European Journal of Chemistry

Structural and electronic effects of the C2’ substituent in 1,4–benzodiazepines



Main Article Content

Lígia Rebelo Gomes
Luís Manuel Neves Belchior Faia Santos
José Beleza
John Nicolson Low

Abstract

Benzodiazepines are drugs used for treatment of several central nervous system disorders, such as anxiety and sleep. In spite of their wide and popular usage in clinics, the mechanism explaining why a certain pharmacological activity is superimposed onto another for a given benzodiazepine remains unclear. The knowledge of the conformation of benzodiazepines and their electronic charge distribution at molecular surfaces may give new insights into the pharmaco-benzodiazepine receptor interactions, contributing to the improvement of the existing models. In the present study, the solid state geometric and conformational parameters of the available X-ray benzodiazepine structures were analyzed and reviewed. The electronic features of two groups of benzodiazepines with different substituents at C7 and C2’ positions were studied by DFT quantum chemical calculations. The conformations of the molecules with optimized geometry were also analyzed. The relative charge distribution around the benzodiazepinic rings and electrostatic potential mapped on electronic density surfaces were obtained. The ring geometric parameters for the diazepine moiety in 1,4-benzodiazepines, do not vary significantly except for a few compounds in which steric and/or intermolecular interactions play a part. The benzodiazepine ring assumes a pseudo-symmetrical boat conformation and the torsion angle around the C5-Ph bond varies depending on the nature of the substituent on C2’. Also, the presence of the nitro or chloride substituent on the C7 position and the presence of a fluorine atom on the C2’ position significantly alter the relative charge distributions at the attached carbon atoms and the topology of the surface electrostatic potential.

2_1_1_7_800


icon graph This Abstract was viewed 1944 times | icon graph Article PDF downloaded 713 times icon graph Article SUPPLEMENTARY FILE downloaded 0 times

How to Cite
(1)
Gomes, L. R.; Santos, L. M. N. B. F.; Beleza, J.; Low, J. N. Structural and Electronic Effects of the C2’ Substituent in 1,4–benzodiazepines. Eur. J. Chem. 2011, 2, 1-7.

Article Details

Share
Crossref - Scopus - Google - European PMC
References

[1]. Abraham, D. J. Nervous System Agents - Burger’s Medicinal Chemistry & Drug Discovery – 6th Ed., Wiley Interscience, John Wiley and Sons; Department of Medicinal Chemistry, School of Pharmacy Virginia Commonwealth, 2003, Vol. 6.

[2]. Kessler, R. C.; Frank, R. G. Psychol. Med. 1997, 27, 861-873.
doi:10.1017/S0033291797004807
PMid:9234464

[3]. Walley, E. J.; Beebe D. K.; Clark, J. L. Am. Fam. Physician. 1994, 50, 1745–1753.
PMid:7977004

[4]. Van Ameringen, M.; Mancini, C.; Farvolden, P.; Oakman J. Curr. Psychiatry Rep. 2000, 2, 358–366.
doi:10.1007/s11920-000-0082-7
PMid:11122982

[5]. Davidson, J. R.; Potts, N. L. S.; Richichi, E. A. J. Clin. Psychopharmacol. 1993, 13, 423–428.
doi:10.1097/00004714-199312000-00008
PMid:8120156

[6]. Gelernter, C. S.; Uhde, T. W.; Cimbolic, Peter; Arnkoff, D. B.; Vittone, Bernard J.; Tancer, M. E.; Bartko, J. J. Arch. Gen. Psychiatry. 1991, 48, 938–945.

[7]. Sternbach, L. H. J. Clin. Psychopharmacol. 1994, 14, 170–179.

[8]. Sanger, D. J.; Benavides, J.; Perrault, G.; Morel, E.; Cohen, C.; Joly, D.; Zivkovic, B. Neurosci. Biobehav. Rev. 1994, 18, 355–372.
doi:10.1016/0149-7634(94)90049-3

[9]. Rudolph, U.; Crestani, F.; Möhler, H. Trends Pharmacol. Sci. 1999, 22, 188–194.
doi:10.1016/S0165-6147(00)01646-1

[10]. Mölher, H.; Crestani, F.; Rudolph, U. Curr. Opin. Pharmacol. 2001, 1, 22–25.
doi:10.1016/S1471-4892(01)00008-X

[11]. Da Settimo, F.; Taliani, S.; Trincavelli, M. L.; Montali, M.; Martini, C. Curr. Med. Chem. 2007, 14, 2680–2701.
doi:10.2174/092986707782023190
PMid:17979718

[12]. Atack, J. R. Expert Opin. Investia. Drugs. 2005, 14, 601–618.
doi:10.1517/13543784.14.5.601
PMid:15926867

[13]. Allen, F. H. Acta Cryst. 2002, B58, 380–388.

