Novel Thiazole Derivatives of Medicinal Potential: Synthesis and Modeling

This paper reports on the synthesis of new thiazole derivatives that could be profitably exploited in medical treatment of tumors. Molecular electronic structures have been modeled within density function theory (DFT) framework. Reactivity indices obtained from the frontier orbital energies as well as electrostatic potential energy maps are discussed and correlated with the molecular structure. X-ray crystallographic data of one of the new compounds is measured and used to support and verify the theoretical results.


Introduction
The thiazole has an important component effect of the pharmacophores of a large number of medicinal significance molecules and the evaluation of their biological activity, such as antibacterial [1], antiprotozoal [2], antitubercular [3], antifungal [4,5], and anthelmintic [6], with emphasis on their potential medicinal applications, is desirable. Here we are interested to study newly synthetized aminothiazoles, especially 2-aminothiazole derivatives which represent a class of heterocyclic ring system possessing antiviral [7], antimicrobial [8], anticancer [9], and anti-inflammatory activities [10]. Previously, in vitro anticancer evaluation studies of different 2-aminothiazole analogs exhibited their potent and selective nanomolar inhibitory activity against a wide range of human cancerous cell lines such as breast, leukemia, lung, colon, CNS, melanoma, ovarian, renal, and prostate cell lines [11][12][13][14]. Substitutions at 2-position benzothiazole have emerged in its usage as a core structure in the diversified therapeutic applications [15][16][17][18][19][20][21]. The studies of structureactivity relationship interestingly reveals that change of the structure of substituent group at C-2 position commonly results in the change of its bioactivity. Though literature survey reports many therapeutic applications of 2-substituted benzothiazoles, their investigation for anti-inflammatory activity is limited [16,[22][23][24][25]. Furthermore, thiazole derivatives have attracted a great deal of interest due to their wide applications in the field of pharmaceuticals. Thiazole derivatives display a wide range of biological activities such as cardiotonic, fungicidal, sedative, anesthetic, bactericidal, and anti-inflammatory [26,27]. In addition, thiazole derivatives are reported to show a variety of biological activities. Depending on the substituents, this heterocycle possesses anthelmintic, antibiotic, and immunosuppressant activity [28]. Recent research indicates that some of 2-aminothiazoles derivatives are inhibitors of enzymes such as kynurenine-3hydroxylase 29 or possess inhibitors activity against enzyme cyclin-dependent kinase [29].
Additionally, monoazo disperse dyes with thiazole-diazo components have been intensively investigated to produce bright and strong color shades ranging from red to greenish blue on synthetic fiber. Color Index described various basic, direct, vat, and disperse dyes wherein thiazole nucleus occurs [30]. Derivative of 2-aminothiazole has a long history of use as heterocyclic diazo components for disperse dyes [31].
In the present study, quantum chemical computations will be performed within DFT using WB97XD/6-31G(d) model to investigate the molecular structure, IR, and NMR of the newly synthetized molecules [32][33][34][35][36][37][38]. X-ray crystallographic data of 3B will be obtained and used to support 2 Journal of Chemistry and verify the theoretical results. The energies of HOMO-LUMO frontier orbitals will be used to estimate molecular reactivation towards nucleophilic/electrophilic reagents. Electrostatic potential energy maps (ESP maps) will be graphically presented to locate binding sites of these new derivatives.

Experimental Section
2.1. Synthesis. All melting points were measured on an electric melting point apparatus and were uncorrected. The infrared spectra were recorded using potassium bromide disks on a Pye Unicam SP-3-300 infrared spectrophotometer; the established values of the gas phase frequencies are given between brackets. 1 HNMR spectra were run at 300 MHz, on a Varian Mercury VX-300 NMR spectrometer and Brukeravance III 400 MHZ, using TMS as an internal standard in deuterated dimethylsulphoxide. Chemical shifts are quoted in ppm. The mass spectra were recorded on Shimadzu GCMS-QP-1000EX mass spectrometers at 70 eV. All the spectral measurements were carried out at the NMR Laboratory of Cairo University, Egypt, and the NMR Laboratory of Faculty of Pharmacy, Ain shams University, Egypt; the microanalytical data were measured in Central Lab of Cairo University, Egypt; the Ministry of Defense Chemical Laboratories, Egypt; and the Microanalytical Center of Ain Shams University, Egypt. All the chemical reactions were monitored by TLC. The bold values corresponded to values calculated from DFT.

