Study of Interactions Between 3-benzoyl-4-hydroxy-2-methyl-2H-1, 2-benzothiazine and Human DNA by Theoretical, Spectroscopic and Viscometric measurements

doi:10.21203/rs.3.rs-2095975/v1

From the last few years mode of interactions between drugs and DNA is an attractive research area as it bridges chemistry, molecular biology and medicinal science. Interactions between small heterocyclic molecules and human DNA is a noteworthy feature in pharmacology for investigation of drugs mechanism and designing of more effective and target specific drugs with fewer side effects. The present research work focuses on the theoretical investigations of 3-benzoyl-4-hydroxy-2-methyl-2H-1, 2-benzothiazine (SASA) by using Gaussian (16W) software to predict optimized geometry, HOMO-LUMO gap, bond length, bond angle, dihedral angle, electronic and vibrational spectra. Possible reaction site observed in SASA was C_7, C₉ and C₁₈ as these atoms show maximum charge density. Later the interactions of SASA with human DNA was explored spectroscopic investigations and viscometric investigations at physiological buffers of pH of 4.7 (stomach pH) and 7.4 (blood pH) respectively. Maximum absorbance between SASA-DNA complex was observed in buffer solution of pH 3.4 at wavelength of 370nm, whereas at 7.4 has maximim absorbance between. Spectroscopic results reflects the bathochromic and hyperchromic shift succeeding the addition of human DNA. During viscosity measurement, intercalation and electrostatic mode of interaction were detected at low and high concentration of drug in solution respectively. Increase in the value of rate constant was observed with the increase in concentration of drug. Larger values of rate constant were observed at pH 7.4 in comparison to pH 3.5. Rate constant, thermodynamic parameters and viscometric analysis prefers the intake of SASA via blood.

Drug-DNA complex

UV/Visible spectroscopy

Density Functional Theory

FTIR

Thermodynamic parameters

Investigations on the interactions between small heterocyclic molecules acting as drugs and human DNA has gathered attention of many scientists as it helps in understanding the mode of interactions and discovery of new drugs[1–4]. Examination of structure of DNA shows the presence of large numbers of positive and negative ions which can react with the drug molecules. As a result of interactions between drug and DNA complex structural changes are observed in both drug and DNA molecules [5, 6]. Association between targeted drug and DNA takes place at definite discrete sites, known as binding sites and resultantly the solvent molecules are dislocated. Both drug and DNA possess opposite charges and due to the reorientation of charges between drug-DNA complex and solvent molecules, solvation of complex is observed, which leads to extra stability [7]. The heterocyclic compounds containing nitrogen and sulphur atoms play a very vital role in the field of medicinal chemistry. Derivatives of Benzthiazine are target of interest due to their incredible biological and pharmacological properties [8–15]. A number of these derivatives show remarkable properties as blocker of various receptors of nicotinic, muscarinic, histamine H and serotonine 5HT3 receptors. 1,2 -benzothiazine nucleus possess exceptional anti-inflammatory [16], antimalarial [17], antipro-liferative[18] and analgesic activities [19]. Various derivatives of 1,2-benzothiazine are excellent drugs for treatment of vascoocclusive disorders [20]. 3-benzoyl-4-hydroxy-2-methyl-2H-1,2 benzothiazine (SASA) was synthesized by multistep reactions [21]. SASA shows remarkable potential as antimicrobial [22], antioxidant [23] and anti-HIV [24]. Most of the derivatives of thiazine are insoluble in water so the co-solvent immiscible with water i.e. benzene, toluene and DMSO [25] was used. Since the derivatives of 1,2-benzothiazine possesses outstanding pharmaceutical properties so the investigation of mode of interaction with DNA will be subject of interest.

Theoretical predictions help to design new compounds. Computational chemistry is rapidly developing subfield of theoretical chemistry, where the main attention is on solving chemical problems by calculations. Computational study is mainly the study of predictions given by the theoretical overview. Hyperchem and Gaussian software were used to examine optimize molecular geometry, bond length, bond angle, torsion angle, energy calculation, kinetics of the reactions, IR, UV-Visible, and NMR spectra of the chemical compound under investigation.

