Synthesis, Antibacterial Activity and Molecular Docking of Phospholidinones in Stigmastane Series

Azhar    U.    Khan; Mahboob       Alam; Soonheum       Park; Poonam       Dwivedi; Sunil    K.   Sharma; Sapna       Jain

Abstract

Introduction: Steroid compounds are widely distributed in nature throughout scientific history. Living organisms such as animals and vegetables have steroids that show a significant effect on their vital activities. Sterols are key components of all eukaryotic cell membranes.

Methods: Steroidal compounds; 3β-oxo-[1’,3’,2’-oxathiaphos-phalidine-2’-one] stigmast-5-ene and 3β- oxo[1`,3`,2`-dioxaphosphalidine-2`-one]-stigmast-5-ene were successfully prepared using easily accessible 3β-hydroxy stigmast-5-ene with phosphorous oxychloride (POCl3), 2- mercaptoethanol/ethylene glycol and triethylamine (Et3N) in dry diethyl ether. Products were obtained in semi-solid state and characterized using physicochemical techniques.

Results: The results of the bioassay showed that the synthesized compound containing the sulfur atom had antibacterial activity. Molecular docking was also done in order to show in silico antibacterial activity and to make out the probable binding mode of compound with the amino acid residues of protein.

Conclusion: The results of the docking study showed that synthesized compound 2 had minimal binding energy with substantial affinity for the active site.

Keywords: Cyclization, stigmasterol, 2-mercaptoethanol, phospholidinones, docking, Steroidal Compounds.

« Previous Next »

