Structure–activity relationships for novel drug precursor N-substituted-6-acylbenzothiazolon derivatives: A theoretical approach Yadigar Gülseven Sıdır ⇑ , _ Isa Sıdır Bitlis Eren University, Faculty of Arts and Science, Department of Physics, 13000 Bitlis, Turkey highlights Structure–activity relationships for novel drug precursor 6-acylbenzothiazolon derivatives are researched. V m , MR, x, EA, E HOMO E LUMO (DE), HOF, v, l, S and g parameters give good correlations with log P. The electronic structures of 6-acylbenzothiazolon derivatives have been expounded. Molecular polarity, hydrophilic character and dipole moment show the same trend. article info Article history: Available online 15 April 2013 Keywords: NSAI drug Benzothiazolon Piperazine SAR Octanol–water partition coefficient Molecular descriptors abstract In this study, the twelve new modeled N-substituted-6-acylbenzothiazolon derivatives having analgesic analog structure have been investigated by quantum chemical methods using a lot of electronic param- eters and structure–activity properties; such as molecular polarizability (a), dipole moment (l), E HOMO , E LUMO ,q , qH + , molecular volume (V m ), ionization potential (IP), electron affinity (EA), electronegativity (v), molecular hardness (g), molecular softness (S), electrophilic index (x), heat of formation (HOF), molar refractivity (MR), octanol–water partition coefficient (log P), thermochemical properties (entropy (S), capacity of heat (C v )); as to investigate activity relationships with molecular structure. The correla- tions of log P with V m , MR, x, EA, E HOMO E LUMO (DE), HOF in aqueous phase, v, l, S, g parameters, respec- tively are obtained, while the linear relation of log P with IP, C v , HOF in gas phase are not observed. The log P parameter is obtained to be depending on different properties of compounds due to their complexity. Ó 2013 Elsevier B.V. All rights reserved. 1. Introduction The two types of molecules have clinic analgesic properties; the first molecule type is non-steroidal anti-inflammatory drugs (NSA- IDs), when the second molecule type is central opioids. But both molecule groups have different kind of side effect. NSAIDs are especially cause gastro-intestinal system lesion, while opiates are particularly bringing about physical dependency. The researches performed in the last years on analgesic active compounds tend to developing new NSAID compounds which haven’t side effect [1,2]. The most important types of these compounds having anal- gesic active properties are benzothiazolinone derivatives which is NSAID groups. Moreover, NSAIDs have biological activity such as antibacterial, anticonvulsive, diuretic, antihistaminic and antiarith- mic [3–11]. The investigated compounds in this work have piperazine moi- ety. Piperazine moiety has a variety of biological activity like anti- fungal, antidepressants, antiviral, serotonin receptor (CS-HT), and antagonists/agonists binding [12–14]. Considering the common use of benzothiazolon and piperazine in drug design we have suggested this work aiming to develop NSAID drugs which are effective as opiates and not having side effects. In this paper, we have performed molecular modeling of N-substituted-6-acylbenzothiazolon derivatives theoretically. In our previous study, we reported the structure–activity relation- ships of novel drug precursor 6-acylbenzothiazolon derivatives though as non-steroidal anti-inflammatory agents [15,16]. In continuation with the work, depending on benzothiazolinone, and different substituent linked to it, new drug precursor N-substi- tuted-6-acylbenzothiazolon derivatives having analgesic activity are modeled. Antinociceptive activity of 1,3-benzothiazol-2(3H)- one derivatives has been reported by Önkol et al. [17] Structure– activity relationship (SAR) of twelve N-substituted-6-acylbenzothiazolon derivatives is investigated by quantum chemical descriptors. In 0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.molstruc.2013.04.006 ⇑ Corresponding author. Tel.: +90 434 2285170; fax: +90 434 228 51 71. E-mail address: [email protected](Y.G. Sıdır). Journal of Molecular Structure 1045 (2013) 131–138 Contents lists available at SciVerse ScienceDirect Journal of Molecular Structure journal homepage: www.elsevier.com/locate/molstruc
Transcript
Journal of Molecular Structure 1045 (2013) 131–138
Contents lists available at SciVerse ScienceDirect
Yadigar Gülseven Sıdır ⇑, _Isa SıdırBitlis Eren University, Faculty of Arts and Science, Department of Physics, 13000 Bitlis, Turkey
h i g h l i g h t s
� Structure–activity relationships for novel drug precursor 6-acylbenzothiazolon derivatives are researched.� Vm, MR, x, EA, EHOMO � ELUMO (DE), HOF, v, l, S and g parameters give good correlations with log P.� The electronic structures of 6-acylbenzothiazolon derivatives have been expounded.� Molecular polarity, hydrophilic character and dipole moment show the same trend.
