DFT Calculation, Hirshfeld Analysis and X-Ray Crystal Structure of Some Synthesized N -alkylated( S -alkylated)-[1,2,4]triazolo[1,5- a ]quinazolines

: The present work aimed to synthesize 2-methylthio-triazoloquinazoline derivatives and study their X-ray, NMR, DFT and Hirshfeld characteristics. The cyclocondensation of dimethyl- N cyanodithiocarbonate with 2-hydrazinobenzoic acid hydrochloride resulted in an intermediate, 2-methylthio-[1,2,4]triazolo[1,5- a ]quinazolin-5-one ( A ), which upon treatment with phosphorus pen-tasulfide, transformed into the 2-methylthio-[1,2,4]triazolo[1,5- a ]quinazolin-5-thione ( B ). Reaction of 2-methylthio-triazoloquinazolines ( A & B ) with alkyl halides (allyl bromide and ethyl iodide) in basic medium afforded 4-allyl-2-methylthio-[1,2,4]triazolo[1,5- a ]quinazolin-5-one ( 1; N -alkylated) and 5-ethylthio-2-methylthio-[1,2,4]triazolo[1,5- a ]quinazoline ( 2 ; S -alkylated), respectively. Their molecular and supramolecular structures were presented. Unambiguously, the molecular structures of 1 and 2 were confirmed via NMR and single-crystal X-ray diffraction. The resulting findings confirmed the structures of 1 and 2 and determined their crystalized system (monoclinic system; P 2 1 / n space group). Hirshfeld analysis of 1 revealed the importance of the significantly short O…H (6.7%), S…S (1.2%) and C…C (2.8%) ; however, the short H···H (42.6%), S···H (16.3%) and C···C (4.3%) were showed in 2 by intermolecular interactions in the molecular packing. The 1,2,4-triazolo-quinzolines ( 1&2 ) were anticipated to be relatively polar compounds with net dipole moments of 2.9284 and 4.2127 Debye, respectively. The molecular electrostatic potential, atomic charge distribution maps and reactivity descriptors for 1 and 2 were also determined. The calculated nuclear magnetic resonance spectra of the targets 1 and 2 were well correlated with the experimental data.


Introduction
In pharmaceutical chemistry, the synthesis of new bioactive agents has recently achieved notable prominence as a result of the increasing spread of various diseases [1,2]. Nitrogen heterocycles, which are found in various natural and synthetic products, represent the most important class of biologically active substances and pharmaceutically relevant molecules. Among them, quinazolines and triazoles have attracted considerable at-tention in synthetic medicinal chemistry and the materials science area. Due to the significance of these pharmacophore classes as well as their roles in the construction of pharmacologically active molecules, including antimicrobial, antimalarial, anti-inflammatory, antihypertensive, anticonvulsant, antidiabetic and anticancer agents as well as cholinesterase inhibitors, their synthesis has been a hot topic in organic synthesis [3,4]. Thus, the combination of both quinazoline and triazole moieties results in the synthesis of a triazoloquinazoline scaffold, which exhibits varied pharmacological activities [3]. Indeed, many triazoloquinazolines have been reported to exhibit promising antihistamine activity [5,6]. Some 1,2,4-triazoloquinazolines have been investigated as potent adrenoblockers and were found to display good hypotensive activity [7,8]. A series of 2-alkoxy-triazoloquinazolines were found to act as potent adenosine receptor antagonists [9,10]. The presence of lactam and thiolactam in triazoloquinazolines skeleton was valuable to appear in more pharmacophoric moieties associated with a diversity in biological properties. For example, S-alkylated triazoloquinazolines showed significant antimicrobial effects [11,12]; however, their N-alkylated compounds demonstrated strong antiviral activity [13,14]. Furthermore, potential antidiabetic activity was reported for triazoloquinazoline, which manifested itself via its ability to inhibit α-glucosidase activity [15]. Additionally, some 1,2,4-triazoloquinazolines have been observed to possess potential antioxidant properties and promising cytotoxicity [16][17][18][19][20][21]. Hence, we focus on triazoloquinazoline chemistry, particularly studying the crystal structure of 1,2,4-triazolo[1,5-a]quinazoline derivatives [22][23][24][25][26][27]; herein, we report X-crystal structures, NMR, MS, IR, DFT and Hirshfeld studies of the synthesized triazoloquinazolines 1 and 2.

