Electronic Structure of some A3 Adenosine-Receptor Antagonist——A Structure Activity Relationship

doi:10.4236/jqis.2011.11004

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Journal of Quantum Informatio n Science, 2011, 1, 26-33

doi:10.4236/jqis.2011.11004 Published Online June 2011 (http://www.SciRP.org/journal/jqis)

Electronic Structure of some A3

Adenosine-Receptor Antagonist

——A Structure Activity Relationship

Rifaat Hilal*, Mohamed F. Shibl, Moteaa El-Deftar

Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt

E-mail: [email protected]

Received April 26, 2011; revised May 27, 2011; accepted June 6, 2011.

Abstract

DFT quantum chemical computations have been carried out at the B3LYP/6-31G(d) level. Full geometry opti-

mization has been performed and equilibrium geometries for a new series of phenyl thiazoles have been located.

Ground state electronic properties, charge density distributions, dipole moments and its components have been

calculated and reported. Effect of substituents on the geometry and on the polarization of the studied series of

compounds are analyzed and discussed. Some structural features have been pinpointed to underline the affinity

and selectivity of the studied compounds as adenosine A3-receptor antagonists. Results of the present work indi-

cate that activity towards A3 receptor sites is directly correlated with both of the polarity and the co-planarity of

the thiazole.

Keywords: DFT/B3LYB, Thiazoles, Substituent Effect, A3-Receptors, Adenosine-Receptor Antagonist

1. Introduction

Adenosine, a metabolite of adenine nucleotides, is a

physiological regulator of several cellular activities and

cellular metabolism. It acts as an autacoid and activates G-

protein-coupled membrane receptors. These receptors are

present on almost every cell. However, receptor subtype

distribution and densities vary greatly. In our previous

work [1] a QSAR model has been developed for 1,3-

dimethylxanthines as adenosine receptor antagonists. The

model is capable of predicting the affinity towards both A1

and A2 receptors. Furthermore, several diverse classes of

heterocyclic compounds have been developed [2-4] and

reported as selective antagonists for A3 receptors. Re-

cently, thiazole and thiadiazole analogues have been de-

scribed as the possible core skeletons of A3 receptor an-

tagonists with moderate affinity and selectivity [5-6].

The current study aims to present the ground state

electronic properties of some new thiazole derivatives

with expected biological activity, namely, A3 Adenosine-

receptor antagonist. A structure-activity correlations

(SAR) will be attempted.

2. Materials and Methods

4-phenylthiazole is considered as the parent to the stud-

ied series of compounds

X = Me, NHMe, NHPh

Y = Ph, 4-ClC

, 4-MeC

, 3,4-CH

, 4-MeOC

, 3-thienyl

Compounds studied in the present work were prepared

[7] through microwave-assisted cross- coupling reactions

in water, and microwave-assisted Suzuki cross-coupling

reactions. These methods have been reviewed [8,9].

Theoretical computations carried out throughout this

work were performed using the Gaussian 2003 program

package [10]. Full geometry optimizations were performed

at the DFT (Density Functional Theory) level of theory

[11]. The B3LYB method [12,13] has been adopted.

3. Results and Discussion

3.1. Electronic Structure of 4-Phenylthiazole

The choice of the appropriate basis set is of prime impor-

R. HILAL ET AL.

tance. The size of the molecules studied in the present

work is medium to large, hence, a cost-effective study of

basis sets, is in order. Such a study revealed that the 6-

31G(d) basis set provides the minimum acceptable level

of accuracy. This point can be appreciated by inspection

of Ta ble (1), where the optimized geometric parameters,

atomic charges and dipole moments of 4-phenylthiazole

are presented, at the 6-31G and the 6-31G(d) levels of

theory. Inclusion of the d-polarization functions has but

limited effect on the geometric parameters of 4-

phenythiazole. Such effect is confined to the sulphur

atom region where significant deformation is observed.

Upon d-orbital inclusion, the C-S bond length shows

>3% shortening whereas, the C-S-C bond angles show

widening by ~1 degree. This angle widening is due to the

much better extension in space of the d-orbitals. This

extension ensures a better description of the molecular

structure.

The effect on the charge density distribution and on

the dipole moment is more pronounced. Thus, the net

charge on “S” is reduced from a value of 0.4 e to a value

of 0.25 e upon inclusion of “d” functions. The “d” po-

larization function enabled a much better description of

the “S” electron-affinity. The effect in this case is not local-

ized; it is transmitted to all atoms of the 5-membered

ring. In case of the 6-31G(d) basis set, the N-atom is able

to accumulate 25% more negative charge, whereas, C5

became more positive. This indicates the direction of

migration of the electron charge density. The 6-

membered ring, on the other hand, shows but little de-

pendence on the d-functions. The overall redistribution

of the charge density is reflected in the increase in the

magnitude of the dipole moment to a value of 1.044 D.