In this study, the twelve new modeled N-substituted-6-acylbenzothiazolon derivatives having analgesicanalog structure have been investigated by quantum chemical methods using a lot of electronic param-eters and structure–activity properties; such as molecular polarizability (a), dipole moment (l), EHOMO,ELUMO, q�, qH+, molecular volume (Vm), ionization potential (IP), electron affinity (EA), electronegativity(v), molecular hardness (g), molecular softness (S), electrophilic index (x), heat of formation (HOF),molar refractivity (MR), octanol–water partition coefficient (logP), thermochemical properties (entropy(S), capacity of heat (Cv)); as to investigate activity relationships with molecular structure. The correla-tions of logP with Vm, MR, x, EA, EHOMO � ELUMO (DE), HOF in aqueous phase, v, l, S, g parameters, respec-tively are obtained, while the linear relation of logP with IP, Cv, HOF in gas phase are not observed. ThelogP parameter is obtained to be depending on different properties of compounds due to theircomplexity.
� 2013 Elsevier B.V. All rights reserved.
1. Introduction
The two types of molecules have clinic analgesic properties; thefirst molecule type is non-steroidal anti-inflammatory drugs (NSA-IDs), when the second molecule type is central opioids. But bothmolecule groups have different kind of side effect. NSAIDs areespecially cause gastro-intestinal system lesion, while opiates areparticularly bringing about physical dependency. The researchesperformed in the last years on analgesic active compounds tendto developing new NSAID compounds which haven’t side effect[1,2]. The most important types of these compounds having anal-gesic active properties are benzothiazolinone derivatives which isNSAID groups. Moreover, NSAIDs have biological activity such asantibacterial, anticonvulsive, diuretic, antihistaminic and antiarith-mic [3–11].
The investigated compounds in this work have piperazine moi-ety. Piperazine moiety has a variety of biological activity like anti-fungal, antidepressants, antiviral, serotonin receptor (CS-HT), andantagonists/agonists binding [12–14].
Considering the common use of benzothiazolon and piperazinein drug design we have suggested this work aiming to developNSAID drugs which are effective as opiates and not having sideeffects. In this paper, we have performed molecular modeling ofN-substituted-6-acylbenzothiazolon derivatives theoretically. Inour previous study, we reported the structure–activity relation-ships of novel drug precursor 6-acylbenzothiazolon derivativesthough as non-steroidal anti-inflammatory agents [15,16]. Incontinuation with the work, depending on benzothiazolinone,and different substituent linked to it, new drug precursor N-substi-tuted-6-acylbenzothiazolon derivatives having analgesic activityare modeled. Antinociceptive activity of 1,3-benzothiazol-2(3H)-one derivatives has been reported by Önkol et al. [17] Structure–activity relationship (SAR) of twelve N-substituted-6-acylbenzothiazolonderivatives is investigated by quantum chemical descriptors. In
addition, relationships between log P and the other moleculardescriptors are researched.
