The Substituent Effects on Chemical Reactivity and Aromaticity Current of Ritalin Drug

الموضوعات :

Arezoo Tahan ¹ (Department of chemistry, Semnan Branch, Islamic Azad University, Semnan, Iran)
Mahya Khojandi ² (Department of Chemistry, Central Tehran Branch, Islamic Azad University, Tehran, Iran)

تاريخ الإرسال : 25 الجمعة , رمضان, 1442 تاريخ التأكيد : 01 السبت , ربيع الثاني, 1443 تاريخ الإصدار : 09 الأربعاء , شعبان, 1444

الکلمات المفتاحية: NBO analysis, Chemical hardness, NICS, ritalin,

ملخص المقالة :

In this study, the effects of four substitutions in two different positions of Methylphenidate (MPH, Ritalin) structure on chemical reactivity indices and aromaticity current of benzene ring were investigated at the density functional theory (DFT) level. The results were interpreted using natural bond orbital (NBO) analysis. The findings indicated that by increasing the participation of the studied substitutions in intramolecular interactions, their effect on the chemical reactivity indices and aromaticity current increased. Therefore, the substituents NO2 and Cl on the benzene ring, with the highest participation in intramolecular interactions, caused the highest increase in the resonance interactions of the benzene ring. As a result, they increased the values of the Nuclear Independent Chemical Shift (NICS) in the geometric center of the ring. Also, the above substitutions decreased the energy gap between HOMO (highest occupied molecular orbitals) orbitals and LUMO (lowest unoccupied molecular orbitals) and increased chemical reactivity indices. On the other hand, The NBO results represented that electron-withdrawing substituents at positions R7 and R9 reduced the accumulation of negative charge on adjacent atoms and the benzene ring.

المصادر:

1. Ding Y.S., Fowler J.S., Volkow N.D., Dewey S.L., Wang G.J., Logan J., Gatley S.J., Pappas N., 1997. Chiral drugs: comparison of the pharmacokinetics of [11C] d-threo and L-threo-methylphenidate in the human and baboon brain. Psychopharmacology (Berl). 131, 71–78.


2. Srinivas N.R., Hubbard J.W., Quinn D., Midha K.K., 1992. Enantioselective pharmacokinetics and pharmacodynamics of dlthero mcthylphenidate in children with attention deficit hyperactivity disorder. Clin Pharmacol Ther. 52, 561–568.


3. Froimowitz M., Wu K.M., George C., VanDerveer D., Shi Q., Deutsch H.M., 1998. Crystal Structures of Analogs of threo-Methylphenidate. Struct Chem. 9, 295–303.


4. Froimowitz M., Patrick K.S., Cody V., 1995. Conformational analysis of methylphenidate and its structural relationship to other dopamine reuptake blockers such as CFT. Pharm Res. 12, 1430–1434.


5. Kim D.I., Deutsch H.M., Ye X., Schweri M.M., 2007. Synthesis and pharmacology of site-specific cocaine abuse treatment agents: Restricted rotation analogues of methylphenidate. J Med Chem. 50, 2718–2731.


6. Steinberg A., Froimowitz M., Parrish D.A., Deschamps J.R., Glaser R., 2011. Solution- and solid-state conformations of C(α)-alkyl analogues of methylphenidate (Ritalin) salts: Avoidance of gauche + gauche - Interactions. J Org Chem. 76, 9239–9245.


7. Bayarı S.H., Seymen B., Ozısık H., Saglam S., 2009. Theoretical study on gas-phase conformations and vibrational assignment of methylphenidate. J Mol Struct Theochem. 893, 17–25.


8. George M.Hanna C.A.L.C., 1993. Determination of the optical purity and absolute configuration of three-methylphenidate by proton nuclear magnetic resonance spectroscopy with chiral solvating agent. J Pharm Biomed Anal. 11, 665–670.


9. Gilbert K.M., Skawinski W.J., Misra M., Paris K.A., Naik N.H., Buono R.A., Deutsch H.M., Venanzi C.A., 2004. Conformational analysis of methylphenidate: comparison of molecular orbital and molecular mechanics methods. J Comput Aided Mol Des. 18, 719–738.


10. Lapinsky D.J., Velagaleti R., Yarravarapu N., Liu Y., Huang Y., Surratt C. K., Lever J.R., Foster J.D., Acharya R., Vaughan R.A., Deutsch H.M., 2011. Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling. Bioorganic Med Chem. 19, 504–512.


11. Misra M., Shi Q., Ye X., Gruszecka-kowalik E., Bu W., Liu Z., Schweri M. ., Deutsch H.M., Venanzi C.A., 2010. Bioorganic & Medicinal Chemistry Quantitative structure – activity relationship studies of threo -methylphenidate analogs. Bioorg Med Chem. 18, 7221–7238.


12. Gatley S.J., Pan D., Chen R., Chaturvedi G., Ding Y.S., 1996. Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters. Life Sci. 58, 231–239.


13. Lee C., Yang W., Parr R.G., 1988. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B. 37, 785.


14. Becke A.D., 1993. Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys. 98, 5648–5652.


15. Parr R.G., Pearson R.G., 1983. Absolute hardness: companion parameter to absolute electronegativity. J Am Chem Soc. 105, 7512–7516.


16. Parr R.G., Szentpály L.V., Liu S., 1999. Electrophilicity index. J Am Chem Soc. 121, 1922–1924.


17. Mulliken R.S., 1934. A new electroaffinity scale; together with data on valence states and on valence ionization potentials and electron affinities. J Chem Phys. 2, 782–793.


18. Iczkowski R.P., Margrave J.L., 1961. Electronegativity. J Am Chem Soc. 83, 3547–3551.


19. Schleyer P. von R., Maerker C., Dransfeld A., Jiao H., van Eikema Hommes N.J.R., 1996. Nucleus-independent chemical shifts: a simple and efficient aromaticity probe. J Am Chem Soc. 118, 6317–6318.


20. Glendening E.D., Landis C.R., Weinhold F., 2013. NBO 6.0: natural bond orbital analysis program. J Comput Chem. 34, 1429–1437.


21. Reed A.E., Curtiss L.A., Weinhold F., 1988. Intermolecular interactions from a natural bond orbital, donor-acceptor viewpoint. Chem Rev. 88, 899–926.


22. Frisch M.J., Trucks G.W., Schlegel H.B., Scuseria G.E., Robb M.A., Cheeseman J.R., Scalmani G., Barone V., Mennucci B., Petersson G.A., 2009. Gaussian 09, revision A. 1. Gaussian Inc. Wallingford CT. 27, 34.