Synthesis, molecular docking, molecular dynamics and evaluation of Drug-Likeness properties of the fused N-Formyl pyrazoline substituted new dehydroepiandrosterone derivatives

Abstract The hybrid molecules bearing heterocyclic structures in the A or D rings of steroids have significant biological activity. 16 (E)-Hetereoarylidene steroids were synthesized from the reaction of different heteroaromatic carbaldehydes and trans-Dehydroepiandrosterone (DHEA) in a basic medium. Then, synthesis of the N-formyl pyrazoline substituted new DHEA derivatives were carried out from the reaction of hydrazine hydrate and 16 (E)-hetereoarylidene steroids. The structures of the synthesized compounds were elucidated by elemental analysis, FT-IR, 1H NMR, and 13C NMR spectroscopy. To investigate the activation pathway of synthesized N-formyl pyrazoline substituted steroid derivatives, a molecular docking study was performed on human cytochrome P450-(CYP17A1: PDB ID 5IRQ) with the help of the free AutoDock Vina. 100 ns molecular dynamic simulation process was performed to monitor the behavior of the complex structure formed by CYP17A1 and to calculate the stability over time of 2a and 2d (-9.8 kcal/mol), which gave the lowest value according to the results obtained in the molecular docking study with AutoDock Vina. Accordingly, RMSD, RMSF, Rg, and SASA analyzes of 2a and 2d were performed, and MMPBSA was calculated. Lastly, the ADMET (absorption, distribution, metabolism, excretion, and toxicity) analyses of the novel steroid derivatives were investigated. Communicated by Ramaswamy H. Sarma

[1]  Ranjit Singh,et al.  Steroidal pyrazolines as a promising scaffold in drug discovery. , 2020, Future medicinal chemistry.

[2]  F. Dumur,et al.  Recent syntheses of steroidal derivatives containing heterocycles , 2019, Arkivoc.

[3]  S. Karataş,et al.  Synthesis of Indole and Benzimidazole Substituted Novel 16-Arylidene Steroid Derivatives , 2019, Letters in Organic Chemistry.

[4]  İrfan Çapan,et al.  Synthesis of Heterocyclic‐Substituted Novel Hydroxysteroids with Regioselective and Stereoselective Reactions , 2018 .

[5]  Ranjit Singh,et al.  Studies on 16,17-Pyrazoline Substituted Heterosteroids as Anti-Alzheimer and Anti-Parkinsonian Agents Using LPS Induced Neuroinflammation Models of Mice and Rats. , 2017, ACS chemical neuroscience.

[6]  J. Medina-Franco,et al.  Molecular docking : current advances and challenges , 2018 .

[7]  P. Kaplan,et al.  The role of CYP17A1 in prostate cancer development: structure, function, mechanism of action, genetic variations and its inhibition. , 2017, General physiology and biophysics.

[8]  Jeffrey Aubé,et al.  Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 , 2017, Drug Metabolism and Disposition.

[9]  Ranjit Singh,et al.  Investigations on 16-Arylideno Steroids as a New Class of Neuroprotective Agents for the Treatment of Alzheimer's and Parkinson's Diseases. , 2017, ACS chemical neuroscience.

[10]  B. L. de Groot,et al.  CHARMM36m: an improved force field for folded and intrinsically disordered proteins , 2016, Nature Methods.

[11]  Berk Hess,et al.  GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers , 2015 .

[12]  Vikas Kumar,et al.  Oxime-dipeptides as anticholinesterase, reactivator of phosphonylated-serine of AChE catalytic triad: probing the mechanistic insight by MM-GBSA, dynamics simulations and DFT analysis , 2015, Journal of biomolecular structure & dynamics.

[13]  I. Zupkó,et al.  Lewis acid-induced intramolecular access to novel steroidal ring D-condensed arylpyrazolines exerting in vitro cell-growth-inhibitory effects , 2015, Molecular Diversity.

[14]  Anil K. Mishra,et al.  In silico thermodynamics stability change analysis involved in BH4 responsive mutations in phenylalanine hydroxylase: QM/MM and MD simulations analysis , 2015, Journal of biomolecular structure & dynamics.

[15]  D. Lamb,et al.  CYP17A1 inhibitors in castration-resistant prostate cancer , 2015, Steroids.

[16]  S. Shameem,et al.  Steroidal pyrazolines and pyrazoles as potential 5α-reductase inhibitors: Synthesis and biological evaluation , 2014, Steroids.

[17]  S. Montiel-Smith,et al.  Synthesis of steroidal derivatives containing substituted, fused and spiro pyrazolines , 2014, Steroids.

