Characterization of Ligand N'-[(1E)-1-Phenylethylidene]-1,3-Benzothiazole-2-Carbohydrazide by Using Marvin Sketch 20.8 Software

Introduction

N’-[(1E)-1-phenylethylidene]-1,3-benzothiazole-2-carbohydrazide(PEBTH)

Synthesis of N’-[(1E)-1-phenylethylidene]-1,3-benzothiazole-2-carbohydrazide(PEBTH) as given in Fig 1 involves three steps (i) conversion of 2-aminothiophenol to benzothiazole -2- ethyl carboxylate by esterification (ii)  conversion of ester to its hydrazide  (iii) conversion of benzothiazole-2-carbohydrazide(BTCH)to N’-[(1E)-1-phenylethylidene]-1,3-benzothiazole-2-carbohydrazide(PEBTH) by reaction with acetophenone.

Figure 1: Structure of PEBTH Click here to View figure

Results and Discussion

By using the Marvin Sketch 20.8 the structure of N’-[(1E)-1-phenylethylidene]-1,3-benzothiazole-2-carbohydrazide (PEBTH) was built and its name is determined as follows

Traditional name: N’-[(1E)-1-phenylethylidene]-1,3-benzothiazole-2-carbohydrazide

Preferred IUPAC name: N’-[(1E)-1-phenylethylidene]-1,3-benzothiazole-2-carbohydrazide

The properties of N’-[(1E)-1-phenylethylidene]-1,3-benzothiazole-2-carbohydrazide (PEBTH) as determined by Marvin Sketch 20.8 are as following.

Mass spectrum for N’-[(1E)-1-phenylethylidene]-1,3-benzothiazole-2-carbohydrazide(PEBTH)

In Marvin sketch software with the help of Elemental Analysis Plugin the elemental composition of a molecule is studied and the basic descriptors were determined.

Elemental Analysis Plugin calculatesbasic descriptors like  Molecular weight ,Exact molecular weight, Formula, Composition ,Atom count associated with  elemental composition of a molecule^1,2.

The structure of N’-[(1E)-1-phenylethylidene]-1,3-benzothiazole-2-carbohydrazide(PEBTH) is drawn as an input structure which gives the following analysis results.

The following data of PEBTH is obtained by making using of  Elemental Analysis Options window.

Table 1: Mass spectrum for N’-[(1E)-1-phenylethylidene]-1,3-benzothiazole-2-carbohydrazide(PEBTH)

Molecular weight :	295.36
Exact molecular weight	295.077933225
Formula	C16 H13N3 OS
Composition :	C (65.07 % ), H (4.44 %), N (14.23 %), O (5.42%), S ( 10.85 %)
Atom count	34

 

From the  standard atomic weights, the average molecular mass of PEBTH is determined and its value is 295.36and the exact molecular weight of PEBTH is  295.077933225. From the weights of the mostabundant natural isotopes of the elements the monoisotopic mass is  calculated and this value is found to be in coincidence with the above value(Table 1).

Chemical formula of the molecule is given in accordance with the Hill system where in  the number of carbon atoms is indicated first followed by  the number of hydrogen atoms next, and then the number of all other chemical elements , harmonizing alphabetical order. Chemical formula of PEBTH is C₁₆ H₁₃N₃ OS.

The elemental composition of PEBTH obtained is C (65.07 % ), H (4.44 %), N (14.23 %), O (5.42%), S ( 10.85 %) . As per the calculation made  from the atomic masses the elemental composition is indicated  in weight percentage (w/w%).    Atom count of PEBTH is 34 and this count  is the  number of all atoms in the molecule PEBTH.

Figure 2: The m/z:relative abundance Mass spectrum of N’-[(1E)-1-phenylethylidene]-1, 3-benzothiazole-2-carbohydrazide(PEBTH) Click here to View figure

Taking into account of   relative abundance of the isotopes the mass distribution of the input molecule PEBTH is calculated using Marvin sketch software. This distribution of  mass is demonstrated as a spectrum and this spectrum in mass spectroscopy is known as the m/z:relative abundance spectrum.

