Design, Synthesis, Pharmacological Evaluation and DFT Investigation of New Bioactive Unsymmetrical Bi-Functional Ligand
Abstract
Compounds with more than one bioactive motif become of great interest. In this regard, a new tridentate 1,2-unsymmetrical ligand consists of flexible and rigid bioactive arms spaced by benzene ring in an ortho position designed to form a bifunctional molecule. The 2-((3-(pyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzonitrile (PPMB) synthesized under phase transfer reaction and characterized using 1H-NMR and mass spectroscopy and studied as potent kinase inhibitors. Theoretically, the molecule structure was investigated at the B3LYP/6-311++G(d,p) level of theory in the gas phase and revealed that all bond lengths and bond angles within the accepted limit. The frontier molecular orbitals (FMO) energies (HOMO and LUMO), energy gap, dipole moment, chemical softness and chemical hardness were calculated. Pharmacologically, the ligand activity was investigated in silico using SWISS ADME. Furthermore, the compound was docked into the transforming growth factor (TGF) beta type I receptor kinase active site to evaluate the ability of ligand as a kinase inhibitor.
Keywords: DFT, pyrazolyl-pyridine, physiochemical, properties molecular docking, bioactive molecules, unsymmetrical ligands
Keywords:
DFT, pyrazolyl-pyridine, physiochemical, properties molecular docking, bioactive molecules, unsymmetrical ligandsDOI
https://doi.org/10.22270/jddt.v12i4.5429References
Najar AM, Tidmarsh IS, Adams H, Ward MD. Cubes, squares, and books: A simple transition metal/bridging ligand combination can lead to a surprising range of structural types with the same metal/ligand proportions. Inorg Chem. 2009 https://doi.org/10.1021/ic901892y
Najar AM, Tidmarsh IS, Ward MD. An octanuclear helical "molecular wheel" from hierarchical assembly of four dinuclear Cu in a mixed-ligand array. RSC Adv. 2012; 2(4). https://doi.org/10.1039/c2ra01177h
Berteotti A, Vacondio F, Lodola A, Bassi M, Silva C, Mor M, et al. Predicting the reactivity of nitrile-carrying compounds with cysteine: A combined computational and experimental study. ACS Med Chem Lett. 2014; 5(5):501-5. https://doi.org/10.1021/ml400489b
Blechert S. Methodenregister organischer Transformationen: "Comprehensive Organic Transformations"︁ - A Guide to functional Group preparations. Von R. C. Larock. VCH Verlagsgesellschaft, Weinheim 1989. 1060 S., DM 118,-. ISBN 3-527-26953-3. Nachrichten aus Chemie, Tech und Lab. 1990; https://doi.org/10.1002/nadc.19900380923
Singh J, Petter RC, Baillie TA, Whitty A. The resurgence of covalent drugs. Nature Reviews Drug Discovery. 2011. https://doi.org/10.1038/nrd3410
Teno N, Miyake T, Ehara T, Irie O, Sakaki J, Ohmori O, et al. Novel scaffold for cathepsin K inhibitors. Bioorganic Med Chem Lett. 2007; https://doi.org/10.1002/chin.200810164
Fleming FF, Yao L, Ravikumar PC, Funk L, Shook BC. Nitrile-containing pharmaceuticals: Efficacious roles of the nitrile pharmacophore. Journal of Medicinal Chemistry. 2010. https://doi.org/10.1021/jm100762r
