Preparation and Antifungal Properties of Cyclopropyl Derivatives of 3-Aminoquinazolin-4(3H)-one and Salicylal Schiff Base Nickel(II) Chelate Complex

Abstract

N-substituted 2-cyclopropyl-3-R-quinazoline-4()-ones [R: NH₂ (1), N=CH(2-hydroxyphenyl) (2)] and Ni(II) chelate compound of 2-cyclopropyl-3-[(Z)-(2-hydroxybenzylidene)amino]quinazoline-4(3H)-one (3) were synthesized and their structures and properties were characterized using X-ray diffraction data, computational optimization, ¹H and ¹³C NMR, IR spectroscopy, and diffuse reflectance spectra. Compounds 1 and 2 are monoclinic (space group P2₁/n). Unit cell parameters (a, b, c) are 9.2529; 4.7246; 22.3460 Å and 10.2811; 4.6959; 30.972 Å for 1 and 2, respectively. Nickel(II) chelate compound crystallizes in an orthorhombic crystal system (space group Pbca). Unit cell parameters (a, b, c) for 3 are 26.5010; 14.8791; 8.904975 Å, respectively. Schiff base 2 in the crystalline state exhibits two rotary isomers in a molar ratio of 1:3, among which only a minor component as a bidentate ligand can form compound 3 with Ni(II) ion. Nickel(II) ion in 3 is coordinated by N donor atoms and deprotonated O atoms of Schiff base ligands to form square-planar chelate node NiN₂O₂. All synthesized compounds revealed high antifungal activity against bread mold (Mucor mucedo).

1. Introduction

Quinazolinone-based substances are of particular importance and extremely relevant for medicine and pharmacology, since they are highly spread among biologically active compounds and drugs [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16]. Far-reaching application of these compounds is also the formation of transition metal complexes, mainly metal chelates, which often show outstanding catalytic activity in biologically marked processes [12,13]. The physiological activity of chelating ligands is often increased in complexes of metals [9]. From a medical point of view, metal chelates of biologically active organic molecules, e.g., based on quinazolinone moieties, allow the introduction of essential microelements into living organisms.

Over recent years, similar quinazoline-4(3H)-ones have been obtained and their crystalline structures and physiological properties have been studied [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]. However, no cyclopropyl derivatives of quinazolin-4(3H)-ones have been yet synthesized. Cyclopropyl bonds are known to undergo efficient cleavage. Electrophilic agents react with cyclopropyl substituted quinazoline-4(3H)-ones to form tricyclic compounds showing new synthetic methods of drug modification. Biological, medicinal, and pharmaceutical properties of quinazoline-4(3H)-ones and its derivatives [16], and also relative compounds, e.g., 2-ethylquinazolin-4(3H)-thione [25], were shown to be related to the features of their molecular structures. A particular feature of all of them is planar configuration. The aim of this work was the synthesis of 2-cyclopropylquinazoline-4(3H)-one and its new 3-R derivatives [R: NH₂ (1), N=CH(2-hydroxyphenyl) (2)] including nickel(II) chelate compound bis [2-cyclopropyl-3-{[2-(hydroxy-κO)benzylidene]amino-κN}quinazolin-4(3H)-onato]nickel(II) (3) (Figure 1a,b) with potential antifungal activity against bread mold (Mucor mucedo).

2. Results and Discussion

2.1. Synthesis, Characterization, and Structure of 2-Cyclopropyl-3-aminoquinazolin-4(3H)-one (1) and 2-Cyclopropyl-3-[(Z)-(2-hydroxybenzylidene)amino]quinazoline-4(3H)-one (2)

Various methods are known for the production of 2-substituted 3-aminoquinazolin-4(3H)-ones [3,4,5,6,7,8]. In this work, 2-Cyclopropyl-4H-benzo[d][1,3]oxazin-4-one was chosen as a precursor to obtain the above derivatives of 2-cyclopropylquinazolin-4(3H)-one. This substance was prepared from anthranilic acid in accordance with a known protocol [14,16]. The interaction of anthranilic acid with cyclopropane carbonyl chloride in chloroform in the presence of NEt₃ produces 2-[(cyclopropylcarbonyl)amino]benzoicacid. The following refluxing of 2-[(cyclopropylcarbonyl)amino]benzoic acid in acetic acid anhydride solution yields 2-cyclopropyl-4H-benzo[d][1,3]oxazin-4-one. The formation of the resulting compound is depicted in Scheme 1.