In DFT calculations entire energy is expressed in terms of the total electron concentration, instead of the wave function. Computational chemistry is used to describe the precise structure and strength of chemical system, to investigate energy variances between different shapes, and to elucidate reaction pathways and mechanism at atomic level. It is also used to examine the properties of solids in materials science. Semiconductors, superconductors, plastics, ceramics; all these have been examined with the aid of computational chemistry.

In pharmacological field computational chemistry has vital role for studying the interaction of drugs with biomolecules, structure of active site of proteins for synthesizing their compatible substrate to bind on these active site to cure or to control the disease. New drugs could be synthesized by the information of theoretical study. The drug control or inhibition of disease is done by making interaction with DNA. Binding of small molecules of drug with DNA by covalent and non-covalent bonds depend upon the interaction between them. [26].

The drug–DNA interaction is a significant feature in pharmacological field and three types of mode of interaction were investigated by non-covalent interaction

Electrostatic interaction: It is the binding of small molecules with negatively charged sugar-phosphate back bone of DNA.
Hydrogen bonding and electrostatic interaction: It is caused by binding of small molecules on minor and major grooves.
Intercalation: It is the binding of small planer organic molecules with DNA base pairs [27].

DNA interacts with the drug by the charged sugar-phosphate groups, through its base pairs that was named intercalation and through minor and major groove binding [28]. Intercalation is the strong binding mode between different biomolecules and DNA [29] [11]. Intercalation mode of interaction was first time proposed by Lerman and he also predicted that planer molecules show intercalation mode of interaction with DNA [30]. More efficient anticancer and antitumor drugs could be designed by the Study of binding of small molecules with DNA [31]. Experimentally a number of spectroscopic techniques like UV-Visible, fluorescence, Raman, Nuclear magnetic resonance and atomic force microscopy could be used to investigate the drug-DNA interactions [1, 32–34]. Viscosity measurement, thermal denaturation and DNA- foot printing could be utilized for the same purpose [35–37]

Predictions during UV-Visible study for interactions between Drug-DNA complex could be obtained by observing the variations in the absorption spectra of the drug, the DNA molecules and Drug-DNA complex [38]. Hypochromism and red shift could be the sign of intercalation while hyperchromism might be the sign of electrostatic interactions. Extension, unwinding and rigidity of DNA resulted due to the intercalative binding of drug with DNA. The UV–Visible absorption spectrum of DNA shows a broad band (200–350 nm) in the UV region with a maximum absorption at 260nm [39]. Strength of binding interaction could be investigated by calculating binding constant (K_f) [40]. Way of collaboration of small molecules with DNA could also be visualized by calculating viscosity of the drug and drug-DNA complexes [41].

The viscosity measurement is based on the flow rate of a DNA solution through a capillary viscometer [42] Intercalation way of interaction is predicted by the increase in viscosity due to the increase in the length of DNA double helix [12]. Evidence about the electrostatic mode of interaction is given by the decrease in viscosity value if the concentration of drug in solution is decreased. Strong argument for mode of interaction could be obtained by Viscometric study [43]

2.1.Materials and methods

3-benzoyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine (SASA), derivative of benzothiazine having molecular formula (C₁₆H₁₃NO₄S) is the molecule under investigation. The structure of this compound is given in Fig. 1.

SASA was synthesized by Dr. Sana Aslam during her PhD in university of Punjab, Lahore, Pakistan and it was provided in pure form after complete purification followed by characterization[21]. This heterocyclic compound under investigation contains nitrogen and sulphur atoms. This compound is of significant importance in the field of medicinal chemistry. Benzthiazine is a diverse compound having biological and pharmacological importance. The researchers have synthesized number of thiazine derivatives which are widely used in drugs due to their remarkable anti-inflammatory, antibacterial, antitumor, insecticidal, fungicidal, anti-tubercular, antimycobacterial, analgesic, antitumor and antipyretic activities [44].

Analytical grade Dimethylsulfoxide was purchased from Sigma Aldrich Chemical Co.USA. Human DNA was purchased from molecular lab, Agriculture University Faisalabad, Pakistan. Stock solution of selected SASA drug was prepared by adding 0.004g selected drug in 100ml DMSO. All investigations were carried out in buffers having pH 3.5 (stomach pH) and pH 7.4 (blood pH).

2.2 Spectrophotometric Study

UV/Vis absorbance spectra were obtained by UV752PC UV-VIS spectrophotometer with a quartz micro-colorimetric vessel of 1-cm path length. Absorption of solution was recorded at constant concentration of DNA and varying the concentration of SASA. Observed Spectral shifts were used to predict the mode of interaction of drug with DNA. Rate constant was calculated with the help of Benesi-Hidebrand equation to observe the strength of binding with the increase in concentration of drug [45]. Rate constant as a function of temperature was calculated to observe the effect of temperature on binding affinity of drug with DNA [46].

2.3 Viscometric measurements

Viscosity measurements were carried out by using Fungi lab S.A ADVR 212008 viscometer. All the calculations were carried out at pH 3.4 and pH 7.4. Viscosity measurements provide further clues about the drug-DNA interaction. Plot of viscosity versus DNA concentration represents the mode of interaction either by intercalation, groove or electrostatic interaction[47]

2.4 Computational studies

Theoretical study of SASA was carried out to get complete information about the structure, energetics, molecular orbitals (HOMO-LUMO gaps), UV-visible spectra, IR spectra, reactive sites and thermodynamic parameters [48]. Theoretical studies were carried out by using Gaussian 09 program package. All geometric parameters (bond length, bond angle, and dihedral angles) were computed with the help of DFT and HF functional by using 3-21G, 6-311G, and 6–311 + G basic sets.

3.1 Optimized geometric parameters of SASA

The optimized geometry of SASA is represented in Fig. 2. Selected optimized parameters including bond lengths, bond angles and dihedral angles were calculated. Bond length, the average distance between two atoms is a transferable property of a bond between atoms of fixed types, relatively independent of the rest of the molecule. Figure 3(a,b) shows the bond lengths of SASA calcualted by DFT and HF methods by using a 3-21G, 6-31G and 6-311G basic sets. Calculated bond angles are represented in Fig. 4(a,b). the optimized ring angles proves benzene ring as a planar. The computational analysis was executed in gas phase, whereas the SASA exists in the solid-state. Small differences between computed and experimental results might be due to the small Vander Waals interactions missing in the gaseous phase [49, 50]. Optimized structure and geometric parameters suggest that SASA has a symmetrical structure in terms of substitutions. Possible reaction site in SASA was predicted at C_7, C₉ and C₁₈ atoms due to possession of maximum charge density

3.2. HOMO-LUMO orbitals.

HOMO-LUMO orbitals, the main chemical participants of a reaction represents the HOMO as electron donor while LUMO as electron acceptor species [51] (Fig. 5). Hyperpolarizability studies provide significant information regarding the unsaturation in organic compounds. Frontier molecular orbital, expression of several energies along with various electronic transitions is sketched in Fig. 6. The energy gap between HOMO and LUMO reflects the chemical reactivity and bioactivity of the molecule [52, 53]. It plays a vital role in examination of the molecular electrical transport properties [54]. Smaller is the band gap between HOMO-LUMO, lesser will be the stability of molecule and greater will be the stabilization of LUMO as a result of its strong capability to accept electrons. Therefore it plays a vital role in deciding the most probable reaction site in a conjugated system.