Le Questel J, Berthelot M, Laurence C. Hydrogen‐bond acceptor properties of nitriles: a combined crystallographic and ab initio theoretical investigation. J Phys Org Chem. 2000; https://doi.org/10.1002/1099-1395(200006)13:6<347::AID-POC251>3.0.CO;2-E
Cuzick J, Sestak I, Forbes JF, Dowsett M, Cawthorn S, Mansel RE, et al. Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial. Lancet. 2020; https://doi.org/10.1016/S0140-6736(19)32955-1
Bhatnagar AS. The discovery and mechanism of action of letrozole. Breast Cancer Research and Treatment. 2007. https://doi.org/10.1007/s10549-007-9696-3
Frizler M, Stirnberg M, Sisay M, Gutschow M. Development of Nitrile-Based Peptidic Inhibitors of Cysteine Cathepsins. Curr Top Med Chem. 2010; https://doi.org/10.2174/156802610790725452
Frizler M, Lohr F, Furtmann N, Kläs J, Gütschow M. Structural optimization of azadipeptide nitriles strongly increases association rates and allows the development of selective cathepsin inhibitors. J Med Chem. 2011; https://doi.org/10.1021/jm101272p
Gaulton A, Hersey A, Nowotka ML, Patricia Bento A, Chambers J, Mendez D, et al. The ChEMBL database in 2017. Nucleic Acids Res. 2017; https://doi.org/10.1093/nar/gkw1074
Gómez I, Alonso E, Ramón DJ, Yus M. Naphthalene-catalysed lithiation of chlorinated nitrogenated aromatic heterocycles and reaction with electrophiles. Tetrahedron. 2000; https://doi.org/10.1002/chin.200042059
Henry GD. De novo synthesis of substituted pyridines. Tetrahedron. 2004. https://doi.org/10.1002/chin.200440246
Busto E, Gotor-Fernández V, Gotor V. Chemoenzymatic synthesis of chiral 4-(N,N-dimethylamino)pyridine derivatives. Tetrahedron Asymmetry. 2005; https://doi.org/10.1016/j.tetasy.2005.09.006
Altaf AA, Shahzad A, Gul Z, Rasool N, Badshah A, Lal B. A Review on the Medicinal Importance of Pyridine Derivatives. 2015;(January). https://doi.org/10.1155/2015/913435
Trofimenko S. The coordination chemistry of pyrazole-derived ligands. Chem Rev. 1972; https://doi.org/10.1021/cr60279a003
Neelarapu R, Holzle DL, Velaparthi S, Bai H, Brunsteiner M, Blond SY, et al. Design, synthesis, docking, and biological evaluation of novel diazide-containing isoxazole- and pyrazole-based histone deacetylase probes. J Med Chem. 2011; https://doi.org/10.1021/jm2001025
Najar AM, Tidmarsh IS, Adams H, Ward MD. Cubes, squares, and books: A simple transition metal/bridging ligand combination can lead to a surprising range of structural types with the same metal/ligand proportions. Inorg Chem. 2009; 48(24):11871-81. https://doi.org/10.1021/ic901892y
Najar AM, Tidmarsh IS, Ward MD. Lead(ii) complexes of bis- and tris-bidentate compartmental ligands based on pyridyl-pyrazole and pyridyl-triazole fragments: Coordination networks and a discrete dimeric box. CrystEngComm. 2010; https://doi.org/10.1039/c0ce00176g
Ma N, Wang Y, Zhao BX, Ye WC, Jiang S. The application of click chemistry in the synthesis of agents with anticancer activity. Drug Des Devel Ther. 2015; 9:1585-99. https://doi.org/10.2147/DDDT.S56038
Luna Parada LK, Vargas Méndez LY KV. Quinoline-Substituted 1,2,3-Triazole-Based Molecules, As Promising Conjugated Hybrids in Biomedical Research. Org Med Chem IJ. 7(2):001-0010.
Duvernelle C, Freund V, Frossard N. Transforming growth factor-β and its role in asthma. Vol. 16, Pulmonary Pharmacology and Therapeutics. 2003. https://doi.org/10.1016/S1094-5539(03)00051-8
Huse M, Muir TW, Xu L, Chen YG, Kuriyan J, Massagué J. The TGFβ receptor activation process: An inhibitor- to substrate-binding switch. Mol Cell. 2001; 8(3). https://doi.org/10.1016/S1097-2765(01)00332-X
McCaffrey TA. TGF-βs and TGF-β receptors in atherosclerosis. Vol. 11, Cytokine and Growth Factor Reviews. 2000. https://doi.org/10.1016/S1359-6101(99)00034-9
Nakamura T, Miller D, Ruoslahti E, Border WA. Production of extracellular matrix by glomerular epithelial cells is regulated by transforming growth factor-β1. Kidney Int. 1992; 41(5). https://doi.org/10.1038/ki.1992.183
Ray S, Broor SL, Vaishnav Y, Sarkar C, Girish R, Dar L, et al. Transforming growth factor beta in hepatitis C virus infection: In vivo and in vitro findings. J Gastroenterol Hepatol. 2003; 18(4). https://doi.org/10.1046/j.1440-1746.2003.02985.x
Zimmerman CM, Padgett RW. Transforming growth factor β signaling mediators and modulators. Vol. 249, Gene. 2000. https://doi.org/10.1016/S0378-1119(00)00162-1
Wang F, Schwabacher AW. A convenient set of bidentate pyridine ligands for combinatorial synthesis. Tetrahedron Lett. 1999; https://doi.org/10.1016/S0040-4039(99)00885-0
Frisch M. No Titl. Gaussian09 http//www gaussian com/. 2009;
Mabkhot YN, Alatibi F, El-Sayed NNE, Al-Showiman S, Kheder NA, Wadood A, et al. Antimicrobial activity of some novel armed thiophene derivatives and petra/Osiris/Molinspiration (POM) analyses. Molecules. 2016; 21(2). https://doi.org/10.3390/molecules21020222
Alnajjar R, Mohamed N, Kawafi N. Bicyclo[1.1.1]Pentane as Phenyl Substituent in Atorvastatin Drug to improve Physicochemical Properties: Drug-likeness, DFT, Pharmacokinetics, Docking, and Molecular Dynamic Simulation. J Mol Struct. 2020; https://doi.org/10.1016/j.molstruc.2020.129628
Molecular Operating Environment (MOE) 2013.08. Molecular Operating Environment (MOE), 2013.08; Chemical Computing Group Inc., 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7. Mol Oper Environ (MOE), 201308; Chem Comput Gr Inc, 1010 Sherbooke St West, Suite #910, Montr QC, Canada, H3A 2R7, 2013. 2016;
Alnajjar R, Mostafa A, Kandeil A, Al-Karmalawy AA. Molecular docking, molecular dynamics, and in vitro studies reveal the potential of angiotensin II receptor blockers to inhibit the COVID-19 main protease. Heliyon. 2020; 6(12). https://doi.org/10.1016/j.heliyon.2020.e05641
Sethi S, Jena S, Das PK, Behera N. Synthetic approach and structural diversities of pyridylpyrazole derived late transition metal complexes. J Mol Struct [Internet]. 2019; 1193:495-521. https://doi.org/10.1016/j.molstruc.2019.04.112
Waring MJ. Defining optimum lipophilicity and molecular weight ranges for drug candidates-Molecular weight dependent lower log D limits based on permeability. Bioorganic Med Chem Lett. 2009;19(10).