X-Ray
Crystallography. X-ray structure analysis offers perfect addition to our synthetic work. X-ray structures of the compound 3b were performed in the Central Service and X-Ray Laboratories, National Research Centre, Cairo, Egypt. Crystal and molecular structures were prepared by Maxus Computer Program for the Solution and Refinement of Crystal Structures. All diagrams and calculations were performed using maXus (Bruker Nonius, Delft; MacScience, Japan). There was no extinction correction. Atomic scattering factors were from Waasmaier and Kirfel, 1995. Data collection parameters are as follows: KappaCCD; cell refinement: HKL Scalepack; data reduction: Denzo Program(s) used to solve structure; SIR92 and Scalepak Program(s) used to refine structure; maXus: ORTEP Software which was used for molecular graphics. Crystal data, fractional atomic coordinates, and equivalent isotropic thermal parameters, anisotropic displacement parameters and geometric parameters of compounds 3b are given in Table 2. The additional data for the molecule 3b are alternatively available from the Cambridge Crystallographic Data Centre as CCDC1402910.

Computations.
Computations were carried out using Gaussian 16 revision A.03 package [32] and/or Spartan'16 parallel QC program [Wavefunction, Inc., USA]. Optimized structures and spectroscopic data derived from quantum chemical calculations have been used within the WB97DX/6-31G(d) model. A Broadberry (UK) 40-core workstation and/or MAC Pro 12-core computers were used.

Synthesis and Spectroscopic
Properties. In our study, 2aminothiazole 1 was used as a key starting material. Reaction of 1 with chloro-N-(4-sulfamoylphenyl) acetamide afforded the amide derivative 2a (Scheme 1). The structure of 2a is substantiated from its spectral data. The IR spectrum shows appearance of absorption band of C=O group for the amide at 1691 cm −1 , as well as the presence of OH-NH tautomerization at 7.1 ppm and 12 ppm. On the other hand, when 1 was refluxed in dimethylformamide with ethyl chloroacetate, the ester 2b was abstained and its structure was confirmed with different spectral data: the presence of the ester C=O at 1730 cm −1 in IR, for example, and the presence of CH 2 CH 3 in H-NMR as quartet and triplet at 3.2, 1.4 ppm, respectively.
In addition, urea and thiourea derivatives 2c, 2d were obtained from the reaction of the aminothiazole with phenyl isocyanate and phenyl isothiocyanate. The IR spectrum revealed the absence of doublet bands of NH 2 in both compounds, the appearance of band that is attributed to  C=O for 2c at 1648 cm −1 , and the appearance of four peaks that is attributed to phenyl ring in C 13 -NMR. The most important compound in this work is compound 2e that resulted from interaction of 1 with chloroacetyl chloride; the structure was proved by appearance of C=O at 1703 cm −1 as well as absence of NH 2 doublets. The amide derivative 2f is obtained from reaction of thiazole derivative with 2-chloro-N-(4-chlorophenyl) acetamide; the IR spectrum shows the presence of C=O band and the presence of double doublets of para-substituted-benzene ring of chlorophenyl in H-NMR.
The compound 2e was the key start for many other reactions; refluxing 2e with anthranilic acid afforded the oxazipin-one 3a (Scheme 2). The cyclic structure was proved from IR spectrum which showed the absence of broad OH band that is attributed to open structure and the appearance of C=O band at 1698 cm −1 .
On the other hand, the amide derivatives 3b were obtained from reaction of 2e with p-toluidine for five hours; the open structure was confirmed with many tools as IR which show two NH bands at 3287, 3150 cm −1 , as well as the X-Ray crystallography; furthermore, refluxing of chloroderivative 2e with thiourea afforded cyclic structure 3c, which had been proved with absence of C=O band in IR and appearance of 3374 and 3275 cm −1 for 2 NH. Furthermore, the appearance of weak band as 2600 cm −1 is attributed to thionethiol SH tautomerization. The thiazine 3d is another cyclic compound resulting from refluxing 2e with 2-aminophenol; the structure was proved by disappearance of C=O, as well as the appearance of peak in H-NMR for thiazine H at 5.1 ppm and appearance for extra peak at 114 ppm for thiazine ring in C 13 -NMR.
At last, refluxing 2e with quinoxaline-2,3-diol in DMF/ anhydrous carbonate produced the ether 3e, whose structure was evaluated from IR by peaks at 1725 cm −1 for C=O, appearance of broad band at 3350 cm −1 that is attributed to OH, and, in addition, aromatic peaks in H-NMR at 7.5 ppm and 7.7 ppm.