[14]. Williams D. B.; Akabas M. H. Mol. Pharmacol. 2000, 58, 1129–1136.
PMid:11040062

[15]. Gaussian 03. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A. Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;. Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T. Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian, Inc., Pittsburgh PA, 2003.

[16]. Becke A. D. J. Chem. Phys. 1997, 107, 8554–8560.

[17]. Lee, C.; Yang, W.; Parr, G. R. Phys. Rev. B: Condens. Matter Mater. Phys. 1998, 37, 785–789.
doi:10.1103/PhysRevB.37.785

[18]. Hehre, W. J.; Random L.; Schleyer P. V. R.; Pople J. A. Ab Initio Molecular Orbital Theory, Wiley, New York, 1986.

[19]. Carpenter, J. E.; Weinhold, F. J. Mol. Struct. Theochem. 1998, 169, 41-62.
doi:10.1016/0166-1280(88)80248-3

[20]. GaussView 3.0. Dennington II, R.; Keith, T.; Millam, J. GaussView, Version 4.1.2, Semichem., Inc., Shawnee Mission, KS, 2007. Available from: <http://www.gaussian.com>.

[21]. Razgulin, A. V.; Mecozzi, S. J. Med. Chem. 2006, 49, 7902–7906.
doi:10.1021/jm0600702
PMid:17181174

[22]. O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308–319.
doi:10.1039/b711844a
PMid:18197347

[23]. Clayton, T.; Chen, J. L.; Ernst, M.; Richter, L.; Cromer, B. A.; Morton, C. J.; Ng, H.; Kaczorowski, C. C.; Helmstetter, F. J.; Furtmüller, R.; Ecker, G.; Parker, M. W.; Sieghart, W.; Cook, J. M. Curr. Med. Chem. 2007, 14, 26, 2755–2775.
doi:10.2174/092986707782360097
PMid:18045122

[24]. Meréndez, J. C.; Avendaño C. Optimizacion de un protótipo. Correlationes cualitativas estrutura química – actividad biológica, in Avendaño C: Introdution a la química Farmaceutica, 2nd Ed. McGraw Hill, Madrid, 2001, pp. 87–88.

[25]. Breimer, D. D.; Jochemsen, R. Br. J. Clin. Pharmacol. 1983, 16, 277S–278S.
PMid:6140947 PMCid:1428230

[26]. Greenblatt, D. J.; Shader, R. I.; Koch-Weser, J. Ann. of Intern. Med. 1975, 83, 237–241.
PMid:238445

[27]. Berlin, A.; Dahlstrom, H. Eur. J. Clin. Pharmacol. 1975, 9, 155–159.
doi:10.1007/BF00614012
PMid:1233263

[28]. Morishita, S. Hum. Psychopharmacol. 2009, 24, 191–198.
doi:10.1002/hup.1015
PMid:19330803

[29]. Mattila, M. A.; Larni, H. M. Drugs, 1980, 20, 353–374.
doi:10.2165/00003495-198020050-00002
PMid:6108205

[30]. Hevers, W.; Lueddens, H. Mol. Neurobiol. 1998, 18, 35–86.
doi:10.1007/BF02741459
PMid:9824848

[31]. Hanson, S. M.; Czajkowski, C. J. Neurosci, 2008, 28, 3490–3499.
doi:10.1523/JNEUROSCI.5727-07.2008
PMid:18367615 PMCid:2410040

Most read articles by the same author(s)

Most read articles by the same author(s)

TrendMD

Dimensions - Altmetric - scite_ - PlumX

Downloads and views

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...
License Terms

License Terms

by-nc

Copyright © 2024 by Authors. This work is published and licensed by Atlanta Publishing House LLC, Atlanta, GA, USA. The full terms of this license are available at https://www.eurjchem.com/index.php/eurjchem/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution, or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (https://www.eurjchem.com/index.php/eurjchem/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry).