A Structure-Activity Relationship Study of Thiazole Derivatives

8/18/2019 A Structure-Activity Relationship Study of Thiazole Derivatives

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A STRUCTURE-ACTIVITY RELATIONSHIP STUDY OF THIAZOLE

DERIVATIVES WITH H1 -ANTIHISTAMINE ACTIVITY

Abstract: A structure-activity relationship (QSAR) analysis of 19 thiazole derivatives with H 1-

antihistamine activity was carried out !he semi-empirical method A"1 was employed to calculate a set

of physicochemical parameters for investi#ated compounds !he principal component analysis ($%A)&

discriminant function analysis ('A) and re#ression analysis (RA) were employed to reduce

dimensionality and investi#ate which suset of variales is effective for classifyin# the thiazole

derivatives accordin# to their de#ree of anti-H1 activity *n $%A the studied compounds were separated

into two #roups+ #roup A with lower de#ree of H 1-antihistamine activity and #roup , with hi#her activity

!he 'A showed that the parameters+ α (polarizaility)& A, (distance etween aliphatic and aromatic

nitro#en atoms)& (indin# ener#y)& Hh (hydration ener#y)& eH .". (H.". ener#y)& and QAr are

responsile for separation etween compounds e/hiitin# hi#her and lower H 1-antihistamine activity

!he importance of hydrophoic and steric parameters for thiazole derivatives 1-19 with H 1-antihistamine

activity was estalished via RA .n the asis of $%A& 'A and RA methods& a prediction rule for

classifyin# new thiazole derivatives with H1-antihistamine activity was elaorated

K!"#r$s: thiazole derivatives& QSAR& discriminant function analysis& principal component analysis& re#ression analysis& dru#

desi#n

!he 0uantitative relations etween physicochemical and structural properties of chemical compounds

and their iolo#ical response are the suect of 0uantitative structure-activity relationship (QSAR) studies

!raditional QSAR studies are often restricted to related or con#eneric series of compounds !he

physicochemical parameters descrie electronic& hydrophoic and steric properties of investi#ated cases !hey

can e otained empirically in laoratory assays Application of molecular descriptors calculated from

structures of these compounds y the use of semi-empirical methods can e useful as well ,oth #roups of

parameters usually successfully correlate with a variety of iolo#ical data in QSAR !he results of previous

study (1) on thiazole derivatives& investi#ated in the present wor2& revealed that the calculated descriptors

stron#ly correlated with the same parameters determined y laoratory methods %onsiderin# that they can e

determined for the planned structures& they are important for the desi#n of new dru#s and in the estalishment

of QSAR models !he previous study showed that the calculated hydrophoic& electronic and steric

parameters effectively descrie the variety of iolo#ical activity of investi#ated compounds !he structural

variaility of the compounds is connected with their pharmacolo#ic variety (1)

!he 0uantitative analysis of the results of other previous studies (345) on thiazole and enzothiazole

derivatives (some of thiazoles were used in this study 4 1& %& &4'& 1%41(& 1)& 1*)& which are anta#onistic

towards H1-histamine receptor revealed the possiility of applyin# iochromato#raphic data and re#ression

analysis (RA) to predict the 0uantitative effect of activity of these compounds !he study reported also some

diver#ence of the results for the #roup of compounds with anti-H1 activity and those which e/hiited oth

anti-H1 and anti-H6 activity in iolo#ical investi#ations *n the ne/t study& the application of iochromato#raphic data and discriminant function analysis ('A) were used for 0ualitative discrimination

and prediction of direction of potential antihistamine dru# activity (7) Similar studies related to 0uantitative

analysis have een reported (8) for antihistamine compounds in which data from R$ H$% and the principal

component analysis ($%A) were used A variety of ehavior of investi#ated compounds in chromato#raphic

environment stron#ly depends on their structure

!he lac2 of the crystal structure of the histamine H1 receptor hinders the development of the new types of

anta#onists A theoretical three-dimensional model of human H1 receptor was recently developed on the asis

of other human receptors structures (:) !he structural re0uirements for histamine H1 indin# for

antihistamines have een reported (:& 9) Application of thermodynamic analysis of li#and-indin# may e a

novel approach to dissect a#onist- and anta#onist-specific H1-receptor conformations (1;)

!he present wor2 employs physicochemical parameters of selected anti-H1 compounds as their structural

descriptors and statistical methods ($%A& 'A and RA) in systematic structure-activity relationship analysis!he $%A and 'A methods were employed in order to reduce dimensionality and investi#ate which suset of


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variales should e more effective for classification of thiazole derivatives accordin# to their de#ree of anti-

H1 activity !he $%A can e useful as a tool for initial selection of the parameters which si#nificantly are

related with hi#her anti-H1 activity !he 'A method can e e/tremely efficient in new anti-H1 dru# desi#n for

classification of new planned structures to #roups of potentially hi#her or lower activity #roup !he RA

method will e used for predictin# the 0uantitative effect of H 1-antihistamine activity of different thiazole

derivatives

MATERIALS AND METHODS

C#+,#.$s

!he investi#ated sustances ma2e the set of 19 thiazole-analo#s with 2nown iolo#ical activity !he

statistical analysis applied the values of iolo#ical activity (pA3) of studied compounds determined in the

particular iolo#ical in vitro tests !he synthesis method& analytical data and iolo#ical activity of thiazole-

analo#s 1-1* were descried previously (11& 13) (i# 1)

Ca/c/at0#. # t2 t2#rt0ca/ $scr0,t#rs # +#/c/ar ,r#,rt0s

t was su##ested that the QSAR analysis& carried out usin# the molecular descriptors of the compounds in

their proaly un-ionized or ionized forms (at particular pH)& can e most effective (1& 16) $hysicochemical

parameters of compounds in the #roup of cases 1-1* were evaluated for un-ionized molecules and& in

addition& for their mono-protonated forms as descried in the previous study (1) !he numer of the

physicochemical parameters calculated from un-ionized forms of structures was 19 Some of them could not

e calculated from ionized forms !he calculation of the percenta#e of ionization of the investi#ated

compounds in their action place was carried out usin# an al#orithm (1>) with p? a values of the particular

compound and pH @ 8> of iolo#ical e/periment environment (11& 13) *n the case of thiazole derivatives 1-

1* with H1-antihistamine activity& the participation of mono-protonated form (at atom of the aliphaticamine) predominates (9>:9498;;B) !he results of the study (1) on these compounds revealed that the

descriptors calculated from oth ionized and un-ionized forms of 1-1* can e successfully used in QSAR

analysis ,ased on them& in the present study the ori#inal data set of variales calculated from un-ionized

forms 11* was used (!ale 1) ,efore applyin# the stepwise 'A method& each variale was standardized so

that they could e compared to each other on the same scale !he dissociation constants (p? a) and distriution

coefficients (lo# '3 values were calculated usin# a p? A%'Cas :; and lo# ' A%'Cas :; software (15)

.ther parameters such as+ van der Daals surface area (AD)& van der Daals volume (ED)& partition

coefficient (lo# $)& molecular refractivity ("R)& polarizaility (a)& molecular wei#ht lo#arithm (lo# " D)&

distance etween aliphatic and aromatic nitro#en atoms (A,)& indin# ener#y ( )& heat of formation (H f )&

hydration ener#y (Hh)& H.". ener#y (εH.".)& F". ener#y (εF".)& electric char#e on aliphatic atom (Q)&

electric char#e focused on aromatic atom (QAr ) and dipole moment (µ) were calculated y the Hyper%hem

8; pro#ram All the structures of the studied compounds were #eometrically optimized y the use of semi-empirical method A"1 (al#orithm $olac-Riiere& R"S #rad @ ;;1 2calC( mol) in vacuo) !he systematic

conformational analysis was not used !he physicochemical parameter values derived from 0uantum

mechanical calculations of the chemical structures are summarized in !ale 1

Ealues of all descriptors were suected to mathematical analyses !he principal component analysis&

stepwise discriminant function analysis and re#ression analysis were carried out usin# the S!A!*S!*%A 8;

software (17) !he use of more than one variale in a multivariate re#ression was ustified y an inter-

correlation study

Statistical methods

$rincipal component analysis ($%A) is a commonly used method for reducin# the dimensionality of a

data set !he dimensionality of data set is the numer of variales that are used to descrie each oect *t is

often found that there are si#nificant correlations etween these variales Fnder such circumstances& other


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assays such as+ cluster analysis (%A)& RA or 'A are often facilitated y usin# $%A to reduce the numer of

variales and to eliminate these correlations (18) !he principal components ($%s)& which e/plain the

variance-covariance structure& are calculated usin# standard matri/ techni0ues (1:) y linear transformation

of the ori#inal data set of variales into a smaller numer of uncorrelated (ortho#onal)& si#nificant descriptors

!he first principal component 4 $%1 corresponds to the lar#est ei#envalue and usually e/plains the maority of

the variation of the data As the result of the $%A a #ood classification of the investi#ated cases can e

otained !he est separation is otained with several variales out of the ori#inal set of data !his su##ests

that other variales are not so important for classification of these compounds %onsiderin# that the

investi#ated compounds can e separated into #roups with hi#her and lower de#ree of activity& the $%s

determines the direction of the lead compounds modification (19)

'iscriminant function analysis ('A) is a multivariate techni0ue useful to determine which variales

discriminate the investi#ated cases etween two or more naturally occurrin# or a priori defined #roups .n

that asis& the cases can e separated from distinct populations e/t& the classification functions are

calculated as models (e0uations) useful to allocate new cases into previously defined populations (19431)

!he QSAR analysis y re#ression analysis (RA) of H1-antihistamine activity and physicochemical

properties of 1-1* thiazole derivatives was made !he correlation etween iolo#ical activity data (11& 13)

(pA3 values in !ale 1) and the calculated molecular descriptors of the e/amined compounds (data in !ale 1)

were investi#ated y univariate and multivariate re#ression analysis method !he #eneral purpose of multiple

re#ressions is to analyze the relationship etween several independent variales (physicochemical parameters

of e/amined compounds) and a dependent variale (anti-H 1 activity of compounds) !he re#ression analysis

was carried out usin# the S!A!*S!*%A 8; pro#ram (17) !he use of more than one variale in a multivariate

e0uation was ustified y inter-correlation study

RESULTS AND DISCUSSION

Pr0.c0,a/ c#+,#..t a.a/!s0s 4PCA3!he $%A was carried out with the application of ori#inal parameters calculated from un-ionized

structures of compounds 1-1* (data in !ale 1) After several attempts to otain the #ood classification of the

compounds& the est separation was achieved with si/ variales !he first three principal components

e/plained 98;3B of total variance in the data as follows+ $%1 @ 7:81B& $%3 @ 1::5B and $%6 @ 9&>7B !he

plot of the score vectors for the first two $%s ($%1 G $%3) is shown in i#ure 3 !his proection conserves

:857B of the total variance of the ori#inal data

!he scatterplot shows that the studied compounds are separated into two #roups (A and ,) roup A

contains compounds 1-11 with lower de#ree of H1-antihistamine activity (pA3 ≤ 5;>)& and #roup , includes

compounds 1%-1* with hi#her activity (pA3 ≥ 5:8) *t is evident in $%A assay that $% 1 alone is responsile

for the separation of compounds with hi#her and lower activity !he less active compounds 1-11 are on the

left hand side of the scatterplot and they are connected with ne#ative values of $% 1 !he more active

compounds 1%-1* are connected with positive $%1 values& on the ri#ht hand side of the plot !he loadin#vectors of the first three $%s were calculated !ale 3 shows the loadin# vectors values of $% 14$%6 and

correlations etween $%s and variales

!he $%1 can e e/pressed y loadin# vectors via the followin# e0uation+

$%1 @ 4 ;>56 6 1> 58 1


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D0scr0+0.a.t F.ct0#. A.a/!s0s 4DFA3

!he 'A was performed y means of S!A!*S!*%A 8; (17) Dithin the current QSAR study&

physicochemical parameters derived from the semi-empirical calculations (!ale 1) were used as #roupin#

variales ,efore applyin# the 'A method& each variale was auto scaled so that they could e compared to

each other on the same scale !he 'A was performed on 19 cases of thiazole derivatives (1-1*) !he

compounds studied were initially divided into two #roups of activity !he #roup codes (A and ,) were

assi#ned to them a priori Affiliation of the particular compounds with two #roups of lower 4 A (compounds

1-11) and hi#her 4 , (compounds 1%-1*) anti-H1 activity was estalished ased on pA3 values (11& 13) and

results of $%A descried aove *n the performed analysis the forward stepwise method was applied *n

stepwise 'A a model of discrimination was uilt step-y-step roupin# variales (physicochemical

parameters) were successively introduced to the analysis Specifically& at each step the pro#ram reviews all

variales and evaluates which one will contriute most to the discrimination etween #roups !hat variale is

then included in the model& and the pro#ram proceeds to the ne/t step !he stepwise procedure is #uided y

the respective to enter and to remove values !he value for a variale indicates its statistical si#nificance

in the discrimination etween #roups *t is the measure of the e/tent to which a variale ma2es a uni0ue

contriution to the prediction of #roup memership (33) !he introduction of sufficient #roupin# of variales

to the model and otainin# ma/imum proaility of a priori classification& discriminant function (root)

discriminatin# activity #roups was calculated *n the two-#roup case& only one discriminant function could e

determined !he last phase of the analysis of the compounds was to determine classification functions for

oth activity #roups (see e0uations elow) !hese functions can e used for classification of cases ach

function allows us to compute classification scores of each case for each #roup !he case is classified as

elon#in# to the #roup for which it has the hi#hest classification score

After si/ suse0uent steps of analysis and introduction of si/ #roupin# variales& discriminant function

(root) was achieved e/t& classification functions for each level of compounds activity were calculated !wo

suse0uent classification functions #roupin# compounds of low and hi#her H 1-antihistamine activity ran#e are

listed in !ale 6

Si/ si#nificant variales were e/tracted such as: a& A,& & Hh& eH.".& QAr 5 %omparin# the results usin#

'A and $%A methodolo#ies& we can see also that a& & Hh& εH.".& QAr are 2ey properties for e/plainin# the H 1-

antihistamine activity of the thiazole derivatives 1-1* ut also the properties lo# $ and A, are important for

desi#n of new thiazoles demonstratin# antihistamine activity !he discrimination function for #roups A and ,

is #iven elow+

A @ 41988 α 4 818 A, I 13>53 I 3;:7 Hh I >611 eH.". I 6988 QAr - 569>

, @ 3819 α I 9:7 A, - 18131 3:79 Hh - 593: eH.". 45>7: QAr 41;1:3

!he 0uality of the discriminant models was determined on the asis of a posteriori proaility (cases in

the model) !he investi#ation of classification matri/ showed that 1;;B of cases were correctly classified

accordin# to the a priori assi#ned #roup codes (!ale >)