The direction of the dipole moment shows also dra-

matic dependence on the “d” functions. Figur e ( 1 ) shows

the dipole moment vectors upon using the 6-31G and the

6-31G(d). The change in direction is most probably due

to the fact that polarization functions are able to provide

much better description of the lone pair electrons on both

“S” and “N”.

The above discussion indicates clearly that the 6-31G

(d) basis set is much more capable of describing the mo-

lecular electronic properties of the studied molecules.

Consequently, this basis set is adopted throughout the

present study.

3.2. Substituted 4-Phenylthiazole

Substituted 4-phenylthiazoles studied in the present work

fall into two main groups: in the first, substituent (X) is

in the five-membered ring and the second represent

variation of the substituent (Y) in the six-membered ring.

Our discussion of the main molecular features will be

along these two lines.

6-31G

6-31G(d)

Figure 1. Perspective view of dipole moment orientation of

4-phenylthiazole using 6-31G and 6-31G (d). The origin of

coordinate system used is located at the center of mass at

point “1” for each molecule; the orientation of dipole mo-

ment is along the bold line from 1 to 2.

3.3. Substituted-2-Methylthiazoles

Substitution by a methyl group is not expected to cause

major geometric deformation. Careful inspection (table

supplementary material) of the main geometric parame-

ters of 4-phenyl-2-methylthiazole reveals that there is no

noticeable change in N1-C2 or C2-S3 bonds in the imme-

diate vicinity of the substitution center. This is true for

all bond lengths. However, there seems to be consider-

able deformation in bond angles. The N1C2S3 bond angle

is reduced by ~2° upon 2-methyl substitution, an effect

which causes an increase in ring strain. However this

effect is not transmitted to the 6-membered ring.

2-methyl substitution causes polarization of the σ-

framework in a direction opposite to that of the polariza-

tion of the π framework. This increase in σ polarization

is reflected in two main effects. First, the increase in the

negative charge density accumulated on the N atom and

the reduction of the dipole moment by ~16%. This po-

larization and the subsequent reduction in polarity would

certainly have the effect of reducing the activity towards

the A3-receptors [1].

Substitution in C9 of the six-membered ring by a halo-

gen atom has a considerable effect on the charge redistri-

bution. While the effect on the C-C bond length is almost

negligible, the dipole moment increases dramatically

R. HILAL ET AL.

from a value of 0.87 D to 2.98 and 2.88 D for the chloro-

and the bromo-derivatives, respectively. The geometric

and electronic features of the chloro-and the bromo- de-

rivatives are given in tables supplementary material.

The high electronegativity of the halogen atom in-

duces polarization in both the σ- and the π-frameworks,

of the phenylthiazole moiety. Both the chloro-and the

bromo-derivatives show their dipole moment vectors

pointing in the same direction, towards the 5-membered

ring. This indicates a net charge transfer from the 6- to

the 5-membered ring. It is very important to realize that,

the planarity of 4-phenylthiazole is due to the fact that

the π-system extends all over the entire σ-framework.

This planarity is a very important geometric feature for

adenosine receptor antagonist [14]. Substitution by a

chloro-, a bromo-or a methyl group lead to an increase in

the tightness of binding. This has the direct consequence

of keeping the two rings co-planar. Figure (2) presents

the geometries of the studied thiazoles and the corre-

sponding dipole moment vectors.

Substitution by an aryl group in the phenyl ring, would

certainly add to the σ/π polarization. Careful inspection

of the geometric and electronic features of aryl-4-phenyl-

2-methylthiazoles studied in this work (tables supple-

mentary material) reveals that, extending the π-system

has the direct consequence of enhancing the polarity of

the system.

Figure 2. Perspective view of dipole moment orientation of

substituted-2-methylthiazole. The origin of coordinate sys-

tem used is located at the center of mass at point “1” for

each molecule; the orientation of dipole moment is along

the bold line from 1 to 2.

R. HILAL ET AL.

It is also evident that the conjugation is much tighter

on the aryl-phenyl region. This shift of π-conjugation,

away from the 5-membered ring, has two main effects.

