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Boletín de la Sociedad Chilena de Química

versión impresa ISSN 0366-1644

Bol. Soc. Chil. Quím. v.46 n.3 Concepción set. 2001

http://dx.doi.org/10.4067/S0366-16442001000300004 

FRONTIER ORBITALS AND IR FREQUENCIES OF CYCLIC
HYDROXAMIC ACIDS RELATED TO ANTIMICROBIAL ACTIVITY

HÉCTOR R. BRAVO,* R. ERNESTO CLAVIJO AND
BORIS E. WEISS-LÓPEZ

Departamento de Química, Facultad de Ciencias, Universidad de Chile.
Casilla 653, Santiago, Chile.

(Received: January 12, 2001 - Accepted: May 4, 2001)

ABSTRACT

HOMO and LUMO energies from a 6-31G** full geometry optimization of a series of 7 cyclic hydroxamic acid derivatives were calculated. According to the LUMO energy, the molecules can be classified as hard electrophiles (ELUMO>3.0 eV) and soft electrophiles (ELUMO<2.5 eV). In general, hard electrophiles show a more important biological activity, suggesting that the active site of the biomolecule could be a hard nucleophile. This interpretation is in agreement with the electrophilic character of the hydroxamic function, as suggested by the C=O and O-H stretching frequency of vibration.

KEY WORDS: Hydroxamic acids, frontier orbitals, IR frequencies, antimicrobial activity.

RESUMEN

Se calcularon las energías del HOMO y LUMO a partir de las geometrías optimizadas 6-31 G** de una serie de 7 ácidos hidroxámicos cíclicos. De acuerdo con la energía del LUMO, estas moleculas se pueden clasificar en electrófilos duros (ELUMO>3.0 eV) y electrófilos blandos (ELUMO<2.5 eV). En general, los electrófilos duros muestran una mayor actividad biológica. Esto sugiere que el sitio activo de la biomelécula sería un nucleófilo duro. Esta interpretación está de acuerdo con el carácter electrofílico de la función hidroxámica, como sugieren las frecuencias vibracionales de estiramiento de los enlaces C=O y OH.

PALABRAS CLAVES: Ácidos hidroxámicos, orbitales frontera, frecuencias IR, actividad antimicrobiana.

INTRODUCTION

Cyclic 1,4-benzoxazin-3-ones, (hydroxamic acids, Hx), are present in a variety of superior plants species 1-4) (figure 1). Their presence in gramineae of economical importance, such as maize, wheat and rye 1), has been associated to a protection factor of these plants against the attack of different pathogens. Different biological activities have been associated to this family of molecules, among others they have proven to function as antimicrobial 5,6) antiinflammatory 7), alellophatic 8-10) and anticancer agents 11). The mode of action of these structures at the molecular level is not well understood, but it has been associated to the electrophilic character of the hydroxamic moiety. The electrophilicity allows the molecule to react with nucleophilic centers present in enzymes involved in fundamental processes 12-14). The nucleophile-electrophile interactions should be mainly determined by the electrophilic character of the nitrogen atom of the hydroxamic function. This hypothesis is sustained mainly from the products obtained when these molecules react with model nucleophiles structurally similar to those present in biomolecules 15,16). To obtain more information about the factors that determine the bioactivity of these structures, we have performed a spectroscopic and theoretical study on a series of seven model derivatives of natural Hx, (figure 1, R2=H). These results allow to perform a qualitative prediction about the reactivity of these molecules.

Fig.1. DIBOA: R1=H, R2=OH; DIMBOA: R1=MeO, R2=OH.

EXPERIMENTAL

The series of molecules studied in this work have been previously prepared,17,18) and their anti-microbial activity measured.5) The FT-IR spectra of the molecules, dissolved in anhydrous dioxane, were recorded in a Perkin Elmer 2000 spectrophotometer. Ab-initio full geometry optimization were performed at the 6-31G** level, using the program G98W.

RESULTS AND DISCUSION

It has been previously suggested that the chemical reactivity of natural Hx and analogs, (figure 1, R2=OH), could be associated to the nature of their frontier orbitals.19) In these compounds, the LUMO orbital is significantly modified by the nature of the aromatic substituent. In the present work we study the effect of the substituents on the frontier orbitals energy of the 6-31G** optimized structures of 7 model Hx (figure 1, R2=H).

Fig.2. LUMO energy of the studied molecules (from 6-31G** full geometry optimization) vs. Hammett´s sp, a measurement of the electronic properties of the substituents.