The interaction of 2-cyclopropyl-4H-benzo[d][1,3]oxazin-4-one with N₂H₄·H₂O results in the formation of 2-cyclopropyl-3-aminoquinazoline-4(3H)-one (1) (Scheme 2).

Compound 1 was obtained as a colorless crystalline substance soluble in polar and non-polar organic solvents. Crystals of 1 obtained from ethanol were studied by X-ray diffraction. Crystal data for 1 (C₁₁H₁₁N₃O, M = 201.209 g/mol) are as follows: monoclinic; space group P2₁/n (no. 169), a = 9.2529(6) Å, b = 4.7246(2) Å, c = 22.3460(14) Å, β = 97.698(5)°, V = 968.08(10) ų, Z = 4, T = 295 K, λ(CuK_α) = 1.54178 Å, d_calc = 1.38 g/cm³, R_int = 0.056, R/R_w (I > 2σ(I)) = 0.045/0.053, 3.99° < θ < 70.98° (Supplementary Information, Table S1).

According to crystallographic data, the atoms N1, N2, and N3 in 1 are coplanar (Figure 2), as for all similar compounds, including related 2-propyl-3-aminoquinazolin-4(3H)-one studied earlier [19]. However, the cyclopropyl substituent in 1 affects the configuration of NH₂ group. The N3-H31 and N3-H32 distances and N2-N3-H31 and N2-N3-H32 valence angles in 1 are not equivalent (Supplementary Information, Figure S1 and Table S2), unlike for 2-propyl-3-aminoquinazolin-4(3H)-one. The discrepancies in the N3-H31 and N3-H32 distances for 1 are definitely beyond the standard deviation (1.03(4) Å and 0.81(4) Å, respectively). The N2-N3-H31 and N2-N3-H32 angles in 1 tend to be different as well (98(2)° and 107(3)°, respectively). The sum of the valence angles around N3 atom in 1 is 337° that is indicative of its sp³ valence state. This feature of the amino group configuration may be a plausible argument for the existence of a betaine-like structure of the ⁻O1-C8=N2⁺ moiety (Figure 3) and the presence of a weak intramolecular H bonding between O1 and H31 atoms.

Schiff base 2-cyclopropyl-3-[(Z)-(2-hydroxybenzylidene)amino]quinazolin-4(3H)-one (2) was obtained by the reaction of 1 with salicylal in n-BuOH.

Crystal data for 2 (C₁₈H₁₅N₃O₂, M = 305.303 g/mol) are as follows: monoclinic; space group P2₁/n (no. 264), a = 10.2811(15) Å, b = 4.6959(6) Å, c = 30.972(3) Å, β = 90.02(2)°, V = 1495.3(3) ų, Z = 4, T = 295 K, λ(CuK_α) = 1.54178 Å, d_calc = 1.36 g/cm³, R_int = 0.012, 2.85° < θ < 74.97°. R/R_w = 0.054/0.079 (I > 2σ(I)) (Supplementary Information, Table S1).

