A Theoretical Study for the Structure of Propranolol and Some Fluorinated Derivatives

Transcription

1 Structural Chemistry, Vol. 6, Nos. 4/5, 1995 A Theoretical Study for the Structure of Propranolol and Some Fluorinated Derivatives Zarreen H. Farooqi 1 and Hassan Y. Aboul-Enein 2'3 Received September 6, 1994; revised January 5, 1995; accepted January 11, 1995 This paper reports on studies of the theoretical geometrical structure of propranolol and three of its fluorinated derivatives: l-(2,2,2-trifluoroethylamino)-3-(l-naphthyloxy)-2-propanol [trifluoroethyl-propranolol], l-(2,2,3,3,3-pentafluoropropylamino)-3-(1-naphthyloxy)-2-propanol [pentafluoropropyl-pmpranolol], and l-(2,2,3,3,4,4,4-heptafluorobutylamino)-3-(l-naphthyloxy)-2- propanol [heptafluorobutyl-propranolol]. The semiempirical method AM 1 was used to optimize the structures. In the minimum energy state the geometries of the naphthyl moiety and the nonfluorinated portions of the analogs are quite similar to that of the parent. Dipole moments, charge density distributions, and electrostatic potential distributions all point to the significance of the ether oxygen in all four compounds and the increasing contribution of the side-chain terminal to the activity of the molecule with increasing number of fluorines. KEY WORDS: Propranolol; fluorinated analogue; molecular models; semiempificaltechniques; fl-adrenergic blocke~. INTRODUCTION Propranolol, chemically known as 1-isopropylamino-3-(1-naphthyloxy)-2-propanol (see Fig. la) is the model parent drug for nonselective/~-blockers, a "pure" antagonist of catecholamines at the receptor sites. It has been used (i) to chronically lower blood pressure in (mild to moderate) hypertension, (ii) to prevent reflex tachycardia in severe hypertension, (iii) to reduce intraocular pressure in glaucomatous eyes, (iv) to reduce the frequency of anginal episodes and improve exercise tolerance in many patients with angina, (v) in the acute phase of a myocardial infarction to limit infarct size (a controversial use), (vi) in the treatment of both supraventricular and ventricular arrhythmias, (vii) to increase stroke i Department of Biomedical Statistics and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia. 2Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia. 3 Correspondence should be directed to Hassan Y. Aboul-Enein, BMR, MBC 03, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Kingdom of Saudi Arabia. volume in obstructive cardiomyopathy patients, (viii) to inhibit peripheral conversion of thyroxine to triiodothyronine (besides H-blockade), (ix) to reduce the frequency and intensity of migraine headaches, (x) to reduce somatic manifestations of anxiety and (xi) to treat alcohol withdrawal [1]. The principal toxicities of propranolol result from the blockade of cardiac, vascular, or bronchial /3-adrenoceptors. Most important predictable extensions are in patients with reduced myocardial reserve, asthma, peripheral vascular insufficiency, and diabetes. Some patients experience a withdrawal syndrome when discontinued after a long use. The manifestations of this are anxiety, tachycardia, increased intensity of angina, or increase in blood pressure [1]. The side effects of propranolol are not desired and a cardioselective H-blocker would be of great importance, not only in terms of specificity but also to reduce the dosage and thus toxicity. Aboul-Enein [2] recently reviewed the effect of introducing fluorine to medicinal agents and its influence in enhancing the pharmacological activity on these therapeutic agents. In search for compounds with better activity, some fluorinated derivatives of propranolol have been synthesized, the structures of three of which are given in Figs. lb and ld, namely, 1-(2,2,2-349 I040-04(0/95/I / Plenum Publishing Corporation