General Information
The IR spectrum was determined using a Perkin Elmer FT-IR Spectrum BX system. The NMR spectra were measured with a Bruker AMX 500-MHz instrument, and the data were described as ppm values relative to tetramethylsilane at 500 and 125 MHz for 1 H and 13 C NMR, respectively, and DMSO-d6 used as solvent. Employing a Micromass Quattro microTM triple-quadruple tandem mass spectrometer to measure ESI-MS spectra.

Synthesis of the Triazoloquinazolines 1 and 2
According to the reported detailed methodologies in our previous papers [28,29], the compounds 1 and 2 were prepared.

X-Ray Crystallography Analysis
Crystals of 2-Methylthiotriazoloquinazolines (1&2) were formed from saturated ethanolic solution by evaporation over 2 days at room temperature. Data collection was conducted on a Bruker APEX-II D8 Venture area diffractometer equipped with graphite monochromatic Mo Kα radiation at 100 (2) K. By employing Bruker SAINT SHELXT software, the cell refinement and reduction data were performed [30,31], and the solved structures were obtained by using SHELXT software. The final refinement was carried out using a full-matrix least-squares techniques with anisotropic thermal data for non-hydrogen atoms on . Triazoloquinazolines 1 and 2 comprise the crystallographic data supplementary and can be obtained free of charge from the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif (2 September 2021).

Spectroscopic Data
Confirmation of triazoloquinazolines structures 1 and 2 was achieved by IR, NMR and MS-spectrometry. Although the chemical structures of the intermediates A and B have been previously determined [28,29] and the physiochemical properties of 1 have also been reported, we reiterated the relevant NMR data of 1 for additional explanation in this study. The IR spectrum of 1 revealed a strong absorption band due to carbonyl group at 1679 cm −1 . The 1 H NMR spectra of 1 and 2 are characterized by the singlet signal of the Smethyl protons at δ 2.65 and 2.69 ppm, respectively, and their 13 C NMR resonances were recorded at δ 13.90 and 13.97 ppm, respectively. Notably, N-alkylation of substrate A with an allyl moiety (Scheme 1) was proven by its four 1  Triazoloquinazoline 1 has shown promising antihistaminic effect against histamine induced bronchospasm (IC50 = 0.6528 mM) in comparison with the theophylline (IC50 = 0.01996 mM) [6]. Furthermore, 1 was evaluated as an α-glucosidase inhibitor in vitro assay and showed the best inhibition effect (IC50 = 72.28 μM) in regards to acarbose (IC50 = 143.54 μM) [14]. Moreover, the triazoloquinazoline 1 was also reported as an antiviral, antimicrobial and antioxidant active agent (see Introduction).

Crystallographic Data
The refinement information and crystallographic data of triazoloquinazolines 1 and 2 (C13H12N4OS and C12H12N4S2) structures are presented in Table 1. As it can be evinced from Figure 1, the asymmetric units of 1 and 2 contain only one molecule. The length of all bonds and the angles demonstrated values in the ordinary ranges [39]. In the crystal packing (Figure 2), the molecules of compounds 1 and 2 are connected to another one via a single non-classical intermolecular hydrogen bonding interaction (Table 2).

Analysis of Molecular Packing
The intermolecular interactions play an essential role for determining the stability of the studied crystals. In this regard, various intermolecular interactions in the crystal structures of both systems are analyzed quantitatively, performing Hirshfeld calculations (Figure S1 and S2). Their percentages and detected contacts are presented in Figure 3. The molecular packing of 1 is controlled by significantly short O…H (6.7%), S…S (1.2%) and C…C (2.8%) (Figure 3). In 2, the packing is controlled by short H···H (42.6%), S···H (16.3%) and C···C (4.3%) interactions. All such interactions have the characteristic features of short interactions and contribute significantly to the stability of 1 and 2 crystal structures. Notably, although the H…H (47.0%), H…C (12.97%), N…H (9.7%) and S…H (5.8%) contacts make a significant contribution to the overall molecular packing interactions in 1 ( Figure  4), these contacts exhibited the characteristic features of intermolecular interactions between atoms found at longer mutual distances than the sums of the said atoms Van der Waals radii. Concerning 2, the contact distances of the most significant H···H, S···H and C···C interactions are summarized in Table 3, and other key contacts that contributed to the molecular packing included the N···H (15.1%) and H···C (9.8%) interactions. Indeed, values for the contact distances of the most important H…H, S…H and C…C interactions were significant, which are highlighted by the corresponding red spots in the dnorm maps. Moreover, characteristics of short interactions were observed in the fingerprint plots (Figure 5). These interactions in 2 exhibited considerably longer interaction distances than the sum of the Van der Waals radii of the interacting atoms as well.   . Figure 5. Results of the Hirshfeld analysis conducted on 2. Red, white and blue colors indicated shorter, equal and longer contacts distances than the vdWs radii sum of the interacting atoms, respectively.