As seen from crystallographic data, 2 is in trans conformation (Figure 4). There are two conformers 2A and 2B within crystallographic network (Figure 1b). The conformers 2A and 2B coexist in a 0.37:0.63 molar ratio, respectively, and are different due to the orientation of the phenolic OH groups. The ADP of atoms in the phenyl moiety is only slightly higher than those for the other atoms in the molecule and smaller than in cyclopropyl moiety. That means that there is no free rotation of the phenyl group and the structure has two definite orientations. Such positions are fixed by two hydrogen bonds: intramolecular N3···H21o-O21 (the N3···H21o distance and N3–H21o–O21 angle are 1.770(8) Å and 162(8)°, respectively) and intermolecular O1···H2o-O2 between 2A and 2B in the crystal network of 2 (the O1···H2o distance and O1–H21o–O21 angle are 1.84(5) Å and 166(4)°, respectively) (Figure 4 and Figure 5).

Atomic displacement parameters of the endocyclic amide N atom are similar to those of surrounding atoms (even somewhat smaller) and close to isotropic, and thus, this site cannot be the result of two overlapping sp³ hybrid sites, rather indicating the sp² hybridization of the amide N atom requiring planar configuration.

The phenyl moiety of salicylaldehyde in the crystal structure of 2 is considerably out of conjugation with quinazolinone quasi-aromatic system (Figure 6). The dihedral angle between the phenyl plane of salicylaldehyde and the quinazolinone moiety is 111–113°. The N3-C12 bond (Figure 4) is close to sesqui-order one (Supplementary Information, Table S3) and practically lies in the phenyl moiety plane of the salicylal. The H21···N3 hydrogen bond (Figure 4) also provides a notable conjugation of the N3-C12 bond with the π-electron system of the phenyl ring. The N3···O21 distance in 2A is 2.589(5) Å (Supplementary Information, Table S3), which is also consistent with the presence of a moderately strong intermolecular hydrogen bond [26,27]. Another O1···H2o-O2 intermolecular distance is slightly longer (2.681(3) Å). The ratio between these two configurations of 2 is probably determined by the crystal packing energy and entropy factor and can hardly be changed by crystal growth conditions as was shown for the referred cases earlier [28].

The infrared spectral data for 1 and 2 are in good agreement with the results obtained by XRD. In the infrared spectrum of 1, there appear two sets of intensive bands at 1657, 1606, 1581 and 1562 cm⁻¹ attributed to stretching vibrations of C=O, C=N, and conjugated C=O and C=N bonds. The bands at 3209, 3269, and 3328 cm⁻¹ are present in both spectra of 1 and 2. These bands, in the case of 1, are due to the stretching (asymmetric and symmetric) valence vibrations of the NH₂ groups and NH₂ associated to the oxygen atom through weak intramolecular H bonding. For 2, these bands result from the stretching N-H and O-H valence vibrations in the systems of intramolecular and intermolecular OH···N (1.766 Å) and OH···O (1.838 Å) bonds, respectively (Figure 5). The existence of weak hydrogen bonding was also found to correlate with values of interatomic distances [26,29,30]. Very strong bands at 2952, 2926, and 2854 cm⁻¹ are also observed in the infrared spectrum of 1. These bands are absent in the infrared spectrum of 2 and are due to stretching vibrations of C=N⁺ moieties [31,32].

Earlier [33], it was shown that there is no free rotation even for the non-cyclic amide group resulting from partial double bond formation due to resonance ⁻O-C=N⁺. Thus, the usual amino-carbonyl formulation seems to be at odds with the large C-N rotation barrier [34,35] indicating partial C-N double bonding requiring sp² hybridization of the atomic orbitals of the amide N atoms. A similar conclusion may be drawn when considering the planar configuration of N amide atom in 1.

Quantum chemical calculations allow optimizing the configuration for 1. The results are also consistent with X-ray diffraction data. Minimum energy possesses the planar geometry of the quinazolinone moiety with an asymmetric orientation of H31 and H32 atoms of the amino group (Supplementary Information, Figures S3 and S4). One of the H atoms is slightly closer to the O1 atom. The quantum chemical calculations showed that there was a bonding critical point between the O1 and N3 atoms that was indicative of weak hydrogen bonding in 1 (Figure 7). Moreover, the O1 atom was found to be markedly negatively charged (−0.25), but at the same time, the charge on the more electronegative (relative to C) endocyclic amide N atom turned out to be even slightly positive (+0.04).