The E_HOMO - E_LUMO was smallest for SASA and other properties like dipole moment, electronegativity etc. calculated by DFT method predicts the decrease in deterioration inhibition efficiency. Minimum HOMO–LUMO energy gap showed the tendency of charge removal within the molecule [55]. Charge density on HOMO also affected the effectiveness of amides and sulfur presented more charge density on HOMO for electrophilic attack.

3.3 ESP diagram of SASA

Distribution of electron density surfaces depends on the type of substitutions and also depends on negative and positive charges (Fig. 7). Electrostatic potential, represented by different colours in the MEP expresses the size, shape, positive and negative potential. Eelectrophile attack is expected near nitrogen and nucleophile attack near carbon atoms. The upper scale represents the value varying from red to blue region [56]

According to this picture, the density distribution on SASA molecule is homogenous Green region is representative of negative charges with high electron density indicate the repulsion while blue is electropositive indicate the attraction with low electron density.

3.4 IR spectra of SASA:

Results of calculated IR spectrum of SASA providing complete information about functional group in-plane and out of plane bending of N-H, C-H groups, stretching of C-O, C-C bonds is represented in Table 1. The obtained results were compared with literature values and close resemblance was observed between computed and experimental results.

Table 1

IR spectra of SASA calculated theoretically.
Frequency Calculated (cm^− 1)								Frequency from literature (cm^− 1)	Functional Group	Reference
Semi-empirical PM6	DFT 6311-G	HF 3-21G	HF 6-311G	HF 631-G	DFT 321-G	DFT 631-G	HF 631-G’	Frequency from literature (cm^− 1)	Functional Group	Reference
512.77	-	-	-	-	-	-	-	330–596	N-H (out of plane –bending)	[57]
719.8	767.8	915	851	822	822	822	822	900 − 667	C-H out of plane bending	[58]
1085	950.8	1389	1077	1028	1116	1144	1188	1067–1218	C-O stretching	[59]
1540	1301	-	1467	1259	1429	1483	1465	1300–1650	C-C stretching	[39]
-	1612	-	-	1599	1599	1617	1599	1300–1650	C-C stretching	[39]
-	2919	-	-	3438	3348	3357	3438	3400–3200	Normal ‘‘polymeric’’ OH stretch	[60]
-	-	1727	1796	-	-	-	-	1820–1775	Aryl carbonate	[61]
2401	-	-	-	-	-	-	-	2400–2800	CH₃ stretching	[62]
-	-	-	3166	-	-	-	-	3300–3030	Ammonium ion stretching	[62]
-	-	3521	-	-	-	-	-	3570–3200	H-bonded OH stretch	[62]

3.5. UV-Visible Spectra of SASA

Spectroscopy, a reliable technique to investigate the interaction of different pharmaceutical compounds with DNA clearly predicts the binding interaction between drugs and DNA in the form of spectral shifts [63]. Figure 8 represents the UV visible spectrum of SASA calculated by HF method with 3-21G, 6-31G, 6-31G^/ and 6-311G basic sets.

Prominent peaks with strong oscillation strength, wavelength, excitation energies and absorption were observed in computed peaks. The HF calculations predicted that maximum absorption peak occurred near at 275nm of set 6-31G and 6-31G^/ with strong oscillator strength. Other two peaks of singlet states occur at 260nm and 264nm of set 3-21G and 6-311G respectively. While DFT calculations predicted that maximum 4 absorption peaks occurred at 573nm, 392nm, 392nm and 392nm with strong oscillator strength of 6-311G set with value of 573.

3.5.1 UV-Vis Spectra of SASA-DNA complexes at 3.4pH and 7.4pH

In experimental spectra the SASA shows maximum absorbance at 370 nm at 3.5 pH and at 380 nm at pH 7.4. The difference between the experimental and theoretical results was due to the presence of weak Van der Waals interactions between solvent and SASA in solution, which are missing while theoretical calculations in gas phase [50]. Later the absorption spectra of SASA with DNA was also calculated with varying concentration of SASA. Increase was noticed in absorption with increase in concentration of SASA at fixed DNA concentration (Fig. 9). The observed spectral shifts predicts binding affinity of SASA with DNA to form SASA-DNA complex. Bathochromic shift and hyperchromic effect was observed at both pH. Bathochromic effect predicts the intercalation mode of interaction between SASA and DNA. This effect is also related with the reduction in the energy gap between the highest (HUMO) and the lowest molecular orbitals (LUMO) after the interaction of SASA to DNA[48].