First, reduction in magnitude of the dipole moment by

almost 20%, and lifting of co-planarity. The thiazole ring

is out of the plane of the rest of the molecule. It should

be noticed that, although the dipole moment has been

reduced considerably, yet its direction is not significantly

affected. This is most probably due to the fact that the

directional character of the lone-pair electrons on “S”

and on “N” plays a dominant role in this respect. P-

chlorophenyl substitution has a pronounced effect on the

polarity of the molecule. Thus, the thiazole ring is forced

back towards the molecular plane and the dipole moment

has increased to 3.15 D. The effect of the chlorine atom

substitution is to considerably polarizes the σ-framework

in a direction opposite to that of the π- system. Replace-

ment of 4-chloro by a 4-methyl group causes a reduction

of the magnitude of the dipole moment to 0.462 D and

forcing the thiazole ring out of the molecular plane.

Thus, an electron-withdrawing substituent in the 4-

phenyl moiety is essential for the A3-adenosine antago-

nist receptors reactivity. This is due to the enhanced po-

larity and co-planarity of the molecule.

This is true for all substituted-2-methylthiazole deriva-

tives studied in the present work. Table (2) summarizes

the dipole moment values, its components and the dihe-

dral angles for the studied 2-methylthiazoles.

It is also important to examine the variation of the

electron-donating strength and the electron affinity val-

ues of the studied molecules. Table (3) presents the ioni-

zation energies (I.P) and electron affinities (E.A) of the

studied molecules. Substitution in the 6-membered ring

has but little effect on the donating strength. However,

this substitution has considerable effect on the electron-

affinity. The halogen atom substitution has pronounced

effect in lowering the LUMO i.e. increasing the electron-

affinity of the molecule. This point is of prime impor-

tance in determining the activity as A3 receptor antago-

nists.

Table 1. Optimized geometry of 4-phenylthiazole.

Bond (Ao) 6-31G 6-31G(d) Angle 6-31G 6-31G(d) Charge 6-31G 6-31G(d)

N1-C2 1.295 1.296 N1C2S3 114.363 115.138 N1 –0.323 –0.401

C2-S3 1.826 1.748 C2S3C4 86.531 88.379 C2 –0.222 –0.122

S3-C4 1.795 1.73 S3C4C5 111.728 110.883 S3 0.401 0.251

C4-C5 1.371 1.375 C4C5N1 114.089 114.057 C4 –0.498 –0.401

N1-C5 1.409 1.388 C5N1C2 113.289 111.543 C5 0.18 0.265

C5-C6 1.474 1.477 C4C5C6 127.297 126.882 C6 0.098 0.115

C6-C7 1.408 1.404 C5C6C7 119.644 119.716 C7 –0.146 –0.174

C7-C8 1.397 1.394 C6C7C8 120.562 120.644 C8 –0.134 –0.131

C8-C9 1.399 1.396 C7C8C9 120.399 120.403 C9 –0.112 –0.125

C9-C10 1.401 1.397 C8C9C10 119.470 119.423 C10 –0.140 –0.137

C10C11 1.396 1.393 C9C10C11 120.268 120.285 C11 –0.140 –0.181

C11-C6 1.408 1.405 C10C11C6 120.706 120.775 H12 0.189 0.185

C2-H12 1.079 1.084 C11C6C7 118.594 118.468 H13 0.182 0.183

C4-H13 1.077 1.08 N1C2H12 125.703 124.127 H14 0.182 0.16

C7-H14 1.083 1.084 S3C4H13 119.130 120.330 H15 0.128 0.131

C8-H15 1.086 1.087 C6C7H114 118.675 118.716 H16 0.127 0.130

C9-H16 1.085 1.087 C7C8H15 119.549 119.52 H17 0.126 0.130

C10-H17 1.085 1.087 C8C9H16 120.334 120.356 H18 0.126 0.122

C11-H18 1.085 1.086 C9C10H17 120.094 120.134

C10C11H18 119.139 119.071

6-31G 6-31G(d)

E (a.u.) –799.968 –800.108

Dipole moment (Debye) 0.877 1.044

R. HILAL ET AL.

Table 2. Dipole moment of 4-substituted-2-methyl thiazole using 6-31G(d).

Cpd No substituent PX (D) PY (D) PZ (D) Total (D) Dihedral angle

(N1C5C6C7)

1 4-phenylthiazole 0.387 –0.97 –0.0002 1.044 0.013

2 H 0.749 –0.447 0.0004 0.872 0.012

3 Cl 2.921 –0.591 –0.0002 2.980 0.043

4 Br 2.833 –0.539 0.0005 2.884 0.012

5 Ph –0.806 –0.379 –0.0505 0.893 3.097

6 4-ClC6H4 –3.113 –0.465 –0.0707 3.149 1.934

7 4-MeC6H4 –0.316 –0.336 –0.0068 0.462 2.973

8 3-thienyl –1.262 –0.068 –0.1842 1.277 1.479

9 3,4-CH2O2C6H4 –0.338 –0.262 –0.3553 0.556 2.749

10 4-MeOC6H4 0.241 –1.422 0.4346 1.506 3.481

11 4-styryl –0.884 –0.296 –0.0007 0.932 –0.108

Table 3. Ionization potential and electron affinity of 4-

substituted-2-methyl thiazole.