2 350 Com Dound Propranolol, la lb lc H ~ t e ~ - Propnma~, ld 19, '~2 ~1o9~ 2~2s 29'30 n "R R1 To C18 on the mdn stnctum 3S To C1tl on the n~ h n 33733~3(~ Toeleon~w~,~s To C1tl on the main structure F ToC16onthem~n~n~tum ~ 311 F 36 ~0 3~_r_ F42,f R2 4o H(34) H(34) H(34) Fig. 1. The chemical structure of: propranolol (la), trifiuoroethylpropranolol (lb), pentafluoropropyl-propranolol (lc), heptafluorobutyl-propranolol (ld). The schematic illustrates the common structure together the numbers of the atoms. The table below the schematic gives the side chains RI and R2 in the four molecules. trifluoroethylamino)-3-(1-naphthyloxy)-2-propanol (lb, known as trifluoroethyl-propranolol), 1-(2,2,3,3,3-pentafluoropropylamino)-3-(1-naphthyloxy)-2-propanol (lc, known as pentafluoropropyl-propranolol), and 1-(2,2, 3,3,4,4,4 - heptafl uorobutylamino) ( 1 - naphthyloxy) - 2-propanol (ld, known as heptafluorobutyl-propranolol). The synthesis of these fluorinated derivatives and the results of their pharmacological activity are presented elsewhere. This paper only describes the computed atomic structure of propranolol and these three fluorinated analogs. This is the first time that their structural geometry is being described. There have been publications describing the synthesis (for example, Ref. 3) and the pharmacological activity of drugs (for example, Ref. 4) that have side chains composed of the "(CF2)nCF3" (n >_ 0) group. There seems to be very little work done describing the electronic structure of organic compounds derived by using these side chains or an effect of fluorine on the molecular structure. What is known is that (i) replacing hydrogen by fluorine as in CF 3 (compared to CH3) can Farooqi and AbouI-Enein increase the lipid solubility and hence increase the rate of transport of biologically active compounds across lipid membranes [4]; and (ii) CF 2 is isopolar and isosteric with O and may be used to increase the stability of a drug by replacing an O at a biochemically labile position [4]. METHODS The four structures above were created using HyperChem for Windows [5] and optimized with a semiempirical technique, namely AM 1. The Polak-Ribiere conjugate gradient method was used for optimization. The minimum energy states (with minimum binding energy) that were achieved were as in Table I. RESULTS AND DISCUSSION Geometries The geometrical coordinates of propranolol together with the charges on each atom are presented in Table II. Similar information about the fluorinated derivatives is given in Tables III to V. All the coordinates and distances in this paper are in angstroms (.~,). Except where significant the particulars of the hydrogen atoms are not given here, and can be obtained from the authors. The naphthyl moiety in all the compounds is fiat. The bond angles of the naphthyl group are all approximately 120 ~ each with minimal torsion within the rings. All the other bond angles range between 105 ~ and 125 ~. In propranolol, the side chain zigzags around an axis in the plane of the naphthyl group (view a in Fig. 2). If the molecule is turned to view it from a side so that the naphthyl moiety becomes a straight line (view b in Fig. 2), the side chain is also more or less a straight line with its axis making an angle of approximately ~ with the plane of the naphthyl group. Keeping the rings fiat and viewing the molecule such that the side chain goes into the plane of the paper perpendicularly (view c in Fig. 2), the bond with O17 atom (oxygen of the hydroxyl group) makes an angle of about -63 ~ and the bond of the C34 atom an angle of about 121 ~ with the plane of the rings. In lb, the side chain zigzags in a similar way as in view a (Fig. 2) of the parent and its axis makes an angle of approximately ~ with the plane of the rings (in a view similar to view b of Fig. 2). While, when the side chain projects perpendicularly into the paper plane (like view c in Fig. 2) the bond with

3 i Computed Structure of Propranolol and Some Fluorinated Analogs 351 Table I. Optimized Energies of the Molecules. S.Nr Compound Ionization Heat of potential formation Min. binding (ev) kcal/mol) energy (kcal/mol) Gradient (kcal/mol/,~) Total energy (kcal/mol) Propranolol (la) Trifluoroethyl-propranolol (lb) Pentafluoropropyl-propranolol (lc) Heptafluorobutyl-propranolol (ld) O17 atom makes about 66 ~ the C36 atom an angle of about 45.5 ~ and the bond with C37 atom an angle of about ~ with the plane of the rings. In lc, zigzagging of the nonfluorinated portion of the side chain is similar to the parent (like view a in Fig. 2) and its axis makes an angle of approximately ~ with the plane of the rings (like in view b of Fig. 2). The --CF 3 group projects almost perpendicularly to the rest of the side chain (i.e., the nonfluorinated portion) in the direction opposite to that of the O17 atom. When viewed from the side with the side chain going perpendicularly into the paper plane (like in view c of Fig. 2) the bond with the O17 atom makes an angle of almost -118 ~ the bond of the C35 atom of about ~ and the bond of C37 atom of almost 115 ~ with the plane of the rings. In ld, the zigzagging of the nonfluorinated portion is similar to the parent (like in view a of Fig. 2) and the axis of the nonflourinated portion of the side chain makes an angle of about ~ with the plane of the rings (like Table 1I. Coordinates of Propranolol (la). # Atom (e-) (A,) (A) (A) 1 c c -0, c -0, C c C c c C o c C c c N C O C C in view b of Fig. 2), the first portion of the fluorinated region of the side chain (i.e., C33--C37 link) is at about 93 ~ to the nonfluorinated region of the side chain and the second region (i.e., C37--C39 link) is at about ~ to the first link (both of these in view b). In a view similar to view c of Fig. 2, the bond of the O17 atom makes an angle of about 67 ~ with the plane of the rings, the bond of C35 atom an angle of about 52 ~ and the bond of C37 atom of about -60 ~ In all four compounds the oxygen of the hydroxyl group (O17 atom) makes almost a fight angle to the side chain in the side view (-90 ~ in propranolol and lc and +90 ~ in lb and ld, respectively, in a view similar to view b of Fig. 2). There were mostly small changes in the geometry of the molecules with the introduction of the fluorine atoms, except near the side-chain terminus. The geom- Table IlL Coordinates of Trifluoroethyl-Propranolol (lb). # Atom (e-) (,~) (A,) (,~) 1 C C C C C C C C C C O C C C N C O C H F F F