Geometric Parameters
The compounds 1 and 2 optimized geometries are presented in Figure 6. It can be evinced from this figure that the calculated geometric features of both structures match very well their counter parts experimentally determined, using X-ray diffraction data. The calculated and optimized bond distances are in good agreement with each other (Table  S1). Good correlations were also determined to exist between the experimental and the calculated bond distances for the 1 and 2 structures (Figure 7). Indeed, the correlation coefficients values are very close to unity, and the maximum absolute errors do not exceed 0.04 Å and 3.8º for bond distances and bond angles, respectively. The calculated natural atomic charges are presented (Table S2)

Analysis of Reactivity
Investigation of the highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO) of 1 and 2 indicated beyond doubt the distribution of these molecular orbitals over the π-system of the studied molecules ( Figure 9). The energies of these orbitals and the corresponding reactivity indices [40][41][42][43][44][45][46], such as ionization potential, electron affinity, chemical potential, hardness and electrophilicity (I, A, μ, η and ω) were calculated (Table 4). Both HOMO levels have almost the same energy in the two compounds. However, the energy of LUMO in 1 is higher than 2. From the results, both compounds have similar ionization potentials but different electron affinities. In the case of 1, the η value (4.3250 eV) is higher than that of 2 (3.8053 eV). In addition, the electrophilicity of 1 is lower (1.7852 eV) than that of 2 (2.2087eV). In Table 4, all the calculated values for I, A, ω, and the HOMO-LUMO gap for both crystals are listed.

NMR Spectra
The chemical shifts of the resonance peaks in the 1 H and 13 C NMR spectra of triazoloquinazolines 1 and 2 were computed, and the findings are listed in Tables S3 and S4, alongside the corresponding experimental data. As it can be evinced from Figure 10, a good relation exists between the calculated and the experimentally determined chemical shifts. In particular, the correlation coefficients are 0.97 and 0.98 for both 1 H and 13 C NMR spectral data.

Conclusions
Triazoloquinazolines 1 and 2 were synthesized and confirmed by NMR and X-ray diffractometry. The crystal structures of 1 and 2, as determined by X-ray diffractometry, were characterized by bond lengths and angles that were in the normal ranges; moreover, molecules of 1 and 2 were observed to be included in a non-classical intermolecular hydrogen bonding interaction. The molecules 1 and 2 were anticipated to be polar, with net dipole moments of 2.9284 and 4.2127 Debye. The practical data were correlated with theoretical DFT calculations (employing the B3LYP/6-311++G(d,p) basis set). The supramolecular structures of the investigated compounds were studied performing Hirshfeld calculations. The calculated geometric features of the studied compounds were appeared to be in good agreement with those experimentally identified by X-ray. Moreover, good agreement was detected between the calculated and the experimental NMR data. Different electronic and reactivity descriptors of 1 and 2 were calculated and discussed.

Supplementary Materials:
The following are available online at www.mdpi.com/2073-4352/11/10/1195/s1, Figure S1: Hirshfeld analysis of 2, Figure S2: Hirshfeld analysis of 1, Table S1: The calculated bond distances of 1 and 2, Table S2: Natural charge populations at the different atomic sites of the studied compounds, Table S3: The calculated and experimental chemical shifts (ppm) for 1 (according to Figure 6), Table S4: The calculated and experimental chemical shifts (ppm) for 2 (according to Figure 6