Compound No. I.P (eV) E.A (eV)

2 5.79 –9.25

3 5.93 –1.17

4 5.90 –1.17

5 7.58 –1.14

6 5.71 –1.31

7 5.49 –1.09

8 5.52 –1.14

9 5.28 –1.09

10 5.33 –1.03

11 5.25 –1.55

4. 2-N-methylthiaz ole-2-amine and Its

Derivatives

Table (4) summarizes the dipole moment data and dihe-

dral angles of the studied compounds. The π-electron

density redistribution in this series of compounds seems

to be dominated by a localized conjugation in the thia-

zole-amine moiety. This would impose a subsequent

cross-conjugation in the phenylthiazole region. This is

reflected in the magnitude of the dihedral angles reported

in Table (4). In general, the aryl group is out of the plane

of the thiazole amine moiety. Substitution in the 4-

position of the phenyl ring does not change much the non

-coplanarity of the studied molecules. Substitution with a

Cl or with a Br atom enhances the polarity considerably;

both the magnitude and direction of the dipole moments

are affected.

Thiazole amines are of better electron donating and of

less electron-accepting strength then the corresponding

methylthiazoles. Table (5) presents the ionization ener-

gies and electron affinities of the studied thiazole amines.

The geometric and electronic features of aryl-4-phenyl

-2-N-methylthiazoles-2-amine studied in this work are

analyzed (presented in (tables, supplementary material)).

This series of compounds do not show significant ge-

ometry changes upon substitution. However, thiazole

amines are characterized by a pronounced increase (

~20%) of the negative electron density accumulated on

the thiazole nitrogen atom. The variation of the charge

density upon substitution is remarkable and reflects itself

in the alteration of the direction of the dipole moments

(cf. Figure 3).

5. 4-Phenyl-2-N-phenylthiazole-2-amine and

Its Derivatives

Table (6) presents the dipole moments, its components

and dihedral angles of the studied compounds.

NH Ph

R. HILAL ET AL.

Table 4. Dipole moments of 4-substituted-2-N- methylthia-

zole-2-amine using 6-31G(d).

NH Me

Cpd

No substituent PX

(D)

Total

(D)

Dihedral

angle

(N1C5C6C7)

12 H –2.133 –0.433 0.582 2.253 2.506

13 Cl –4.342 –0.307 0.546 4.387 2.072

14 Br –4.253 –0.410 0.550 4.308 2.413

15 Ph –2.227 –0.566 0.672 2.394 –2.675

16 4-ClC6H4 –4.567 –0.601 0.488 4.632 4.0978

17 4-MeC6H4 –1.441 0.728 –0.590 1.719 0.733

18 3-thienyl 2.404 0.859 0.518 2.605 –3.920

19 3,4-CH2O2C6H4 1.763 –0.900 0.917 2.182 2.598

Table 5. Ionization potential and electron affinity of 4-subs-

tituted-2-N-methylthiazole-2-amine.

Compound No. I. P (eV) E. A (eV)

11 5.25 –0.62

12 5.41 –0.87

13 5.41 –0.9

14 5.19 –0.03

15 5.30 –1.14

16 5.14 –0.92

17 5.17 –0.98

18 5.09 –0.898

Figure 3. Perspective view of dipole moment orientation of

substituted-2-N-methylthiazole-2-amine. The origin of co-

ordinate system used is located at the center of mass at

point “1” for each molecule; the orientation of dipole mo-

ment is along the bold line from 1 to 2.

R. HILAL ET AL.

Table 6. Dipole moments of 4-substituted-2-N-phenyl thiazole-2-amine using 6-31G(d).

NH Ph

Cpd No substituent PX (D)PY (D) PZ (D) Total (D)Dihedral angle

(N1C5C6C7)

20 H 1.1453 –0.11 –0.13381.1583 9.269

21 Cl 3.4309 0.2951–0.20813.4499 4.226

22 Br 3.3616 0.17 –0.19773.3717 3.454

23 Ph 1.1034 –0.82560.05331.3792 –15.122

24 4-ClC6H4 –3.4104 –1.3513–0.04213.6686 –15.758

25 4-MeC6H4 0.6603 –0.61640.09270.908 –15.631

26 3-thienyl 1.4437 1.196 0.12571.879 –15.496

Inspection of geometric data of these compounds (tables

and figures, supplementary material) indicates clearly that:

 All the studied molecules show accumulation of the

negative charge density on the thiazole N-atom. This

negative charge facilitates hydrogen bonding which is

a very important structural feature related directly to

the ability to bind to the A3 receptor sites.