Mass spectral data recorded for N’-[(1E)-1-phenylethylidene]-1,3-benzothiazole-2-carbohydrazide (PEBTH) by using Marvin sketch 20.8 software shows peaks of 295 :1.00, 296:0.19, 297:0.06, 298:0.01as given in fig 2. Mass spectrum data of PEBTH  (m/z : relative abundance): 295 :1.00, 296:0.19,   297:0.06,   298:0.01. This is in agreement with the experimentally recorded mass spectrum data which shows molecular ion peak  M⁺ at m/z 295.

Structure display models of PEBTH

In Marvin sketch it is possible to obtain the different structure display of the molecules. This is done by navigating in Marvin sketch as view followed by structure Display. The structure display formats of the molecule N’-[(1E)-1-phenylethylidene]-1,3-benzothiazole-2-carbohydrazide(PEBTH) like stick, ball and stick and space fill forms of the molecule PEBTH are given in the following figures.

figure 3 displays  the  structure of PEBTH in various forms like stick, ball and stick and space fill models .

Figure 3: Structure display models of N’-[(1E)-1-phenylethylidene]-1, 3-benzothiazole-2-carbohydrazide(PEBTH) Click here to View figure

pKa of N’-[(1E)-1-phenylethylidene]-1,3-benzothiazole-2-carbohydrazide(PEBTH)

Molecules in general contain specific functional groups that can lose or gain protons under suitable conditions. The coincidence  of the protonated and deprotonated forms of the molecule is described by a  constant value of pK_a.  In marvin software by making use of the pK_a Plugin it is possible to calculate the pK_a values of the molecule. It is well known that the based on its partial charge distribution the pKa value of molecule changes.

By using the marvin sketch 20.8  pKa of N’-[(1E)-1-phenylethylidene]-1,3-benzothiazole-2-carbohydrazide (PEBTH) is determined³ and it is found to be 9.82 which indicates the dissociation of the proton from the ligand  PEBTH(figure 4).In PEBTH as there are less than 8 ionizable atoms , microspecies distribution is displayed on the chart given in figures 4,5 with data given in Table 2.

This is agreement with the experimental  data of potentiometric Titrations carried out with N’-[(1E)-1-phenylethylidene]-1,3-benzothiazole-2-carbohydrazide (PEBTH) in 70% v/v DMF-water medium at 0.1M ionic strength and 303K temperature. The dissociation of proton of  PEBTH  corresponds to pKa value of 10.6 .

The comparision of pKa value of PEBTH reveals that in aquo organic medium of 70% v/v DMF-water medium pKa value is high because  the proton dissociation of the ligand is influenced by the Basicity and dielectric constant of the medium. Changes in dielectric constant and the basicity of the medium influences the acid- base equilibria. With the addition of organic solvent DMF miscible with water,to an aqueous medium, a number of changes occur like decrease in dielectric constant of the medium, breakdown of structuredness of water and solvation of proton in high concentration of organic solvent.

In marvin software the display option tab provides the following options which can be set

The number of decimal places for the result is set as 2

Distribution chart gives  the range of displaying the microspecies distribution diagram as following and it  can be set like pH lower limit( taken as 0), pH upper limit( taken as 14), pH step size( taken as 0.2).

Figure 4: microspecies distribution of PEBTH is displayed on the chart Click here to View figure

Table 2: pKa Plugin window showing the calculated pKa values of N’- [(1E)-1-phenylethylidene]-1,3-benzothiazole-2-carbohydrazide(PEBTH) Click here to View table

Figure 5: microspecies distribution (in %) of N’-[(1E)-1-phenylethylidene]-1, 3-benzothiazole-2-carbohydrazide(PEBTH). Major microspecies is obtained at pH= 7.40 Click here to View figure

Isoelectric point of PEBTH

Isoelectric point (IEP)is the pH at which a particular molecule or surface has no electrical charge. In chemaxon software the total charge distribution of PEBTH is determined as a function of pH. applying the  isoelectric point plugin.The table 3  as given below  shows result of Isoelectric point (IEP )and the pH of PEBTH molecule.and the figure shows the pH:charge plot

