Substituent width

Fig. 22.4 Molecular properties can be divided into experimental (subdivided into biological and physicochemical) and in silico (subdivided into structural and substructural) properties, physicochemical and biological properties. Examples of experimental data are IC50 (binding affinity), MIC (antibacterial minimum inhibition concentration), LD50 (lethal dose), Vd (volume of distribution), F% (bioavailability), pKg (ionization constant), log P (partition coefficient from shake flask determination), log kn,(lipophilicity from HPLC measurement), A (hydrogen bond capability), solubility. Examples of calculated properties, either for whole molecule or for substituents or buildings blocks, are MW (molecular weight), MR (molar refractivity), molecular volume, PSA (polar surface area), HA (number of H-bond acceptors), HD (number of H-bond donors), CLOGP (calculated log P values), L (substituent length), B5 (substituent width), cr (Hammett constant), F, R (field and resonance parameters), TT (Hansch constant), f (hydrophobic fragmental constant).

In equation (17), x is the dipole moment (calculated by CNDO/2 method [16], and B4 is Verloop s width parameter (values taken from [19]). It thus follows that enzyme inhibition depends on both steric and electronic effects, inhibitory potency increasing with increasing dipole moment or electronic-donating power of the substituents and with increasing substituent width. 

The STERIMOL parameters (Verloop, Hoogenstraaten and Tipker, 1976) are based on van der Waals radii, standard bond length and angles for so-called reasonable conformations of the molecules the derived constants describe the length of a substituent along the binding axis between the substituent and the parent molecule (L) and the substituent width in the four directions perpendicular to the L axis as well as to each other (BJ-B4). 

Bl, B5 L Verloop s sterimol parameters for substituent width and length CMR calculated molar refractivity... 

The Kd(X) values thus obtained (Table 3) were analyzed by the multivariant technique using such parameters as n, a0, Bt, Ibmch, and Ihb, where Bj is a STERIMOL parameter showing the minimum width of substituents from an axis connecting the a-atom of the substituents and the rest of molecule, and Ibrnch, an indicator variable representing the number of branches in a substituent. 

In these equations, Dmax is the larger of the summed values of STERIMOL parameters, Bj, for the opposite pair 68). It expresses the maximum total width of substituents. The coefficients of the ct° terms in Eqs. 37 to 39 were virtually equal to that in Eq. 40. This means that the a° terms essentially represent the hydrolytic reactivity of an ester itself and are virtually independent of cyclodextrin catalysis. The catalytic effect of cyclodextrin is only involved in the Dmax term. Interestingly, the coefficient of Draax was negative in Eq. 37 and positive in Eq. 38. This fact indicates that bulky substituents at the meta position are favorable, while those at the para position unfavorable, for the rate acceleration in the (S-cyclodextrin catalysis. Similar results have been obtained for a-cyclodextrin catalysis, but not for (S-cyclodextrin catalysis, by Silipo and Hansch described above. Equation 39 suggests the existence of an optimum diameter for the proper fit of m-substituents in the cavity of a-cyclodextrin. The optimum Dmax value was estimated from Eq. 39 as 4.4 A, which is approximately equivalent to the diameter of the a-cyclodextrin cavity. The situation is shown in Fig. 8. A similar parabolic relationship would be obtained for (5-cyclodextrin catalysis, too, if the correlation analysis involved phenyl acetates with such bulky substituents that they cannot be included within the (5-cyclodextrin cavity. 

A very different route to soluble PPP derivatives was demonstrated by Yoshino and coworkers [586], who introduced perfluorinated alkyl substituents into PPP 471 by reaction with perfluorobutanoyl peroxide. The resulting modified polymer 475 was soluble in common organic solvents and a solution-fabricated PLED ITO/475/Mg In emitted blue to green light (depending on voltage) with band half-width of over 200 nm. 

The interaction of nicotinates with human plasma hydrolases (Eqn. 8.4) is determined principally by their lipophilicity (optimal log k°w = 23). Affinity also increases with increasing width of the substituent, and shows the same complex dependence on AS as in Eqn. 8.3. 

Another classical measure of the molecular geometry of substituents is the Verloop steric parameter. This is calculated from bond angles and atomic dimensions— primarily the lengths of substituent groups and several measures of their width. Trivial as this may sound, the consideration of molecular bulk is an important and often neglected factor in making multiple quantitative correlations of structure and pharmacological activity. Balaban et al. (1980) devised several related methods that are still in use today. 

In equation (1) the parameter (9) expresses the length of substituent R. to the rest of the molecule. W. is the width upward of R. when one views it from the connecting end along the bond axis defining L. The electronic parameter, a, was estimated for the structure substituted on the common aspartyl-amino moeity, so that the electronic effect is directed to the peptide bond. Ten compounds of the original 61 do not fit equation (1) hence n=51, not 61. 

Although these parameters represent the shape of substituents as a set, there is some collinearity among Bx, B2 and B3 for a number of substituents. Thus, Bx, B4 and L, as the most independent variables, are usually used in QSAR analysis 33). More recently, Verloop proposed the maximum width parameter, B5, and showed that, in most cases, B5 works well in place of B4 35). Since they are defined mechanically as the length or width, the background of their utilization along with other free-energy related parameters is not necessarily clear. 

In Eq. 39, substituents, the dimension of which is larger than 5.1 A in terms of the sum of the opposite-pair Bj values, are not included, since their log (1/Kd) values are much lower than those expected from the correlation for others. They are supposed not to be accomodated into the cavity of the a-cyclodextrin, the diameter of which is 4.5-5 A. Thus, the inclusion complex formation with a-cyclodextrin is more limited than that with P-cyclodextrin and the extent of dehydration is less significant. The term B in Eq. 39 implies that the larger the minimum width of substituents the maximum diameter of which is less than 5.1 A, the more uniform would be the van der Waals interaction with the cavity wall resulting in the more stable inclusion complex. 

In the course of developing herbicides possessing N-phenyl tetrahydrophthalimide structure (20), Ohta et al. investigated structural requirements for the activity against sawa millet, Echinochloa utilis, of m- and p-substituted derivatives42 . As shown by Eq. 43, the steric dimensions expressed by the STERIMOL length parameter Lp and maximum width B of p-substituents play a decisive role in determining activity. 

The significance of the term B4 in Eq. 44 indicates that there is an optimum steric condition (ca. 5.2 A) for N6-alkyl groups in terms of the maximum width to exhibit the activity. The B4 value for the benzyl substituents is always higher than the optimum B4 value for the alkyl groups, even that for the unsubstituted benzyl being... 

---