¹H NMR data also confirm the nonequivalence of the H31 and H32 atoms. The chemical shifts calculated for H31 (7.30 ppm) and H32 (2.97 ppm) protons of amino group in the asymmetric conformer are in line with experimental ¹H NMR signals (7.37 and 2.83 ppm, respectively). So, the computational calculations predict the highest stability for the refined structure of 1.

The higher stability of the planar configuration of the heterocycle moiety in 1 is reasonable due to the formation of a more stable quasi-aromatic heterocycle. The C8-N2, N2-C7, C7-N1, and N1-C5 distances (1.380(3); 1.392(3); 1.298(3), and 1.378(3) Å, respectively, Supplementary Information, Table S2) also testify in favor of the aromatic character of the bonds in heterocyclic quinazolinone moieties.

In addition to the intermolecular hydrogen bonds, crystal packing is probably stabilized by N-π and O-π interactions of neighboring molecules in solid 1 (Figure 8) (Supplementary Information, Figure S1) and 2 (Figure 9) (Supplementary Information, Figure S2), respectively [26].

According to XRD data, intermolecular H-bond O21(-H21o)… N3 is equal to 2.590(5) Å and intramolecular H-bond O1…(H2o)-O2 is equal to 2.681(3) Å. The distances between acceptors and hydrogen atoms are H21o…N3 1.84(7) Å and H2o…O2 1.81(4) Å.

Quantum chemical optimization of 2 likewise predicts the co-existence of two conformers 2A and 2B. The optimized energy (ΔE) and Gibbs free energy (ΔG) are lower for 2A (E = −1008,685757 a.u. and G = 150.9 kcal mol⁻¹ for 2A and E = −1008,669703 a.u. and G = 149.8 kcal mol⁻¹ for 2B), it reasonable originates from the weak intramolecular N3···H21o–O21 hydrogen bond. The chemical shifts calculated for protons of OH groups in 2A (H21o) and 2B (H2o) conformers are 12.669 and 9.390 ppm, respectively, whereas the value of the chemical shift for 2 in solution is 10.62 ppm (δ H2o for 2B). The H21o proton resonance is not observed due to the effective hydrogen exchange of H2o in 2A and protons of water in the solvent (DMSO).

In the agreement with calculations, the conformer 2A is thermodynamically more stable at room temperature (ΔG are 0 and 9.0 kcal mol⁻¹ for 2A and 2B, respectively), although the 2A molar ratio is half as much in the solid phase; this obviously follows from the packing requirements (Figure 9). The reason becomes clear when considering crystallographic data indicating the presence of intermolecular hydrogen bonding O2–H2o···O1 (the distance H2o···O1 is 1.84(5) Ǻ).

2.2. Synthesis, Characterization, and Structure of Bis[2-cyclopropyl-3-{[2-(hydroxy-κO)benzylidene]amino-κN}quinazolin-4(3H)-onato]nickel(II) (3)

Nickel(II) chelate 3 is moderately soluble in benzene at room temperature and poorly soluble in polar solvents (methanol, ethanol, chloroform, ethyl acetate, acetone). Compound 3 was obtained as a green polycrystalline solid and characterized using IR and diffuse reflectance spectroscopy data.

The diffuse reflectance spectra of the free ligand 2 and the Ni(II) complex of 2 are shown in Figure 10. The diffuse reflectance spectrum of Ni(OAc)₂ is also depicted for comparison.

Two bands at 437 and 630 nm attributed to CT and d–d transitions [36], respectively, are observed in the diffuse reflectance spectrum of 3. The band near to UV region (421 nm) was observed also in the electronic spectrum of the most similar slight distorted square-planar Ni(II) complexes of Schiff bases of salicylal derivative [36], which was attributed to CT transition. The d–d band at 630 nm is also observed in the diffuse reflectance spectrum of Ni(OAc)₂ (Figure 10, curve 2). Three ligand bands also appear in the spectrum of nickel(II) chelate in the UV region, which is indicative of the complex formation, the ligand bands being absent in the spectrum of Ni(OAc)₂.