Table 3: Data for Isoelectric point of PEBTH Click here to View table

LogP result window of PEBTH

The octanol/water partition coefficient is calculated employing logP Plugin and is further applied in QSAR analysis. Molecular hydrophobicity^{4 -7} can be judged by octanol/water partition coefficient and this is also applied for rational drug design. Log P is calculated by the methodsuggested by Viswanadhan et al publication. Log P value of PEBTH is 3.33 as obtained by Marwin software and displayed in figures 7. and the atomic increments  are displayed in figure 6

Figure 6: LogP result window of PEBTH with atomic increments displayed in Marvin Space Click here to View figure

Figure 7: LogP value of PEBTH with atomic increments displayed in Marvin View. Click here to View figure

In Marwin software  following points were considered in order to modify the algorithm 1.In order to accommodate electron delocalization many atomic types were redefined and as a result the assistance made by the ionic forms were included. The logP of zwitterions are determined from their logD value at their isoelectric point the effect of hydrogen bonds on the logP is determined and the probability of  forming the six membered ring among the suitable donor and acceptor atoms is evaluated. atoms like S, C, N and metal atoms were introduced.

Charge of PEBTH

Certain properties like like ionization constants, reactivity and pharmacophore pattern  which describes the Physico-chemical behavior  of a molecule are determined by partial charge distribution. partial charge value of each atom can be computed by Charge Plugin. From sigma and pi charge components , total charge is calculated.

The results of the charge calculation of PEBTH are shown in a new window. From the results obtained it is clear that negative charge values are highest for oxygen . Also it is observed that negative charge values are higher on N atoms of  amine group (N-NH) and N of benzothiazole ring .( Fig.8 ).

Figure 8: Charge calculation of PEBTH Click here to View figure

Polarisability of PEBTH

The relative tendency of an electron cloud which is deformed by an external electric field is Polarizability. The more polarizable  ion  vicinity is the more stable ionized site. Because of this atomic polarizability is considered as an significant element in the measurement of pK_a. Partial charges of atoms^8,9 influence the polarizability  of atoms . with the help of Polarizability Plugin the values of atomic and molecular polarizability were determined. Molecular Polarisability value of PEBTH is  32.47 as given in figure 9

Figure 9: Polarisability calculation of PEBTH Click here to View figure

Orbital electronegativity of PEBTH

Orbital electronegativity (orbital EN) of the atoms in the molecule determines the Partial charge distribution of the molecule. It is possible to evaluate orbital EN values of atoms with the help of orbital EN values of atoms in PEBTH molecule are displayed in figure 10 and Table 4

Figure 10 Orbital electronegativity values  of PEBTH Click here to View figure

Table 4: Orbital electronegativity calculation  of PEBTH Click here to View table

Geometrical Descriptors of PEBTH

The energy of the 3D structure of the molecule is calculated by making use of Dreiding force field Dreiding energy of PEBTH   is 63.42 kcal/mol

The energy of the 3D structure (conformation) of the molecule using MMFF94 force field is calculated and its value of PEBTH is  170.68 kcal/mol 

Steric hindrance of an atom is  calculated from the values of  covalent radii and geometrical distances

Based on the van der Waals radius (in Ų) the minimum of projection areas of the conformer is determined and its value of PEBTH is 36.38 Ų

The maximum of projection areas of the conformer is also calculated by using the van der Waals radius (in Ų) and its value of PEBTH is 90.98 Ų

The radius for the minimal projection area of the conformer (in Å) is determined as Minimal projection radius and for PEBTH  its value is 4.28

The radius for the maximal projection area of the conformer (in Å) is  Maxiimal projection radius  and for PEBTH  its value is 8.75

maximal extension length of the conformer perpendicular to the minimal projection area for   PEBTH  (in Å) is 6.93

In the same way   maximal extension length of the conformer perpendicular to the maximal projection area of PEBTH  (in Å) is 17.19

van der Waals volume of the conformer(in ų) is calculated and for PEBTH its value is 252.54. All these  above values are displayed in figure 11

Figure 11: Geometrical Descriptors Plugin result window of PEBTH Click here to View figure

Conformers of PEBTH

Conformational isomerism is defined for molecules with same structural formula but with different 3D structure. Conformers are converted from one form to other by rotation along rotatable bonds. Conformers possess different energies and they cannot be separated from one another in laboratory.