 The NH-phenyl derivatives are non-coplanar. Indicat-

ing cross-conjugation between the phenyl and the thi-

azole moieties. It should be noted that the chlorine

and bromine atom substituents have exactly the same

effect as noted before. First, it reduced the dihedral

angles forcing the phenyl ring towards coplanarity.

Second, it enhances the polarity of the molecule as

indicated by the magnitude of the dipole moments

(cf. Table 6).

 The dipole moment vectors seem but little affected by

substitution in the 6-membered ring. The dipole mo-

ments are dominated by contributions from heteroa-

toms especially “N” lone-pair.

 NH-phenyl derivatives have almost the same elec-

tron-donating and electron-accepting strength as that

of the NH-CH3 derivatives.

Substituted 4-phenylthiazoles studied in the present

work fall into three main categories.

Y X groups

Cl, Br, Ph, 4-ClC6H4, 4-MeC6H4,

3,4-CH2O2C6H3, 4-MeOC6H4, 3-Thienyl

CH3 I

Cl, Br, Ph, 4-ClC6H4, 4-MeC6H4,

3,4-CH2O2C6H3, 3-Thienyl

NHCH3 II

Cl, Br, Ph, 4-ClC6H4, 4-MeC6H4 NHPh III

Substitution in general, has but little effect on the

geometric features of phenylthiazoles, the major geo-

metric effect, however, is traced in the co-planarity of the

molecules studied.

Thus, while 4-phenylthiazole itself is coplanar, substi-

tution in the 5-membered ring lefts this co-planarity. It is

very important to notice the effect of substitution by Cl-

or Br-, in the phenyl ring. This substitution has the geo-

metric effect of restoring the co-planarity back. It seems

that Cl- or Br- substituents would have a marked effect

on the activity of phenylthiazole as A3-receptor antago-

nists.

Substitution has a remarkable effect on the dipole

moments, magnitudes and directions. Analysis of dipole

moments show fluctuations of their values by substitu-

tion. It has been indicated that activity towards A3-

receptor sites is directly proportional to the polarity of

the thiazole. In the present work, the enhanced polarity

of some phenylthiazoles has been analyzed and attributed

to σ-/π-polarization. In some cases, especially for N-CH3

and N-Ph substitutents, cross-conjugation has but a very

little effect on the polarity of molecules. This elaborates

upon our previous conclusion that, the contributions

from the lone-pair electrons dominate the dipole mo-

ments.

Analysis of the effect of substitution, on the net elec-

tronic charge on the thiazole “N” atom, shows that the

NH-CH3 and NH-Ph derivatives accumulate more than

0.53e on the thiazole “N” atom. On the other hand, sub-

stitution in the phenyl ring has but little effect on the

amount of charge on the thiazole N atom. This charge is

of prime importance in H-bond formation with

A3-receptor sites. This hydrophilic interaction seems to

underlie the selectivity for the human A3-receptor. In

vitro, the thiazole moiety is surrounded by many hydro-

phobic amino acids.

The tendency of the studied phenylthiazoles to act as

electron-donors or electron-acceptors has also been in-

R. HILAL ET AL.

vestigated. The energies of the HOMO's of the studied

series of thiazoles are around 5 eV. This low ionization

potential indicates a high tendency toward electron dona-

tion. Furthermore, aryl-2-methylthiazoles are character-

ized by low lying LUMO's, indicating considerable elec-

tron-affinity. This is of prime importance in enhancing

the activity towards A3-receptor sites.

The present analysis of the structure and electronic

properties of phenylthiazoles focuses on four main

structural features. The first feature is the co-planarity of

molecules. The second is the polarity, as indicated by the

dipole moments and their directions. The third feature is

the net negative charge on the thiazole “N” atom. This

charge enhances H-bond formation; a property of prime

importance for binding to A3-receptor sites. Finally, the

fourth feature is the electron donating and accepting ten-

dency of the studied thiazoles. A substituent that forces

co-planarity increases the dipole moment and the charge

accumulated on the thiazole “N” atom, and lowers the

LUMO, would certainly enhance the activity as potent and

selective adenosine A3-receptor antagonists.

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