Only the minor conformer 2A is clear to be available for metal complex formation through the donor azomethyne atom N3 and O2 atom of the deprotonated OH group of each salicylic moiety. The conformer 2B is evidently not suitable for chelating nickel(II) ion. However, the rotation of salicylic moiety being hindered in crystalline phase becomes relatively free in solution especially by heating. Heat treatment of the reaction mixture leads to a shift in the equilibrium between the conformers and the crystalline dominant 2B is converted to 2A to yield almost quantitatively 3.

Crystal structure of 3 was found by the powder X-Ray diffraction technique (Figure 11). Crystal data for 3 (Ni(C₁₈H₁₄N₃O₂)₂, M = 667.292 g/mol) are as follows: orthorhombic; space group Pbca (no. 48), a = 26.5010(8) Å, b = 14.87917(16) Å, c = 8.04975(9) Å, V = 3174.12(13) ų, Z = 4, T = 295 K, λ(CoK_α1) = 1.78965 Å, d_calc = 1.40 g/cm³, R_p/wp (I > 2σ(I)) = 0.065/0.042, 1.95° < θ < 40.05° (Supplementary Information, Table S1).

It could be assumed that chelating ligand 2 is potentially tridentate for the coordination of nickel(II) through azomethyne N and two oxygen atoms of carbonyl and phenolic groups. This expectation is due to a low-frequency shift of the bands in the infrared spectrum of nickel(II) chelate attributed to C=O and C=N stretching vibrations by 10–15 cm⁻¹ compared to their positions in the IR spectrum of the free ligand. However, the low-frequency shift of the above bands does not provide adequate evidence for the number of chelating atoms, since the effective conjugation of C=O and C=N bonds in the ligand leads to a decrease in the frequency of valence vibrations of both C=N and C=O groups.

The moieties of salicylaldehyde are coplanar to the NiN₂O₂ chelate node (Figure 11), the interatomic Ni-N distances being longer than Ni-O ones (Supplementary Information, Table S4). No O1 atom of the quinazolinone moiety coordinates with the Ni(II) ion and 2 acts exclusively as a bidentate ligand.

The above results were confirmed using quantum chemical optimization performed for 3. According to these data, the optimal configuration of nickel(II) chelate 3 is depicted in Figure 12. As can be seen, the metal atom is coordinated by two bidentate chelating ligands through donor N atoms and O atoms of deprotonated OH groups of 2. The nickel chelate node, NiN₂O₂, exhibits a slightly distorted square-planar configuration (Supplementary Information, Table S4).

The proton chemical shifts are also important indicators of the ring current effects of the aromatic molecules [37]. Aromaticity is estimated by calculating nuclear-independent chemical shifts (NICS), which are known to be effective criteria for aromaticity [38]. The NICS values for 1–3 are summarized in Table 1. The points +1 and −1 are away from the ring centers and reflect the π electron toroid density [39] where the maximum chemical shieldings are [38].

Negative NICS values for the heterocyclic quinazolinone moieties in 1–3 are unambiguously indicative of the aromaticities of heterocycles. On the contrary, the positive NICS values indicate antiaromatic features [38]. However, as can be seen from the Table, there are no positive NICS values for all the cases under consideration.

The results of the quantum chemical optimization listed in Table 1 indicate that pronounced aromaticity of the heterocycle moieties is also observed in 3. The negative NICS values are also observed for quasi-aromatic metal chelate cycles although the NICS values are slightly lower in this case.

The existence of a certain degree of aromatic character in the heterocyclic quinazolinone moieties of 1–3 confirmed by X-ray studies, ¹H NMR data, and computational optimizations is in good agreement with the betaine-type formulation of the 2-cyclopropyl-3-aminoquinazolinone moiety, which explains the planar configuration and sp² hybrid state of the atomic orbitals of the endocyclic amide N atom.

