H-indol-3-yl)acrylates and (E)-3-(1H-Indol-3-yl)acrylonitriles , 2012 .

[30]  H. F. Rizk,et al.  Synthesis of pyrazolo[3,4-b]pyridines under microwave irradiation in multi-component reactions and their antitumor and antimicrobial activities - Part 1. , 2012, European journal of medicinal chemistry.

[31]  P. Mohan,et al.  Synthesis, antioxidant and toxicological study of novel pyrimido quinoline derivatives from 4-hydroxy-3-acyl quinolin-2-one. , 2010, Bioorganic & medicinal chemistry letters.

[32]  A. Tolmachev,et al.  Approach to the library of fused pyridine-4-carboxylic acids by Combes-type reaction of acyl pyruvates and electron-rich amino heterocycles. , 2010, Journal of combinatorial chemistry.

[33]  M. Karabacak,et al.  An experimental and theoretical study of molecular structure and vibrational spectra of 2-chloronicotinic acid by density functional theory and ab initio Hartree–Fock calculations , 2008 .

[34]  S. Dall’Acqua,et al.  Evaluation of in vitro antioxidant properties of some traditional Sardinian medicinal plants: Investigation of the high antioxidant capacity of Rubus ulmifolius , 2008 .

[35]  S. Emanuel,et al.  Synthesis and evaluation of pyrazolo[3,4-b]pyridine CDK1 inhibitors as anti-tumor agents. , 2007, Bioorganic & medicinal chemistry letters.

[36]  I. Gülçin,et al.  Synthesis of dimeric phenol derivatives and determination of in vitro antioxidant and radical scavenging activities , 2007 .

[37]  R. Schliebs,et al.  Aging-related increase in oxidative stress correlates with developmental pattern of beta-secretase activity and beta-amyloid plaque formation in transgenic Tg2576 mice with Alzheimer-like pathology , 2004, International Journal of Developmental Neuroscience.

[38]  Chang Yong Lee,et al.  Comprehensive Study on Vitamin C Equivalent Antioxidant Capacity (VCEAC) of Various Polyphenolics in Scavenging a Free Radical and its Structural Relationship , 2004, Critical reviews in food science and nutrition.

[39]  S. Fabris,et al.  Evaluation of the Antioxidant Properties of Propofol and its Nitrosoderivative. Comparison with Homologue Substituted Phenols , 2004, Free radical research.

[40]  Matthew P. Repasky,et al.  Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. , 2004, Journal of medicinal chemistry.

[41]  P. Geerlings,et al.  Conceptual density functional theory. , 2003, Chemical reviews.

[42]  M. Tabaton,et al.  Amyloid‐β Deposition in Alzheimer Transgenic Mice Is Associated with Oxidative Stress , 1998, Journal of neurochemistry.

[43]  W. L. Jorgensen,et al.  Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids , 1996 .

[44]  Raymond E. Davis,et al.  Patterns in Hydrogen Bonding: Functionality and Graph Set Analysis in Crystals , 1995 .

[45]  M. Frisch,et al.  Ab Initio Calculation of Vibrational Absorption and Circular Dichroism Spectra Using Density Functional Force Fields , 1994 .

[46]  A. Becke.  Density-functional thermochemistry. III. The role of exact exchange , 1993 .

[47]  R. Floyd,et al.  Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[48]  K. Jellinger,et al.  Accumulation of abnormally phosphorylated τ precedes the formation of neurofibrillary tangles in Alzheimer's disease , 1989, Brain Research.

[49]  J. Pople,et al.  Self—Consistent Molecular Orbital Methods. XII. Further Extensions of Gaussian—Type Basis Sets for Use in Molecular Orbital Studies of Organic Molecules , 1972 .

[50]  K. Courtney,et al.  A new and rapid colorimetric determination of acetylcholinesterase activity. , 1961, Biochemical pharmacology.

[51]  Tarik El-Sayed Ali.  Synthesis of some novel pyrazolo[3,4-b]pyridine and pyrazolo[3,4-d]pyrimidine derivatives bearing 5,6-diphenyl-1,2,4-triazine moiety as potential antimicrobial agents. , 2009, European journal of medicinal chemistry.