2. Material and methods
2.1. Quantum chemical data set
The formulations of the molecular descriptors used in this workare given as following;
g � 12 ðIP � EAÞ � 1
2 ðeLUMO � eHOMOÞ
Molecular hardness IP � �eHOMO Ionization potential EA � �eLUMO Electron affinity l Dipole moment v ¼ IPþEA
2
Electronegativity
S ¼ 1g
Molecular softness
x ¼ v2
2g
Electrophilic index
<a> = 1/3(axx + ayy + azz)
Mean molecularpolarizability
ELUMO � EHOMO = DE
LUMO–HOMO energy gap S Entropy Cv Capacity of heat HOF Heat of formation LogP Octanol–water partition
coefficient
The molecular descriptors represent different classes of molec-ular properties like electronic, thermochemical and hydrophobicproperties of the compounds. These features are important toinvestigate the SAR of N-substituted-6-acylbenzothiazolon deriva-tives with biological activity. Thus, these molecular properties aretalking about our group’s early work [16]. Quantum chemicaldescriptors, molecular polarizability (a), dipole moment (l), en-ergy of the highest occupied molecular orbital (EHOMO), energy ofthe lowest unoccupied molecular orbital (ELUMO), q� (hydrogenbond donor center), qH+ (hydrogen bond acceptor center), molecu-lar volume (V), ionization potential (IP), electron affinity (EA), elec-tronegativity (v), molecular hardness (g), molecular softness (S),electrophilic index (x), molar refractivity (MR), EHOMO � ELUMO
(DE), entropy (S), capacity of heat (Cv), both heat of formation(HOF) in aqueous phase, and in gas phase and octanol–water par-tition coefficient (logP) are used to investigate structure–activityrelationships for novel drug precursor N-substituted-6-acylbenzo-thiazolon derivatives. We have researched relationships betweenmolecular properties and log P which indicates biological activityof a molecule.
2.2. Computational methodology
In order to research geometry conformational stability, thewhole molecular structures were initially submitted to HF/3-21Glevel of theory by using Spartan 08 [18]. As a result of this calcula-tion, only the most stable conformer found for a given compound isused for the further calculations. The final calculations were per-formed in Gaussian 03W software [19]. Molecular structures wereoptimized by using B3LYP/6-31G(d,p) level of theory [20]. Theirfundamental vibrations were controlled whether molecular struc-tures were true minima. Gaussian 03W output files give directlythe dipole moment, polarizability, HOMO and LUMO values andsome molecular parameters. Some of the other parameters(ionization potential, electron affinity, electronegativity, molecularhardness, molecular softness, electrophilic index) were derivedfrom these results.
Octanol–water partition coefficient (logP), molar refractivityand heat of formation parameters of the investigated moleculeswere calculated by CS ChemOffice2004 software. All of the mole-cules were constructed by using ChemDraw Ultra 8.0 and weresaved as initial structure. This structure was suitably changedconsidering its structural features copied to Chem3D Ultra 8.0 tocreate a 3-D model and, finally, the model was cleaned up and sub-jected to energy minimization using molecular mechanics (MM2).The Austin Model-1 (AM1) method was used for re-optimizationthe studied molecules using MOPAC [21]. The lowest energy struc-ture was used for each molecule to calculate lipophilicity (logP)parameter. Gas phase heat of formation and aqueous phase heatof formation was calculated by using AM1 semi-empirical methodin CAChe Ab Initio Version 6.1.12.33 software [22].
3. Results and discussion
The IUPAC names, molecular formulas and the structure–activ-ity relationship properties of N-substituted-6-acylbenzothiazolonderivatives are listed in Tables 1 and 2, respectively. Molecularstructure of the studied compounds is given in Fig. 1. Some ofthe atomic charges of these compounds calculated at B3LYP/6-31G(d,p) level of theory is listed in Table 3.
Octanol–water partition coefficient (logP) is one of the mostimportant parameter, because it gives information about the maininteractions between drug molecule and its biological receptor. Ifthe logP value of drug molecule has higher value, the moleculehas the more analgesic activity and lipophylic character. The inves-tigated analgesic compounds have high logP values (in the range of2.5–4.5 values), thus, these molecules have a higher lipophyliccharacter than the inactive ones. Because biological membrane isconsisted of mainly by lipid cells, these molecules are able to reacheasily the biological receptor and have a higher capacity of crossingthe biological membrane. The biggest logP value among the stud-ied compounds is found as molecule 4 as 4.298. As shown in Fig. 1,this molecule has both methyl and butyl substituents. The lowestlogP value is calculated as 2.443 for molecule 9 which has fluorineand methyl substituents. Considering the logP values of N-substi-tuted-6-acylbenzothiazolon derivatives, these molecules are clas-sificated to three groups in Fig. 1; as 1–4, 5–8 and 9–12molecules. We have observed that logP values increase with thelengthening in alkyl group located in R position. As can be seenfrom Fig. 2, F and OCH3 substituent give rise to decrease in logP.The differences between logP values of molecules are trendingbelow;
In here, we observe that change of DlogP is dependent on thelengthening of alkyl group in R position. However, the biggermolecular volume means the bigger biological activity.