2.3. Antifungal Activity

Some kinds of mold are poisonous and dangerous to humans. Quinazolinone-based substances are well known to be very active against many pathogens (bacteria, fungi, viruses, and so on) [2,6,40,41,42]. To date, the physiological activity of cyclopropyl derivatives of quinazolin-4(3H)-ones has been poorly studied. The antifungal activity of various inhibitors based on quinazolin-4(3H)-one derivatives was established to depend on the nature of the substituent in the 2- and 3-positions of the heterocycle [2,6].

The cyclopropyl derivatives of quinazolin-4(3H)-one obtained here were screened for antifungal activity against widespread species of Mucor mucedo fungi. In this study, white bread was chosen as a medium for the visual monitoring of fungal growth. The mold on white bread is of various colors from white to black, depending on the experimental conditions. However, regardless of the mold color, the inhibition of the mold growth is quite obvious for all the samples tested.

Here it was found that mold on bread is sensitive to cyclopropyl derivatives of quinazolin-4(3H)-one. The results are shown in Figure 13, which represents a photograph of samples of white bread after exposure to an atmosphere saturated with water vapor in a gas chamber at a temperature of 23–25 °C for 12 days.

The mold-free areas on samples 1–3 were pretreated with 1–3, respectively. The sample totally covered with mold (Figure 13, sample 4) was not treated with the compounds synthesized and was presented for comparison.

The various shapes of the areas free of fungal growth seem to correspond exactly to the previously untreated areas with corresponding compounds synthesized. The behavior of compound 3 is of particular interest. There was no mold on the entire area of the sample 3, although only half of it was preliminarily impregnated with compound 3. So, no mold growth was observed on the area of this sample during the same time period.

Thus, all cyclopropyl derivatives of 3-aminoquinazoline-3(4H)-one have proven to be very effective inhibitors of fungal growth on bread.

The distinct antifungal activity of 1–3 was found against mold on concrete plaster. The effect of inhibition of 1 and 2 against the concrete plaster mold is seen in Figure 14. The middle area of the concrete plaster sample, which was not treated with either 1 or 2, is seen to be covered with brown mold.

The upper and lower areas of the concrete plaster sample were treated with ethanolic solutions of 1 and 2, respectively. The mold growth is observed only in the inhibitor-free area of the sample.

The inhibitory properties of the Ni(II) chelate are seen in Figure 15. There is a distinct boundary between the upper (treated with Ni(II) chelate) and lower (inhibitor-free) areas of the concrete plaster sample.

3. Experiment

3.1. Materials and Equipment

Anthranilic acid, cyclopropanecarbonyl chloride, acetic anhydride, salicylic aldehyde, NEt_3, and hydrazine hydrate were used as commercial reagents (ACS grade, Aldrich, Burlington, MA, USA). Solvents (CHCl₃, MeOH, EtOH, i-BuOH) were distilled under atmospheric pressure. Ni(OAc)₂·4H₂O was used as purchased and crystallized from EtOH.

IR spectra were recorded on an FTIR Shimadzu Spectrophotometer (Kyoto, Japan). ¹H and ¹³C NMR spectra were measured on a Bruker-DPX 400 MHz with TMS as internal standard. UV-VIS spectra were obtained using a Shimadzu UV-VIS-3600 Plus spectrophotometer.

3.2. Synthesis

3.2.1. 2-[(Cyclopropylcarbonyl)amino]benzoic Acid

Cyclopropanecarbonyl chloride (20.8 g, 205 mmol) in 100 mL of CHCl₃ was added drop-wise for 2 h to a mixture of anthranilic acid (26 g, 190 mmol) and NEt₃ (20 g, 198 mmol) in 50 mL CHCl₃ at 273–278 K followed by stirring for 1 h. Then 3 mL of NEt₃ was added and the resulting solution was kept at room temperature for 12 h. The mixture was diluted with 150 mL of water and the NEt₃ excess was neutralized to pH 2–3 by 10% of HCl. The chloroform solution was isolated, rinsed with water, and evaporated in a vacuum.