4 352 Farooqi and Aboul-Enein Table IV. Coordinates of Pentafluoropropyl-Propranolol (lc). # Atom (e-) (A) (A) (A) 1 C C C C C C I C C C C O C C C N C O C H F F C F F F etries are illustrated in Fig. 3 with the molecules displayed along their longitudinal axes together with charges on individual atoms. The most important bond lengths, bond angles and the torsion angles of propranolol and the fluorinated analogs may be obtained from the supplementary material. Molecular Volumes The sizes of the four molecules are not very different. In fact, there is a reduction in size from the parent to the first derivative (--CF3). The dimensions of the molecule boxes together with the molecular volumes for the four molecules are as follows: propranolol A, 3, trifluoroethyl propranolol A, 3, pentafluoropropyl-propranolol ~3, and heptafluorobutyl propranolol A, 3. Energies The various energies (total energies, minimum binding energies, heats of formation, ionization potentials) relevant for the molecules are given in Table I. From the data presented above, it appears that the influence of the fluorine atoms is primarily at the terminal in Table V. Coordinates of Heptafluorobutyl-Propranolol (ld). # Atom (e-) (A) (A) (A) 1 C C C C C C C C C C O C C C N C O C H F F C F C F F F F ! Fig. 2. Propranolol viewed perpendicular to its (a) longitudinal (primary or 1") axis, (b) secondary (2 ~ axis, and (c) tertiary (3*) axis. 3

5 Computed Structure of Propranolol and Some Fluorinated Analogs 353 <tls7 - o.. s ~ -o.alw -o.in Ii ~ ;.,.- "*' la.~.i~ / The heat of formation of the CF 2 increment group may be estimated from the various compounds given in Table 1-1 of Ref. 6, and turns out to be in the range of kcal/mol to kcal/mol, with a mean of kcal/mol. From the same table [6] heat of formation attributable to CF 3 may be estimated to be approximately -160 kcal/mol. Given the heat of formation of propranolol (-58 kcal/mol), the estimated heats of formation for the three derivatives from these figures come out to be -218 kcal/mol, -321 kcal/mol and -424 kcal/mol which are not significantly different from the respective values obtained from the AM1 calculations (given in Table I) lb 127 ~.0.1S2 "%...,,.a~.o~.a.~a,..,,~" " ~/.a.f~... ~; I; ~.om.:oeo a,~ ~ yso "~ '~t ~*~ lc 9 0. fs7. O. 0 f ~ ~ f 3 7 ~a,1 'm.o.al~ Fig. 3. The atomic charges and the structure of (a) propranolol, (b) trifluoroethyl-propranolol, (c) pentafluoropmpyl-propranolol, and (d) heptafluorobutyl-propranolol. the geometry of the molecules. With each addition of the CF2 group the nonfluorinated portion of the side chain rotates about 180 ~ about its axis. In their stable configurations the molecules are in the following order with respect to the values of the energies: for binding energies: lb > la > lc > ld; for total energies: la > lb > le > ld; and for heat of formation: la > lb > le > ld. For the values of the energies see the tables. The ionization potentials of the four compounds discussed in this paper are almost the same (they differ in the second decimal place). As far as is known to the authors there does not seem to be a precedence of this in other series of polyfluoroalkyl amines. ld Dipole Moments The molecules do exhibit a sudden increase in the dipole moment from Debyes to Debyes when the two terminal methyl groups are replaced one by a hydrogen and the other by a --CF 3 group in lb. With further addition of fluorines there is a further increase in the dipole moment (to and then to Debyes), but not as dramatic. This simple measure indicates a significant redistribution of charge density. To quantify this change further, charge distributions and electrostatic potentials were studied and are discussed below. Charge Distributions The changes in the charges distribution in the four compounds involve the ether oxygen (O11) and all the terminal fluorines. In propranolol most of the charge is concentrated on the ether oxygen. In lb, the charge is mostly distributed around the same oxygen and the terminal fluorines and to a lesser extent around the nitrogen. In lc and ld, charge distribution is again mostly around the ether oxygen (O11) and the terminal fluorines and to a lesser extent around the hydroxyl oxygen (O17) and the nitrogen. The charge density distribution in the different molecules is shown in Fig. 4. Electrostatic Potential The sites of most negative electrostatic potential move toward the terminal of the molecules from the parent to the derivatives as the number of fluorines increase. In propranolol the site is near the ether oxygen, in lb it is more or less equally distributed between the ether oxygen and the fluorinated terminal. In lc the region of influence of the electrostatic potential progressively increases as it does again in ld. The volume