!he separation of the two #roups is #ood Dhen H1-antihistamine activity of new thiazole derivatives is

investi#ated& there are the followin# allocation rules derived from the 'A results+ to calculate the values of

si/ variales otained here via the 'A method (a& A,& & Hh& eH.".& QAr ) for the new thiazole derivativeJ to

sustitute these values in the two discrimination functions otained hereJ to chec2 which discrimination

function presents the hi#her value *f the hi#her value is related to the discrimination function of #roup A& the

thiazole derivative is proaly active

R6rss0#. A.a/!s0s 4RA3

!he application of the iochromato#raphic data in QSAR analysis of some thiazole derivatives with H 1-

antihistamine activity was descried in the previous papers (3 ñ5) Additionally& the lipophilicity data of

solutes were applied as independent variales in the re#ression analysis .n the asis of descried results it

was found that lo# $ is a crucial indicator of the H1-antihistamine effect of thiazole derivatives An increase in

the lo# $ value favors hi#her iolo#ical activity of the tested compounds umerous si#nificant multivariaterelationships of the antihistamine effect involved lo# $ values (345) !he present RA started with inter-


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correlation study of the used independent variales .nly the uncorrelated physicochemical data can e used

in the multivariate relationships (see !ale 5)

e/t& the systematic analysis was performed As result& over :; statistically si#nificant relationships

were determined !he otained relationships of H 1-antihistamine effect and molecular descriptors values

e/plained 88495B of the variance !he est univariate and multivariate relationships are shown in !ale 7

*t is evident in QSAR investi#ation that the est correlations otained y the RA method for thiazole

derivatives 1-1* with H1-antihistamine activity underline important role of hydrophoic and steric parameters

for this 2ind of activity !he same parameters (ADJ EDJ lo# $J lo# 'J "RJ a) with stron# factor loadin#s uilt

the most si#nificant factor& which was otained in factor analysis of the investi#ated compounds 1-1* (1) *t is

also evident that some of the electronic parameters are very important !hese parameters were lin2ed to

hi#her and lower compounds activity via 'A (a& A,& Hh& eH.".& QAr ) and $%A (a& lo# $& H h& εH.".& QAr )

methods

All calculated si#nificant relationships can e applied to predict the pharmacolo#ical activity of new

dru# candidates !he est of these relationships can e e/pressed y the e0uation 20 (!ale 7)& which e/plains

95B of the total variance+

pA3 @ 517(K ;;5) I ;81(K ;;7) lo# $ I ;166(K;;7) m 4 ;188(K ;;5) QAr

*t was concluded that the hi#h lipophilicity and dipole moment comined with less ne#ative char#e on

aromatic nitro#en atom are the properties of active H1-antihistamine thiazole derivatives

*t is clearly seen that e0uation 20 may have predictive value for the desi#n of new thiazole derivatives as

the H1-antihistamine dru#s (!ale 8 and i# 6) !he correlation of calculated pA 3(H1) values of the tested

compounds predicted y the use of the aove mentioned e0uation versus their pA3(H1) values otained from

iolo#ical tests was si#nificant (R 3 @ ;95)

However& the ran#e of pA3 data of the e/amined compounds otained from iolo#ical tests clustered

around two sets (compounds 1-11 have pA3 values etween >;; and 5;>J compounds 1%-1* have pA3 values

etween 5:8 and 76:) or the two-point data distriution the possiility of coincidence in the model

presented in the fi#ure cannot e eliminated

CONCLUSION

!he dimensionality of physicochemical parameters was reduced y the $%A and 'A methods& and the

suset of variales more effective for classification the thiazole derivatives accordin# to their de#ree of anti-

H1 activity were determined !he $%A method can e useful as an efficient tool for initial selection of the

parameters which si#nificantly enhance anti-H1 activity !he analysis determined the direction of the lead

compounds modification !he results of 'A method showed that α& A,& & Hh& eH.". and QAr parameters are

2ey properties for e/plainin# the H1-antihistamine activity of thiazole derivatives 1-1* ut lo# $ is also

important for desi#n of new thiazoles e/hiitin# antihistamine activity !he determined discrimination

function for #roups A and , can e an efficient tool in further investi#ations ood univariate and multivariate

relationships otained y the use of RA method can e used for predictin# the 0uantitative effect of

H1antihistamine activity of different thiazole derivatives !hese relationships involved the parameters

determined via 'A and $%A methods

Documents

A Structure-Activity Relationship Study of Thiazole Derivatives