Crude 2-[(cyclopropylcarbonyl)amino]benzoic acid was crystallized from the mixture of water and ethanol (1:5, v/v). Yield: 28.79 g (74%), mp. 418–419 K. Anal. calc. for C₁₁H₁₁NO₃: found (calculated), %: C 64.38 (64.45), H 5.40 (5.49), N 6.83 (6.91); ¹H NMR (DMSO-d₆, 400 MHz, δ, ppm, J, Hz): 0.80–0.90 (m, 4 H, 2CH₂, cyclopropyl (CP)), 1.64–1.76 (m, 1 H, CH, CP), 7.11 (ddd, ³J = 7.6, ³J = 8.7, ⁴J = 0.85, 1 H, Ar), 7.54 (ddd, ³J = 7.1, ³J = 7.6, ⁴J = 1.40, 1 H, Ar), 7.97 (dd, ³J = 8.0, ⁴J = 1.5, 1 H, Ar), 8.45 (dd, ³J = 8.4, ⁴J = 0.85, 1 H, Ar), 11.36 (s, 1 H, NH); ¹³C NMR (DMSO-d₆, 400 MHz, δ, ppm): 8.2 (2CH₂, CP), 16.4 (CH, CP), 116.6 (Ar), 120.4 (Ar), 122.8 (Ar), 131.5 (Ar), 134.5 (Ar), 141.4 (Ar), 170.1 (>C=O), 172.2 (>C=O).

3.2.2. 2-Cyclopropyl-4H-benzo[d][1,3]-oxazinone-4

Refluxing of 2-[(cyclopropylcarbonyl)amino]benzoic acid (12.41 g, 60 mmol) in acetic anhydride (100 mL) for 4 h yielded 2-cyclopropyl-4H-benzo[d][1,3]-oxazinone-4. Evaporation of the solution followed by crystallization from methanol resulted in colorless crystals of 2-cyclopropyl-4H-benzo[d][1,3]oxazin-4-one. Yield: 10.88 g (70%), mp. 383–385 K. Anal. calc. for C₁₁H₉NO₂: found (calculated), %: C 70.58 (70.65), H 4.85 (4.91), N 7.48 (7.55); ¹H NMR (CDCl₃, 400 MHz, δ, ppm, J, Hz): 0.95–1.02 (m, 2H, CH₂, CP), 1.13–1.20 (m, 2H, CH₂, CP), 1.78–1.86 (m, 1 H, CH, CP), 7.26–7.36 (m, 2 H, Ar), 7.61 (ddd, ³J = 7.6, ⁴J = 1.6 1 H, Ar), 7.98 (dd, ³J = 8.3, ⁴J = 1.0, 1H, Ar); ¹³C NMR (CDCl₃, 400 MHz, δ, ppm): 9.3 (2 CH₂, CP), 14.3 (CH, CP), 116.6 (Ar), 125.9 (Ar), 127.2 (Ar), 128.3 (Ar), 136.2 (Ar), 146.8 (Ar), 159.3 (>C=N−), 164.0 (>C=O).

3.2.3. 2-Cyclopropyl-3-aminoquinazolin-4(3H)-one (1)