3.5.2. SASA-DNA binding constant

The interactions between SASA and DNA results is spectral shifts in absorption spectra and binding constant K_f was calculated by using the Benesi–Hildebrand equation[64].

Initially increase was observed in the value of binding constant with the increase in the concentration of SASA but at much higher concentration decrease was observed in the value of binding constant. It is clearly seen that K_f values at 7.4 pH is large than at 3.5 pH. (table 2)

Table 2

Binding constant (K_f) in solution of pH 3.5 and 7.4 at room temperature.

Sr #	Concentration of SASA	Absorbance of SASA-DNA complex		K_f
Sr #	Concentration of SASA	pH 3.4	pH 7.4	pH 3.4	pH 7.4
1.	0.4µM	0.343	0.286	4.489 ± 0.001	4.982 ± 0.001
2.	0.5µM	0.472	0.381	5.197 ± 0.001	6.409 ± 0.001
3.	1 µM	0.646	0.610	8.551 ± 0.001	9.976 ± 0.001
4.	1.5 µM	0.826	0.623	7.934 ± 0.001	5.267 ± 0.001
5.	2 µM	0.867	0.998	1.235 ± 0.001	4.404 ± 0.001

Later the effect of temperature was investigated on the rate of binding constant and it was observed to be decreasing showing the weakening of SASA-DNA complex (Table 3). This behaviour might also be due to the deformation in the DNA conformation in turn weakening the SASA-DNA complex and thus affecting the binding ability of drug with the base pairs of DNA.

Table 3

Rate constant of SASA-DNA complex at variable temperatures.
Temperature (K)	K_f at solution of pH 3.5	K_f at solution of pH 7.4
303	2.740 ± 0.001	3.200 ± 0.001
308	2.161 ± 0.001	3.051 ± 0.001
313	1.680 ± 0.001	2.074 ± 0.001
318	1.182 ± 0.001	1.376 ± 0.001
323	1.042 ± 0.001	1.075 ± 0.001

3.5.3. Thermodynamic parameters

Negative value of Gibbs free energy was noticed for SASA-DNA complex (Table 4) at both pH representing that the complexation reaction under investigation is spontaneous and thermodynamically favourable.

Table 4

Free energy change for SASA-DNA complex at pH 3.5 and pH7.4.
Temperature (k)	ΔG J/mol
Temperature (k)	pH 3.5	pH 7.4
303	-2539.28	-2932.61
308	-1973.28	-2856.5
313	-1350.100	1898.38
318	-455.476	-843.897
323	-110.487	-192.219

Thermodynamic results clearly reflect the spontaneous complexation between SASA and DNA at both pH. pH 7.4 was found to be more favourable in comparison to pH 3.5. Main binding forces between SASA and DNA in complex, predicted from negative value of enthalpy and positive value of entropy (Table 5) was vander waals force of attraction[65].

Table 5

Values of Enthalpy and entropy for SASA-DNA complex at pH 3.5 and 7.4.
SADA-DNA complex at pH	∆H J/mol	∆S mol^− 1K^− 1
3.5	-9820.1	41.68
7.4	-1685.16	79.38

3.6. Viscometric measurements

An effective way to predict the mode of interaction between SASA molecule and DNA is viscosity measurement. In present case initially increase was observed in the viscosity with increase in concentration of drug representing the intercalation mode of interaction and, at further higher concentration of drug decrease was observed in the viscosity behaviour representing the electrostatic mode of interaction. The mode of interaction was found to be dependent upon the concentration of SASA. Consequence of intercalation might be the conformational changes in DNA and result of electrostatic interaction might be damage of DNA structure.