https://doi.org/10.1016/j.bmcl.2009.03.109
Mannhold R, Poda GI, Ostermann C, Tetko I V. Calculation of molecular lipophilicity: State-of-the-art and comparison of log P methods on more than 96,000 compounds., Journal of Pharmaceutical Sciences. 2009: 98. https://doi.org/10.1002/jps.21494
Hughes JD, Blagg J, Price DA, Bailey S, DeCrescenzo GA, Devraj R V., et al. Physiochemical drug properties associated with in vivo toxicological outcomes. Bioorganic Med Chem Lett. 2008; 18(17). https://doi.org/10.1016/j.bmcl.2008.07.071
Ritchie TJ, MacDonald SJF, Peace S, Pickett SD, Luscombe CN. Increasing small molecule drug developability in sub-optimal chemical space. Medchemcomm. 2013; 4(4):673-80. https://doi.org/10.1039/c3md00003f
Ottaviani G, Gosling DJ, Patissier C, Rodde S, Zhou L, Faller B. What is modulating solubility in simulated intestinal fluids? Eur J Pharm Sci. 2010; 41(3-4). https://doi.org/10.1016/j.ejps.2010.07.012
Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017; https://doi.org/10.1038/srep42717
Doak BC, Over B, Giordanetto F, Kihlberg J. Oral druggable space beyond the rule of 5: Insights from drugs and clinical candidates. Chemistry and Biology. 2014; 21 https://doi.org/10.1016/j.chembiol.2014.08.013
Franc I, Lipinski A, Feeney PJ. Lipinski Rule, AdvDrugDelivRev 1997. Adv Drug Deliv Rev. 1997; 23. https://doi.org/10.1016/S0169-409X(96)00423-1
Ertl P, Schuffenhauer A. Estimation of synthetic accessibility score of drug-like molecules based on molecular complexity and fragment contributions. J Cheminform. 2009; 1(1). https://doi.org/10.1186/1758-2946-1-8
Villela lucia maria aversa. Graham L. Patrick - An Introduction to Medicinal Chemistry-Oxford University Press (2013). J Chem Inf Model. 2013; 53(9).
Ertl P, Rohde B, Selzer P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J Med Chem. 2000; 43(20). https://doi.org/10.1021/jm000942e
Daina A, Zoete V. A BOILED-Egg To Predict Gastrointestinal Absorption and Brain Penetration of Small Molecules. ChemMedChem. 2016; https://doi.org/10.1002/cmdc.201600182
Arnott JA, Planey SL. The influence of lipophilicity in drug discovery and design. Vol. 7, Expert Opinion on Drug Discovery. 2012. https://doi.org/10.1517/17460441.2012.714363
Savjani KT, Gajjar AK, Savjani JK. Drug Solubility: Importance and Enhancement Techniques. ISRN Pharm. 2012; 2012. https://doi.org/10.5402/2012/195727
Tetko I V., Bruneau P, Mewes HW, Rohrer DC, Poda GI. Can we estimate the accuracy of ADME-Tox predictions? Drug Discovery Today. 2006; 11 https://doi.org/10.1016/j.drudis.2006.06.013
Montanari F, Ecker GF. Prediction of drug-ABC-transporter interaction - Recent advances and future challenges. Vol. 86, Advanced Drug Delivery Reviews. 2015. https://doi.org/10.1016/j.addr.2015.03.001
Testa B, Krämer SD. The Biochemistry of Drug Metabolism - An Introduction. Chem Biodivers. 2007; 4(9). https://doi.org/10.1002/cbdv.200790169
Potts RO, Guy RH. Predicting Skin Permeability. Pharm Res An Off J Am Assoc Pharm Sci. 1992; 9(5).
Lipinski CA. Lead- and drug-like compounds: The rule-of-five revolution. Vol. 1, Drug Discovery Today: Technologies. 2004. https://doi.org/10.1016/j.ddtec.2004.11.007
Brenk R, Schipani A, James D, Krasowski A, Gilbert IH, Frearson J, et al. Lessons learnt from assembling screening libraries for drug discovery for neglected diseases. ChemMedChem. 2008; 3(3). https://doi.org/10.1002/cmdc.200700139
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews. 1997. https://doi.org/10.1016/S0169-409X(96)00423-1
Ghose AK, Viswanadhan VN, Wendoloski JJ. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J Comb Chem. 1999; 1(1). https://doi.org/10.1021/cc9800071
Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002; 45(12). https://doi.org/10.1021/jm020017n
Sawyer JS, Beight DW, Britt KS, Anderson BD, Campbell RM, Goodson T, et al. Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-β type I receptor kinase domain. Bioorganic Med Chem Lett. 2004; 14(13). https://doi.org/10.1016/j.bmcl.2004.04.007
Published
Abstract Display: 506 
PDF Downloads: 536 PDF Downloads: 103 How to Cite
Issue
Section
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
How to Cite
.