With the help of Conformer Plugin a selected number of conformers can be generated. Fig 12 displays the different possible Conformers of PEBTH

Figure 12: Conformers of PEBTH Click here to View figure

Topology analysis of PEBTH

Table 5: Topology analysis of PEBTH

Topology analysis of PEBTH
count of aliphatic atoms	6	count of  aromatic  ring	3
count of  aliphatic bonds	7	count of  carbo ring	2
count of  aromatic  atom	15	count of  carboaliphatic  ring	0
count of  aromatic  bond	16	count of  carboaromatic  ring	2
count of  asymmetric  atom	0	count of  Fused aliphatic ring	0
count of  atoms	34	count of  Fused aromatic  ring	2
count of  bonds	36	count of  Fused  ring	2
count of  Chain atoms	6	count of  Hetero  ring	1
count of  Chain bonds	7	count of  Heteroaliphatic ring	0
count of  Chiral centers	0	count of  Heteroaromatic  ring	1
count of  Ring  atoms	15	Largest ring size	6
count of  Ring  bonds	16	Largest ring system size	2
count of  Rotatable   bonds	3	count of  Ring	3
count of    stereo double bonds	1	count of  Ring system	2
count of  aliphatic rings	0

Topology analysis plugin calculates different topological descriptors of PEBTH molecule as given in Table 5

Polar surface area  of PEBTH

Polar Surface Area (PSA)   is the accumulation of all polarized atoms of a molecule and  PSA  descriptor      is in coordination with molecular membrane transport. Ertl et al¹⁴  provided a method for estimation of Topoligical Polar Surface Area (TPSA). TPSA value can be calculated at a given pH both for the neutral form of the molecule and for the major microspecies TPSA value of PEBTH is calculated and its value is 54.35 as shown in figure 13.

Figure 13: Polar surface area  of PEBTH Click here to View figure

Molecular surface area  of PEBTH

Molecular surface area calculations are of two types van der Waals (vdW) and solvent accessible (SA). van der Waals surface area of PEBTH is determined ^15-16 and its value is found to be 385.64 as shown in figure 14.

Figure 14: Molecular surface area  of PEBTH Click here to View figure

The Hydrogen Bond Donor/Acceptor Plugin calculation of PEBTH

The hydrogen bond donor and acceptor properties of the atoms in the molecule are  calculated by Hydrogen Bond Donor/Acceptor Plugin. The following figure shows the atomic data and overall multiplicity of hydrogen bond donor and acceptor at a given pH for the corresponding atoms of PEBTH

The distribution the multiplicities of the weighted average hydrogen bond donor and acceptor over the set of microspecies of PEBTH at a given pH can be calculated by using this plugin and for PEBTH molecule it is as follows (fig 15) and  it also shows the distribution of their occurrences at a pH range

Figure 15: H bond Donor /Acceptor of EPBTH Click here to View figure

Huckel Analysis  of  PEBTH

Structural descriptors for  aromatic atoms  of PEBTH can be calculated  by Huckel Analysis.  By using this method for electrophilic and nucleophilic attack  Localization energies L(+) and L(-) are determined.According to their localization energies in E(+) or in Nu(-) attack the order of atoms are adjusted. Also with the help of Hückel method the total π energy, the π electron density and the total electron density can also be determined.

Atoms like B, C, N, O, S, F, Cl, Br, I  have optimal Coulomb and resonance integral parameters depending on the chemical environment. The following figure (fig 16) shows the calculated values of Huckel Analysis  results  at the  atoms in the aromatic ring of  PEBTH  ^17-19  and these values are result of aromatic E (+) Nu(-) order calculation

Figure 16: Huckel Analysis  of PEBTH Click here to View figure

Refractivity of PEBTH

It is to be noted that the  refractivity  is based on the volume of the molecules and  dispersive forces ²⁰. Atomic method  as given by Viswanadhan et al. is used for calculation of  refractivity . The results of this calculation of PEBTH are displayed in 2D or 3D with the value of refractivity (the dimension is 10⁶⋅[m³⋅mol^-1])  as given in the following figure (fig 17).