Increase in molecular volume of a molecule makes the moleculemore active in joining the reactions. The molecular surface area islinearly depending on molecular volume. Briefly, for eventuate ofthis reaction, the biological activity of a molecule must be havelarge molecular surface area. If the molecule has small molecularvolume or molecular surface area, then, biological interactions be-tween the molecule with biological receptor cannot be material-ized [16,23]. Fig. 3 shows the linear relationships between Vm
and logP of the investigated molecules with the regression coeffi-cients (R2) of 0.8063. The logP value of molecule 1 is bigger thanmolecule 5 and 6. This case is because of the substituent effect.Electron donating substituents (CH3) in molecule 1 increased the
Table 1IUPAC name and molecular formula of studied 6-acylbenzothiazolon derivatives.
The all other parameters have been calculated with Gaussian 03W software using B3LYP/6-31G(d,p) level of theory.<a> = Molecular polarizability. l = Dipole moment. EHOMO = high-occupied molecular orbital energy. ELUMO = lowest-unoccupied molecular orbital energy.Vm = molecular volume. IP = ionization potential. EA = electron affinity. v = electronegativity. g = chemical hardness. S = chemical softness.x = Electrophilic index. MR = molar refractivity. HOF = heat of formation.Cv: J mol�1 K�1; entropy: J mol�1. K�1.
a Calculated with CS ChemOffice2004.b Calculated with AM1 method.
logP, whereas electron-withdrawing substituents (F, OCH3) de-creased it. Table 2 indicates that logP values are inversely trendingwith molecular volumes for molecules 5–6, 7–8 and 9–10.
One of the most important physicochemical properties used inQSAR studies is molar refractivity (MR). It has been shown to be re-lated to lipophilicity, molar volume and steric bulk [24]. Moreover,the molar refractivity (MR) is related to the size and the polariz-ability of a substituent added to molecule, the larger polar partof a molecule and the larger MR value [24]. MR represents disper-sive forces which help the interaction between substituents andthe biological receptor and, addition; it also represents a measure
of volume. In other words, it measures the capacity of substituentchanging molecular conformation of molecule [24]. Molecule 12has the biggest molar refractivity value among the other studiedmolecules. Thus, this molecule easily interacts with the biologicalreceptor [16]. In this work, molar refractivity of the whole investi-gated compounds is found positive. Resultantly, these moleculescan interact with the biological receptor by two ways. Firstly, stud-ied molecules are through polar groups of the biological receptorbecause of polarizability effects. Secondly, it constitutes throughsteric effects due to the size of the substituents. According toFig. 4 (plot of MR vs. logP), we can say that first two groups
Fig. 1. The molecular structure of N-substituted-6-acylbenzothiazolon derivatives.
Table 3Selected atomic charges of the studied molecules calculated at B3LYP/6-31G(d,p) level of theory.
(Group-1 and Group-2) are doing the similar interaction with thebiological receptor since regression coefficient of correlation be-tween MR and logP is 0.9733 value. However, Group-3 is partici-pating in different one way to interact with biological receptordue to R2 = 0.9761. Increase in size of alkyl chain committed piper-azine moiety gives rise to the bigger molar refractivity.
Parthasarathi et al. reported that there is linear correlation be-tween electrophilic index (x) and hydrophobic parameter (logP)of biological active molecules [25]. We have observed in Fig. 5 thatGroup-1 and Group-3 except for molecule 9 produce linear corre-lation (R2 = 0.9733) between electrophilic index (x) and hydropho-bic parameter (logP), while Group-2 does not present linearcorrelation (R2 = 0.0079). In addition, this parameter is satisfactory
Fig. 5. The plot of x vs. logP values of N-substituted-6-acylbenzothiazolonderivatives.
Fig. 6. The plot of EA vs. logP values of N-substituted-6-acylbenzothiazolonderivatives.
Fig. 7. The plot of DE vs. logP values of N-substituted-6-acylbenzothiazolonderivatives.