[18]  Rajendra Kumar,et al.  g_mmpbsa - A GROMACS Tool for High-Throughput MM-PBSA Calculations , 2014, J. Chem. Inf. Model..

[19]  J. Molnár,et al.  Anticancer and Multidrug Resistance-Reversal Effects of Solanidine Analogs Synthetized from Pregnadienolone Acetate , 2014, Molecules.

[20]  He Li,et al.  Synthesis and cytotoxic activity of some novel steroidal C-17 pyrazolinyl derivatives. , 2013, European journal of medicinal chemistry.

[21]  Hoong-Kun Fun,et al.  Synthesis and Crystal Structures of N-Substituted Pyrazolines , 2013, Molecules.

[22]  A. Amr,et al.  Steroidal pyrazolines evaluated as aromatase and quinone reductase-2 inhibitors for chemoprevention of cancer. , 2012, International journal of biological macromolecules.

[23]  T. Wittmann,et al.  Synthesis of D-ring-substituted (5′R)- and (5′S)-17β-pyrazolinylandrostene epimers and comparison of their potential anticancer activities , 2012, Steroids.

[24]  Atta-ur-rahman,et al.  Pregnenolone derivatives as potential anticancer agents , 2011, Steroids.

[25]  R. Hartmann,et al.  Synthesis and biological evaluation of 16E-arylidenosteroids as cytotoxic and anti-aromatase agents. , 2011, Chemical & pharmaceutical bulletin.

[26]  Tamar Schlick,et al.  Molecular Modeling and Simulation: An Interdisciplinary Guide , 2010 .

[27]  Arthur J. Olson,et al.  AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading , 2009, J. Comput. Chem..

[28]  T. Schlick.  Molecular Dynamics: Basics , 2010 .

[29]  R. Lesyk,et al.  Synthesis of novel thiazolone-based compounds containing pyrazoline moiety and evaluation of their anticancer activity. , 2009, European journal of medicinal chemistry.

[30]  I. Zupkó,et al.  Efficient approach to androstene-fused arylpyrazolines as potent antiproliferative agents. Experimental and theoretical studies of substituent effects on BF(3)-catalyzed intramolecular [3 + 2] cycloadditions of olefinic phenylhydrazones. , 2009, Journal of the American Chemical Society.

[31]  W. Khalil,et al.  Androgenic profile and genotoxicity evaluation of testosterone propionate and novel synthesized heterocyclic steroids , 2008, The Journal of Steroid Biochemistry and Molecular Biology.

[32]  John L. Klepeis,et al.  Anton, a special-purpose machine for molecular dynamics simulation , 2007, ISCA '07.

[33]  A. S. Girgis,et al.  Novel bis(1-acyl-2-pyrazolines) of potential anti-inflammatory and molluscicidal properties. , 2006, Bioorganic & medicinal chemistry.

[34]  A. Amr,et al.  Synthesis and antiandrogenic activity of some new 3-substituted androstano[17,16-c]-5'-aryl-pyrazoline and their derivatives. , 2006, Bioorganic & medicinal chemistry.

[35]  E. J. Tavares da Silva,et al.  Structure-activity relationships of new A,D-ring modified steroids as aromatase inhibitors: design, synthesis, and biological activity evaluation. , 2005, Journal of medicinal chemistry.

[36]  Conrad C. Huang,et al.  UCSF Chimera—A visualization system for exploratory research and analysis , 2004, J. Comput. Chem..

[37]  D. P. Jindal,et al.  16-(4-Isopropylbenzylidene)androst-4-ene-3,17-dione. , 2004, Acta crystallographica. Section C, Crystal structure communications.

[38]  K. Binder,et al.  Molecular dynamics simulations , 2003, cond-mat/0308148.

[39]  A. Levai,.  Synthesis of 2-Pyrazolines by the Reactions of α,β-Unsaturated Aldehydes, Ketones, and Esters with Diazoalkanes, Nitrile Imines, and Hydrazines , 2002 .

[40]  L. Troisi,et al.  Chemoselective construction of novel steroid derivatives , 2002, Steroids.

[41]  S. Thamotharan,et al.  16-[3-Methoxy-4-(2-piperidin-1-ylethoxy)benzylidene]-17-oxoandrost-5-en-3beta-yl acetate monohydrate. , 2002, Acta crystallographica. Section C, Crystal structure communications.

[42]  A. Katritzky,et al.  Regioselective synthesis of polysubstituted pyrazoles and isoxazoles. , 2001, The Journal of organic chemistry.

[43]  HighWire Press,et al.  Drug metabolism and disposition : the biological fate of chemicals. , 1973 .

[44]  A. Hassner,et al.  The Formation of the N—N Bond in Pyrazolines , 1962 .