Viscosity plots in Fig. 10 initially predicts the intercalation mode of interaction but at higher concentration of SASA decrease in viscosity, not equal to zero, reflects the change in conformation and development of electrostatic interaction. On the other hand, at pH 7.4, after initial decrease in viscosity, approaching zero, upon further increase in concentration of SASA reflects the damage in DNA structure. Maximum suitable interaction between SASA and DNA was observed at pH 7.4 thus preferring the intake of SASA via blood.

The drug under investigation shows band in absorption spectra at both pH (3.5 and 7.4) representing π→π* transitions. Predominant hypochromic and very small red shifts were observed in absorption spectra on addition of DNA. Strong binding was observed between SASA and DNA and this was reflected from the values of binding constant. Association decreases between SASA and DNA with the increase in temperature from 293 till 323 K. Complex formations between SASA and DNA was a spontaneous process and this was reflected from the negative value of free energy. Strong and stable complex was formed at pH 7.4 as evident from the shifts in absorption peaks, binding constant and thermodynamic parameters. Thus the intake of medicine via blood at pH 7.4 is preferred over the oral intake i.e at pH 4.7. The interpretation of physical mode to intake the newly synthesized SASA drug into human body through blood rather than oral intake is the novelty of this research work.

AUTHOR DECLARATION

AUTHOR’S CONTRIBUTION

Concept and design of this article is collective contribution of all authors. They all read and approve the final manuscript of this research article. Sana Fatima long with Sadia Asim plays a vital role in material preparation, data collection, and analysis. All theoretical calculations were performed by Asim Mansha. The first draf of manuscript was written by Sana Fatima which was later refined by Sadia Asim and Asim Mansha.

CONFLICT OF INTEREST

The review article entitled “Study of Interactions Between 3-benzoyl-4-hydroxy-2-methyl-2H-1, 2-benzothiazine and Human DNA by Theoretical, Spectroscopic and Viscometric Measurements.” is carried out with the financial help from Higher Education Commission, Pakistan (Project number: 9922). All the authors involved in the write up of this article do not have any conflict of Interest. The complete details of authors are given as under:

Dr.Sadia Asim (First author) (corresponding Author)

Associate Professor.

Department of Chemistry

Government College Women University

Faisalabad, Pakistan.

Email: : [email protected]

Dr.Asim Mansha (Second author)

Assocaite Professor

Department of Chemistry

Government College University, Faisalabad, Pakistan.

Email: [email protected]

Dr.Sana Aslam (Third author)

Associate Professor

Department of Chemistry

Government College Women University

Faisalabad, Pakistan.

Email: [email protected]

ETHICS APPROVAL

Not applicable

FUNDING’S

No fundings

CONSET TO PARTICIPATE

Yes, i got permission

CONSENT FOR PUBLICATION

Yes, u can publish it

AVAILABILITY OF DATA AND MATERIAL

All the written material is new not a copy

CODE AVAILABILITY

Not Applicable

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No competing interests reported.

Study of Interactions Between 3-benzoyl-4-hydroxy-2-methyl-2H-1, 2-benzothiazine and Human DNA by Theoretical, Spectroscopic and Viscometric measurements

Status:

Version 1

Abstract

Figures

1. Introduction

2. Experimental

2.1.Materials and methods

2.2 Spectrophotometric Study

2.3 Viscometric measurements

2.4 Computational studies

3. Result And Discussion

3.1 Optimized geometric parameters of SASA

3.2. HOMO-LUMO orbitals.

3.3 ESP diagram of SASA

3.4 IR spectra of SASA:

3.5. UV-Visible Spectra of SASA

3.5.1 UV-Vis Spectra of SASA-DNA complexes at 3.4pH and 7.4pH

3.5.2. SASA-DNA binding constant

3.5.3. Thermodynamic parameters

3.6. Viscometric measurements

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1