Fig. 8. The plot of HOF vs. logP values of N-substituted-6-acylbenzothiazolonderivatives.
Fig. 9. The plot of v vs. logP values of N-substituted-6-acylbenzothiazolonderivatives.
Fig. 10. The plot of dipole moment vs. logP values of N-substituted-6-acylbenzo-thiazolon derivatives.
Fig. 11. The plot of entropy (S) vs. logP values of N-substituted-6-acylbenzothiaz-olon derivatives.
Fig. 12. The plot of g vs. logP values of N-substituted-6-acylbenzothiazolonderivatives.
parameter to determine the biological activity. Besides, accordingto molecular structure, the x parameter depends on size and nat-ure of the substituents of the investigated molecules. In that, elec-tron-withdrawing substituents (F) increase the electrophilicitywhen electron-donating substituent (CH3, OCH3) decrease it. Whenalkyl chains of molecules are lengthening, electrophilicity is
increasing. We observed the same trend in our previously pub-lished work [16]. But, molecules 7, 10 and 11 do not participatedto this trend. This case can be expounded with steric effect depend-ing on molecular geometry.
The electron affinity of a molecule is measure of needful energyto attain nucleophilicity of a negative charged ion or a molecule
including lone pair. Moreover, toxicity of novel drug precursor isrelated to this parameter [26–29]. The magnitude of electron affin-ity is partly depended on toxic potential of a molecule. In addition,importance to electron affinity of a molecule can be measured tobiological activity of the molecule. As can be seen from Fig. 6 thatthe correlations between EA and logP are allocate two groups incorrelation to each other. The F substituent in 5–8 molecules givesrise to increasing in nucleophilicity character while CH3 and OCH3
substituent in the other molecules decreases nucleophilicitycharacter.
When DE (ELUMO � EHOMO), which term presents the reactivityof the molecule, has minor values, the molecule can easy join tointeraction with biological environment. Linear correlation be-tween DE and logP is shown in Fig. 7, and, we have observedtwo different slopes in this graph. Firstly, the correlation coefficientbetween DE and logP of Group-1 and Group-2 except for molecule8 and 3 and including molecule 9 is found as R2 = 0.976. Secondly,the correlation coefficient between DE and logP of Group-3 includ-ing molecule 8 and 3 is found as R2 = 0.6791. But, if DE of a mole-cule have the smaller values, when is the easer electron transferfrom HOMO orbital to LUMO orbital, the molecule can have thebigger toxicity character [16]. Moreover, DE show whether themolecule is kinetically stable or not. According to HOF values, allof the molecules are exothermic. In that, exothermic property ofHOF means the investigated molecules thermodynamically stable.In Table 2, negative sign of HOF are propping to this interpretation[16,30,31]. In addition, the correlation between HOF and logP canbe found in Fig. 8. In that, HOF value is partly depending on chang-ing value.
Biological activity is not observed to depend on ionization po-tential (IP). The lowest IP value is found for molecule 4 as 5.711 eV.
According to Pauling [32], electronegativity of a molecule isdescribed as electron accepting ability of a molecule. It is early re-ported that electronegativity depends on biological activity [31].Fig. 9 indicates that there are two different correlations betweenelectronegativity and hydrophobic parameters. Firstly, linear cor-relation between logP and v of molecules 3, 4, 5, 6, 7 and 12 isfound as R2 = 0.9789 and secondly, linear correlation is observedas R2 = 0.8569 for molecules 1, 2, 9 and 10.
Our previously study showed the presence of good correlationbetween dipole moment and logP of some NSAI drugs [16]. Wecan say that logP values for investigated derivatives expect formolecules 2, 8 and 11 give good linear correlation with dipole mo-ments as depicted in Fig. 10. Calculated dipole moments of thesederivatives change in the range of 0.6–7.6D.
Dipole moments are increasing in the following;
Entropy, which is thermodynamic parameter, is especiallydepending on molecular size. This parameter is effecting intermo-lecular dispersive interactions between molecule and active site ofthe action in conjunction with other molecular characteristic [33].As shown in Fig. 11 that logP is linearly depending on entropy (S).When alkyl changes linked to piperazine are expanding likemethyl, ethyl, isopropyl and butyl, both logP and entropy (S) areincreasing.