Figure 17: Refractivity of PEBTH Click here to View figure

Conclusion

These results show the application of Marvin Sketch 20.8 software  for characterization of the compound N’-[(1E)-1-phenylethylidene]-1,3-benzothiazole-2-carbohydrazide(PEBTH).

Conflict of Interest

There is no conflict of interest.

Funding sources

There is no funding sources.

References

1. G. Audi, A.H.Wapstra, The 1995 update to the atomic mass evaluation, Nuclear Physics A, Vol. 595, Issue 4, pp. 409-480, 1995;
   CrossRef
2. E. A. Hill, On A System Of Indexing Chemical Literature; Adopted By The Classification Division Of The U. S. Patent Office., J. Am. Chem. Soc., 22(8), pp. 478-494, 1900;
   CrossRef
3. Adam C. Lee and Gordon M. Crippen , Journal of Chemical Information and Modeling 2009 49 (9), 2013-2033 , DOI: 10.1021/ci900209w
   CrossRef
4. Viswanadhan, V. N.; Ghose, A. K.; Revankar, G. R.; Robins, R. K., J. Chem. Inf. Comput. Sci., 1989, 29, 163-172; DOI: 10.1021/ci00063a006
   CrossRef
5. Klopman, G.; Li, Ju-Yun.; Wang, S.; Dimayuga, M.: J.Chem.Inf. Comput.Sci., 1994, 34, 752;DOI: 10.1021/ci00020a00
   CrossRef
6. PHYSPROP^© database
7. Csizmadia, F; Tsantili-Kakoulidou, A.; Pander, I.; Darvas, F., J. Pharm. Sci., 1997, 86, 865-871; doi.org/10.1021/js960177k
   CrossRef
8. Miller, K. J.; Savchik, J. A., J. Am. Chem. Soc. , 1979 , 101 , 7206-7213; https://doi.org/10.1021/ja00518a014
   CrossRef
9. Jensen, L.; Åstrand, P.-O.; Osted, A.; Kongsted, J.; Mikkelsen, K.V. J. Chem. Phys. , 2002 , 116 , 4001-4010; https://doi.org/10.1063/1.1433747
   CrossRef
10. J.Gasteiger and M.Marsili: Tetrahedron Vol. 36. , pp. 3219-3288 (1980)
    CrossRef
11. M.Marsili and J.Gasteiger: International Symposium on Aromaticity, Dubrovnik, Yugoslavia , Sept (1979), Croat.Chim.Acta. (1979)
12. Steven L. Dixon and Peter C. Jurs: J.Comp.Chem., Vol.13. No.4, 492-504 (1992)
    CrossRef
13. W.J.Mortier, K.V.Genechten and J.Gasteiger: J.Am.Chem.Soc., Vol. 107,829-835 (1985)
    CrossRef
14. Ertl, P., Rohde, B., Selzer, P., J. Med. Chem. 2000, 43, 20, 3714–3717 Publication Date:September 19, 2000https://doi.org/10.1021/jm000942e
    CrossRef
15. Ferrara P,. Apostolakis J., Caflisch A., Proteins 2002,46, 24-33, https://doi.org/10.1002/prot.10001
    CrossRef
16. Hasel W., Hendrickson T., Still W., Tetrahedron Computer Methodology , 1988, Vol. 1, Issue 2, 103-  116; https://doi.org/10.1016/0898-5529(88)90015-2
    CrossRef
17. Isaacs, N.S., Physical Organic Chemistry , John Wiley & Sons, Inc., New York,  1987, ISBN 0582218632
18. Streitwieser, A.,Molecular Orbital Theory ,  John Wiley1961, ISBN 0471833584
19. Pirok, Gy. et al.,Making “Real”Molecules in Virtual Space, J. Chem. Inf. Model. 2006 , 46, 563-568
    CrossRef
20. Viswanadhan, V. N.; Ghose, A. K.; Revankar, G. R.; Robins, R. K., J. Chem. Inf. Comput. Sci. , 1989 , 29 , 163-172;https://doi.org/ 10.1021/ci00063a006
    CrossRef

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