The energy of the HOMO orbitals did not show a significant dependence with the substituents (-8.0 to -9.0 eV), however the LUMO energies are more sensitive to this structural modifications. This dependence correlates with the Hammett´s sp of the substituent (figure 2), where sp is representative of the electronic properties of the substituent at R1.20)

Figure 2 shows that the LUMO energy is inversely proportional to the electron acceptor character of the aromatic substituent R1. The observed trend is similar to previous observations,19) and suggest that a OH group at position 2 (R2) do not influence significantly the dependence of the LUMO energies with the substituent at R1. According to frontier orbitals theory,21) molecules with higher LUMO energy are harder electrophiles and consequently should react faster with hard nucleophiles. Similarly, molecules with lower energy LUMO should be less hard and should react comparatively slower with hard nucleophiles. To test the predictability of the LUMO energy criterion in the bioactivity of Hx derivatives, table 1 lists these parameters along with the minimum inhibitory concentration (MIC) against the bacteria Staphylococcus aureus, the fungi Candida albicans and the microalga Chlorella xanthella.

Table I. Antimicrobial activity (CMI) , selected IR vibrational frequencies and LUMO energy of a series of substituted cyclic hydroxamic acids (Fig. 1. R2=H ; R1= substituent).


CMI(ug/ml)


R1

nOH(cm-1)

nCO(cm-1)

ELUMO(eV)

C.xanthella

C.albicans

S.aureus


MeO

3247

1704

3.662

75

150

666

CH3

3246

1705

3.547

60

350

333

H

3245

1707

3.437

200

350

333

F

3176

1701

3.323

150

500

333

Cl

3180

1703

3.168

50

—

—

CO2Me

3164

1710

2.470

300

>1500

1000

CN

3148

1712

2.110

50

>1500

>15000


According to the LUMO energy, the molecules can be classified as hard electrophiles (ELUMO>3.0 eV) and soft electrophiles (ELUMO<2.5 eV). In general, hard electrophiles show a more important biological activity, suggesting that the active site of the biomolecule could be a hard nucleophile. Despite the fact that the antimicrobial activity of these compounds is also influenced by other factors, like lipophilicity of the substituent,5) the LUMO energy seems to be an adequate theoretical parameter to predict qualitatively the antimicrobial activity of these Hx.

It is well known that the polarization of the C=O and N-H bonds in amides is mainly determined by a mesomeric effect, due to delocalization of the unshared electron density of the nitrogen atom.22) Therefore, the canonical form 1 should be essential in the polarization of this bond. This structure contributes to increase the N-H stretching frequency and to decrease the C=O stretching frequency of vibration. In analogy to normal amides, the canonical form 2, proposed in Hx, has been postulated to rationalize the electrophilic characteristic of the Hx function.15,16) In this case the contribution of the polarized structure to the ground state should induce a similar behavior. For a better understanding of the electrophilic characteristics of the nitrogen atom in the hydroxamic function, present in model Hx with different substituents in the aromatic ring, we have obtained the stretching vibrational frequency of the O-H (nOH) and C=O (nCO) bonds. These values are listed in table I. The nCO increases and the nOH decreases with the increase of the electron acceptor character of the substituents. This suggest that the degree of polarization of the Hx function should be dependent on the electronic characteristics of the substituents in the aromatic ring, in such way that electron donor groups contribute to the stabilization of the canonical structure 2. On the other hand , electron acceptor groups increases the energy of canonical structure 2, decreasing the polarization degree of the Hx function and influencing the electrophilic character of the nitrogen atom.

The O-H and C=O stretching vibrational frequencies seems to provide a qualitative experimental criterion to predict the electrophilic character of the Hx function. Table I shows the agreement between the antimicrobial activity and the degree of polarization of the Hx function, as predicted by the C=O and OH stretching vibrational frequency. More polarized molecules display higher nOH, lower nCO, and a greater bioactivity. Therefore, the spectroscopic and theoretical results of this work support the hypothesis that nucleophile-electrophile interactions should be involved in the mechanism of action of these cyclic Hx at molecular level. Even more, they suggest that the active site in the biomolecule should be a hard nucleophilic center, for example an amine group.19)

ACKNOWLEDGEMENTS

The authors are pleased to acknowledge financial support from D.I.D., Universidad de Chile and Fondecyt Grant No.1980838. We also want to acknowledge Prof.Dr. Patricio Fuentealba the use of the G98W program.

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