6 354 Farooqi and Aboul-Enein 'i i E L i f la i lb E! lc ~ ld Fig. 4. Distribution of charge densities in (a) propranolol, (b) tdfluoroethyl-propranolol, (c) pentafluoropropyl-propranolol, and (d) heptafluorobutyl-propranolol. For each molecule two views are presented, one perpendicular to the 2 ~ axis and the other perpendicular to the 3* axis. of this influence covers the region occupied by the nitrogen and the terminal fluorines in the three derivatives, but the increase in the number of fluorines make this region bigger. Thus the most likely site of protonation or electrophilic attack move from the ether oxygen in the parent through equally likely at this oxygen and the terminal to more likely at the fluorinated portion of the side-chain terminal particularly in ld. The regions are similar to those suggested by the charge density. As the number of fluorines increase in the molecule the corresponding region of influence also increases and reactivity would be expected to be stronger (i.e., stronger bonds are more likely to form). It is possible the binding to the receptor involves both the ether oxygen and the fluofines. CONCLUSION Optimized geometries (using the AM1 semiempirical technique) were discussed above. The molecular volumes and ionization potentials for the four compounds are almost equal. Significant changes in the molecules occur in the dipole moments, charge densities and the electrostatic potentials. Probably, the contribution from the changes in the charge density are sufficient to explain the changes in the biological activity of the four compounds as the number of fluorines on the molecules increases. Their activity increases (the volumic region of negative influence) with the increase in the number of fluorines. Maps of electrostatic potential distributions are given in Fig. 5.

7 Computed Structure of Propranolol and Some Fluorinated Analogs 355 ";2:. I ] G. "...~ '~ '.i f ld Fig. 5. Distribution of electrostatic potential in (a) propranolol, (b) trifluoroethyl-propranolol, (c) pentafluoropropylpropranolol, and (d) heptafluorobutyl-propranolol. This view is perpendicular to the 3 ~ axis of each molecule. Notice the changes in the dotted contours, which represent the negative values. SUPPLEMENTARY MATERIAL AVAILABLE A listing of the following is available from the authors upon request for all four compounds: bond lengths, bond angles, and torsion angles; dimensions of the molecule boxes and their volumes; and dipole moments of the molecules. ACKNOWLEDGMENTS The authors would like to thank the Administration of the King Faisal Specialist Hospital & Research Centre for their support of the Bioanalytical and Drug Development Research Program. REFERENCES 1. Katzung, B. G., Ed. Basic and Clinical Pharmacology, 5th ed.; Prentice-Hall: Englewood Cliffs, NJ, Aboul-Enein, H. Y. Toxicol. Environm. Chem. 1991, 29, Morken, P. A.; Bachand, P. C.; Swenson, D. C.; Burton, D. J. J. Am. Chem. Soc. 1993, 114, Bergstrom, D. E.; Swartling, D. J. In Molecular Structure and Energetics; Leibman, J. F.; Greenberg, A.; Dolbier, W. R. Jr., Eds.; VCH: New York, 1988; Vol HyperChem for Windows (version 3.0), Reference Manual for the Software; Autodesk, Inc.: Sausalito, CA, Smart, B. E., In Molecular Structure and Energetics; Liebman, J. F.; Greenberg, A., Eds.: VCH: New York, 1986; Vol. 3.