X-Ray Crystallography and Optimized Molecular Struc-
ture. X-ray results are depicted in Table 1. X-ray structure analysis offers perfect addition to our synthetic work. X-ray structures of the compound 3b (Figure 1) showed that the molecule is planar. Table 2 shows the agreement between the optimized parameters and the experimentally obtained geometry of 3B molecule. The structure produced (Figure 1 and Table 2) is in excellent match with the optimized structure obtained by quantum chemical calculations within the density functional theory (DFT) [33,34] using WB97XD/6-31G(d) model.

Molecular Reactivities.
Chemical reactivity theory quantifies the reactive propensity of isolated species through the introduction of a set of reactivity indices or descriptors. Its roots go deep into the history of chemistry, as far back as the introduction of such fundamental concepts as acid, base, Lewis acid, and Lewis base. It pervades almost all of chemistry.
The most relevant indices defined within the conceptual DFT [33] for the study of the organic reactivity are discussed elsewhere [35][36][37][38][39]. Molecular reactivity indices [35][36][37][38][39] such as chemical potential ( ), hardness ( ), and electrophilicity ( ) were computed from the energies of frontier orbitals and defined as follows: (1) Chemical potential is given by or simply = 0.5(LUMO + HOMO). (2) Hardness is given by or simply = 0.5(LUMO − HOMO). The chemical hardness can be thought as a resistance of  The redder the area is, the higher the electron density is susceptible to nucleophilic attack and the bluer the area is, the lower the electron density is that could easily binds with an electrophile. (3) Electrophilicity: in 1999, Parr defined the electrophilicity index [40] = 2 /2 , which measures the total ability to attract electrons. The electrophilicity index gives a measure of the energy stabilization of a molecule when it acquires an additional amount of electron density from the environment. The electrophilicity index comprises the tendency of an electrophile to acquire an extra amount of electron density, given by and the resistance of a molecule to exchange electron density with the environment, given by . Therefore, a good electrophile is a species characterized by a high absolute value and a low value. The electrophilicity index has become a powerful tool for the study of the reactivity of organic molecules [36].
(4) Nucleophilicity (N): while the electrophilicity of the molecules accounts for the reactivity towards nucleophiles, it has been shown by Domingo and his coworkers [36][37][38][39] that a simple index chosen for the nucleophilicity, , based on the HOMO energy, within DFT, is useful to explain the reactivity of these new compounds towards electrophiles.
It is noteworthy to mention that this nucleophilicity scale is referred to tetracyanoethylene (TCE) taken as  a reference, because it presents the lowest HOMO energy in a large series of molecules investigated [36].
The numerical parameters reflect the tendency of transferring electronic charges during chemical interactions between molecules (Table 3). Electrophilicity is an important reactivity descriptor that is considered as a measure of a compound's willingness to participate as an electron acceptor during a chemical reaction, or, in other words, the electron deficiency of a compound. 3E is the molecule with the largest electrophilicity , whereas 3D is the one showing smallest electrophilicity indicating lower susceptibility towards nucleophilic reaction. Table 3 shows that chemical potential value, which is the negative of molecular electronegativity reflecting the escaping tendency of electrons, decreases in the following order: By examining the nucleophilicity descriptor (Table 3) for these molecules, we found that 2E ( = 0.78 eV) is one of the poorest nucleophiles of this series, while 3D ( = 2.97 eV) represents the best nucleophile. Generally, nucleophilicity increases in the following order: 2E < 2A < 3C < 3E < 2C < 2B < 2F < 2D < 3B < 3A < 3D These results are consistent with the expected reactivity pattern. Investigation of a molecule's surface is probably a good start for considerations of the molecule's reactivity since this is where two approaching molecules would first interact. ESP maps are depicted in Figure 2. The results should improve our knowledge about the binding sites, which are of importance in chemical reactivities and medical applications. Color codes point to the binding sites when interacting with other reagents [41][42][43] (see caption of Figure 2).

Conclusions
One-step syntheses of 12 thiazole derivatives of medicinal importance are performed. Optimized structures, reactivity indices, electrostatic potential energy maps, and spectroscopic properties such as IR and NMR of the newly reported molecules are computed within DFT using WB97XD/6-31G(d) model. Satisfactory agreement between experiment and theory is observed. Trends in chemical reactivities are investigated. Molecules 3E and 3D have the largest and smallest electrophilicity, respectively. Generally, based on relative nucleophilicity index , nucleophilicity increases in the following order: 2E < 2A < 3C < 3E < 2C < 2B < 2F < 2D < 3B < 3A < 3D. These results are consistent with the expected reactivity pattern.
The graphically visualized ESP maps enable locating the binding sites of these molecules.