Graphical Abstract

[1] 
Brueggemeier, R.W.; Li, P.K. Fundamental of steroid chemistry and biochemistry. In:Burger’s Medicinal Chemistry and Drug Discovery, 3: Cardiovascular agent and endocrines, 6th ed; Abraham, D.J., Ed.; John Wiley and Sons, Inc: New York, 2003, pp. 594-627.
[2] 
Lednicer, D. Steroids Chemistry at a Glance; John Wiley Sons Ltd, 2011. 
[3] 
Alam, M.; Lee, D.U. Eco-friendly synthesis, physicochemical studies, biological assay and molecular docking of steroidal oxime-ethers. EXCLI J.,  2015, 14, 394-407.
[4] 
Mehtab, P.; Mohammad, M.A.; Akhtar, A.; Mahboob, A.; Faisal, M.M. Silica-supported thionyl chloride-assisted synthesis and bioassay of novel tetrazinan-3-thione and 3-oxo-pyrazolidine-4-carbonitrile derivatives of steroids. Chem. Res. Chin. Univ.,  2014, 30, 55-62.
[5] 
Mushfiq, M.; Manuel, T.; Rehman, R. Synthesis of steroidal oxazolidine thiones in the cholestane series. Synth. Commun.,  2004, 34(21), 3989-3996.
[6] 
Shamsuzzaman, K.H.; Mashraia, A.; Asif, M.; Ali, A.; Barakat, A.; Mabkhot, Y.N. Synthesis, crystal structure, Hirshfeld surfaces and thermal, mechanical and dielectrical properties of cholest-5-ene. J. Taibah Univ. Sci.,  2017, 11, 141-150.
[7] 
Nicolaou, K.C.; Montagnon, T. Steroids & the Pill. In: Molecules
that changed the world Wiley-VCH Verlag GmbH & Co. KGaA,
Weinheim,, 2008, pp. 79-90.
[8] 
Salvador, J.A.K.; Carvaiho, J.F.S.; Neves, M.A.S.; Silvestre, S.M.; Leitao, A.J.; Silva, M.M.C.; Sa e Melo, L.M. Anticancer steroids: Linking natural and semi-synthetic compounds. Nat. Prod. Rep.,  2013, 30, 324-374.
[9] 
Kiuru, P.S.; Wahala, K. Microwave-assisted synthesis of deuterium labelled estrogen fatty acid esters. Steroids,  2006, 71, 54-60.
[10] 
Foldes, R.S.; Pfeiffer, P.; Horvath, J.; Tuba, Z.; Kollar, L. Microwave-assisted stille-coupling of steroidal substrates. Steroids,  2002, 67, 709-713.
[11] 
Marwah, P.; Marwah, A.; Lardy, H.A. Microwave induced selective enolization of steroidal ketones and efficient acetylation of sterols in semisolid state. Tetrahedron,  2003, 59, 2273-2287.
[12] 
Khan, A.U.; Mushfiq, M. Reaction of steroidal ketones with substituted alkyl azide. Asian J. Res. Chem,  2010, 3, 747-750.
[13] 
Khan, A.U.; Mushfiq, M. Synthesis of novel [6,7-b]indole of cholestane series. Orient. J. Chem.,  2010, 26, 1091-1095.
[14] 
Khan, A.U.; Alam, M.; Mushfiq, M. The synthesis of 2-amino-5α-cholest-6-eno[6,7- ] thiazole derivatives under microwave irradiation using dry-media conditions. Chin. Chem. Lett.,  2008, 19, 1027-1030.
[15] 
Rajnikant, Dinesh. A.N.; Mushfiq, M.; Alam, M.; Khan, A.U. Synthesis and structure determination of 7a-Aza-B-homostigmast-5-eno[7a,7-d] tetrazole-3β-yl chloride (C29H47N4Cl). J. Chem. Crystallogr.,  2006, 12, 793-798.
[16] 
Alam, M.; Lee, D.U. Synthesis, spectroscopic and computational studies of 2-(thiophene-2-yl)-2,3-dihydro-1H-perimidine: An enzymes inhibition study. Comput. Biol. Chem.,  2016, 64, 185-201.
[17] 
Clinton, R.O.; Manson, A.J.; Stonner, F.W.; Neumann, H.C.; Christiansen, R.G.; Clarke, R.L.; Ackerman, J.H.; Page, D.F.; Dean, J.W.; Dickinson, W.B.; Carabatea, C. Steroidal [3,2-c]prazoles. II Androstanes, 19-Norandrostanes and their unsaturated analogs. J. Am. Chem. Soc., 1961, 83, 1478-1491; Green, B.; Jenseen, B.L.; Lalan, P.L. The synthesis of steroidal [16α, 17α-d]-2′- pyrazolines and [16,17-d]-pyrazoles. Tetrhedron,  1978, 34, 1633-1639.
[18] 
Banothu, J.; Vaarla, K.; Bavantula, R.; Crooks, P.A. Sodium fluoride as an efficient catalyst for the synthesis of 2,4-disubstituted-1,3-thiazoles and selenazoles at ambient temperature. Chin. Chem. Lett.,  2014, 25, 172-175.
[19] 
Zhao, B.; Xu, Y.; Deng, Q-G.; Liu, Z.; Wang, L-Y.; Gao, Y. One-pot three components synthesis of novel 15H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylate derivative by microwave irradiation. Tetrahedron Lett.,  2014, 55, 4521-4524.
[20] 
Hill, R.A.; Kirk, D.N.; Makin, H.L.J.; Murphy, G.M. Description of main steroid types. In:Dictionary of steroids; Chapman & Hill: London, 1991, pp. XIV-XXIX.
[21] 
Shamsuzzaman, M. A.; Khanam, H.; Mabkhot, Y.N.; Frey, W. 3β-Acetoxy-6-nitrocholest-5-ene: Crystal structure, thermal, optical and dielectrical behaviour. J. Mol. Struct.,  2014, 1063, 219-225.
[22] 
Laitonjam, W.S.; Rajkumar, T.S.; Chingakham, B.S. Synthesis of some A-and D-ring fused steroidal pyrazoles, isoxazoles and pyrimidines. Steroids,  2002, 67, 203-209.
[23] 
Norbeck, D.W.; Kramer, J.B.; Larty, P.A. Synthesis of an isosteric phosphonate analog of cytidine 5′-monophospho-3-deoxy-D-manno-2-octulosonic acid. J. Org. Chem.,  1987, 52, 2174-2179.
[24] 
Baker, R.H.; Squire, E.N. Derived steroids; cholesteryl ketones. J. Am. Chem. Soc.,  1948, 70, 1487-1490.
[25] 
Mohamed, N.R.; Elmegeed, G.A.; Younis, M. Studies on organophosphorus compounds VII. Transformations of steroidal ketones with Lawesson’s Reagent into thioxo and heterofused steroids. Results of antimicrobial and antifungal Activity. Phosphorus Sulfur,  2003, 178, 2003-2017.
[26] 
Ahmad, D. Ph.D. Thesis Chapter 3 section B, A.M.U. Aligarh,
India,. 1992.
[27] 
Brown, J.M.; Laing, J.C.P. Nucleophilic displacement routes to P-chiral phosphines; the introduction of sterically encumbered groups. J. Organomet. Chem.,  1997, 529, 435-444.
[28] 
Morris, G.M.; Goodsell, D.S.; Halliday, R.S.; Huey, R.; Hart, W.E.; Belew, R.K.; Olson, A.J. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J. Comput. Chem.,  1998, 19, 1639-1662.
[29] 
Sanner, M.F. Python: A programming language for software integration and development. J. Mol. Graph. Model.,  1999, 17, 57-61.
[30] 
Morris, G.M.; Ruth, H.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. Software news and updates AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem.,  2009, 30, 2785-2791.
[31] 
Sandhaus, S.; Annamalai, T.; Welmaker, G.; Houghten, R.A.; Paz, C.; Garcia, P.K.; Andres, A.; Narula, G.; Felix, C.R.; Geden, S.; Netherton, M.; Gupta, R.; Rohde, K.H.; Giulianotti, M.A.; Tse-Dinh, C-H. Small-molecule inhibitors targeting Topoisomerase I as novel antituberculosis agents. Antimicrob. Agents Chemother.,  2016, 60, 4028-4036.
[32] 
Accelrys Software Inc. Discovery studio modeling environment. Release 3.1. 2011.
[33] 
Thomsen, R.; Christensen, M.H. MolDock: A new technique for high-accuracy molecular docking. J. Med. Chem.,  2006, 11, 3315-3321.

Rights & Permissions Print Cite

Article Metrics

46

4

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1573409914666181029122448	Print ISSN 1573-4099
Publisher Name Bentham Science Publisher	Online ISSN 1875-6697

Current Computer-Aided Drug Design

Synthesis, Antibacterial Activity and Molecular Docking of Phospholidinones in Stigmastane Series

Abstract

Graphical Abstract

Related Journals

Related Books