Molecular hardness is described as stability of a molecule. In-versely, molecular softness is known as reactivity of a molecule.We have observed in Fig. 12 that molecular hardness is correlatedwith logP, which is determined as hydrophobic parameters and isto be associated with biological activity. But, this graph showsdecreasing of g values against increasing logP values. Then, thecorrelation between logP and molecular softness is inverselyproportional.
The 3D plots of the HOMO (Highest occupied molecular orbital)and LUMO (Lowest unoccupied molecular orbital) of some mole-cules calculated by using B3LYP/6-31G(d,p) method/basis set aredepicted in Fig. 13. These molecular orbitals show the location ofpossible sites responsible from electron transfer between mole-cules and its biological target. Thus, we can discover that how mol-ecules react and where is the active sites in reaction. As shown inFig. 13, HOMO plots are similar for all of the molecules. TheHOMOs are only localized on benzothiazolon ring system includingCO group linked to phenyl ring. The HOMO plot is not localized onN atom in thiazole ring due to its sp3 hybridization. The LUMO of1–4 molecules are localized on benzothiazole ring system, meth-ylbenzoyl ring system and N atom in thiazole ring except for Catom linked to S atom in thiazole ring due to increasing chargedensity of S atom and sp3 hydribization of H atom, while LUMOof 5–12 molecules are localized on benzothiazole ring system,methylbenzoyl ring system and C–N bond of thiazole rings. Be-cause of their non-planar geometry, CH2–CO–piperazin–R systemdoes not contain any HOMO, LUMO charge density.
The biggest negative and positive charged hydrogen atoms in amolecule show the local interactions in biological medium. Thecharge distribution of selected atoms of N-substituted-6-acy-lbenzothiazolon derivatives in Table 3 indicate that O1, O2, O3,N1, N2, N3 and C1 atoms are donor due to having negative charge,while S, C2, H1 and H2 atoms are acceptor because of having posi-tive charge. On the other hand, if a molecule has the most positivenet atomic charge on hydrogen atom, then, this molecule can beformed to hydrogen bonds. Thus, this molecule is coming intothe stronger interactions with water molecule. Addition, toxicityeffect of this molecule is reduced via this interaction for examplehydrogen bonding [33]. We can observe in Table 3 that qH+ chargeon H1 of these derivatives are increasing, when alkyl change linkedto piperazine moiety of these derivatives are lengthen. In that, tox-icities of studied molecules are decreasing with increasing of alkylchange length. Ultimately, alkyl charge lengths are comparativelyaffecting toxicity of investigated molecules.
4. Conclusions
This handle work is a study on theoretical application of struc-ture–activity relationships of novel drug precursor N-substituted-6-acylbenzothiazolon derivatives. It is observed that molar vol-ume, molar refractivity, electrophilicity, electron affinity, heat offormation and entropy are linaearly depending on hydrophobicparameter (logP). We have observed that logP values are increas-
9 (HOMO) 9 (LUMO)
12 (HOMO) 12 (LUMO)
8 (HOMO)
5 (LUMO)
1 (HOMO) 1 (LUMO)
4 (HOMO) 4 (LUMO)
5 (HOMO)
8 (LUMO)
Fig. 13. The 3D graph of HOMO and LUMO of investigated some molecules.
ing when alkyl size is increasing. The DELUMO–HOMO, absolute elec-tronegativity and molecular hardness are increasing while logPvalues are decreasing, in that; these parameters are change as in-versely proportional with hydrophobic parameter. According toHOMO and LUMO, we can say that these molecules are coming intointeraction from benzothiazolon moiety with biological medium.The logP values are linearly changing with dipole moment valuesof these compounds.
Acknowledgements
We are grateful to Turkish Scientific Council (TÜB_ITAK) for thefinancial support to this work via the Research Project with thenumber of 108T192. We would like to thanks Asst. Prof. Dr. HalilBerber (Anadolu University, Faculty of Science, Department ofChemistry) for his support with CAChe 6.1. software and Gaussian03W software.
This work is dedicated to the memory of our colleague DearProf. Dr. Cemil Ögretir, who passed away on January 19, 2011.
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