The mixture of 0.9 g (4.86 mmol) of 2-cyclopropyl-4H-benzo[d][1,3]-oxazinone-4 and 0.73 g (14.6 mmol) of 80% hydrazine hydrate in 35 mL of ethanol was refluxed for 5 h. After partial evaporation of the solvent colorless 1 was obtained. The crude material was then crystallized from the mixture of ethanol–H₂O (9:1, v/v). Yield: 0.69 g (70.5%), mp. 406–407 K. Anal. calc. for C₁₁H₁₁N₃O: found (calculated), %: C 65.66 (65.69), H 5.51 (5.57), N 20.88 (20.95); ¹H NMR (CDCl3, δ, ppm, J, Hz): 1.04–1.12 (m, 2 H), 1.25 (m, 2 H), 2.83 (m, 1 H), 5.04 (s, 2 H), 7.37 (t, 1 H, J = 7.58), 7.54 (d, 1 H, J = 8.08), 7.67 (t, 1 H, J = 7.07), 8.19 (d, 1 H, J = 8.08); ¹³C NMR (CDCl₃, δ, ppm): 9.89, 11.78, 119.49, 125.38, 126.31, 126.84, 133.77, 147.17, 158.50, 161.41. IR (cm⁻¹): 3329, 3268, 3209, 2952, 2925, 2854, 1672, 1612, 1583, 1471.

3.2.4. 2-Cyclopropyl-3-[(Z)-(2-hydroxybenzylidene)amino]quinazolin-4(3H)-one (2)

Schiff base 2 was obtained by the treatment of 0.51 g (0.25 mmol) of 1 with 0.26 cm³ (0.25 mmol) of salicylic aldehyde in refluxing EtOH (or i-BuOH) (10 mL) solution for 1 (or 0.5) h. After cooling the resulting solution down to 278 K the rose-tinted crystals of 2 were precipitated, filtered off and rinsed with cool EtOH (or i-BuOH). The crystals of 2 were obtained by slow evaporation from i-BuOH at 278–283 K. Yield: 0.128 g (97%), mp. 395–396 K. Anal. calc. for C₁₈H₁₅N₃O₂: found (calculated), %: C 70.81 (70.79), H 4.95 (4.84), N 13.76 (13.66); ¹H NMR (CDCl3, δ, ppm, J, Hz): 0.98–1.00 (m, 2 H), 1.12–1.15 (m, 2 H), 2.31–2.34 (m, 1H), 3.37–3.39 (d, H), 6.93–7.01 (m, 2H), 7.39–7.41 (m, 2H), 7.39–7.45 (m, 2H), 7.50–7.52 (d, 1H), 7.70–7.73 (m, 1H), 7.90–7.92 (dd, 1 H), 8.06–8.08 (dd, 1H), 9.10 (s, 1H), 10.62 (s, 1H); ¹³C NMR (DMSO-d6, δ, ppm): 117.18, 118.58, 120.12, 121.06, 126.25, 127.09, 127.15, 128.86, 134.67, 134.90, 146.82, 157.18, 157.92, 168.16; IR (cm⁻¹): 3328, 3270, 3147, 1657, 1606, 1581, 1562, 1469, 1400, 767.

3.2.5. Bis[2-cyclopropyl-3-{[2-(hydroxy-κO)benzylidene]amino-κN}quinazolin-4(3H)-onato]nickel(II) (3)

Ethanol solution (10 mL) of Ni(OAc)₂·4H₂O (0.125 g, 0.5 mmol) was added to a solution of 2 (0.300 g, 0.99 mmol) in EtOH (10 mL) followed by refluxing for 1 h. A green residue precipitated just after the solution getting boiled was filtered off, rinsed out with cool EtOH and dried in air at room temperature. Green polycrystalline powder of 3 was obtained from benzene–ethanol–chloroform (1:1:1, v/v) solution after being cooled to 278–283 K and slow evaporation of the solvent. Yield: 0.124 g (99%), mp. 508–511 K Anal. calc. for Ni(C₁₈H₁₄N₃O₂)₂: found (calculated), %: C 64.76 (64.80), H 4.12 (4.23), N 12.61 (12.59); IR (cm⁻¹): 1645 (υ C=O+C=N), 1601, 1572 (υ C=N), 1559.

3.3. X-Ray Data Collection and Structure Determination

X-ray analysis was carried out on STOE STADI VARI PILATUS-100K and CAD4 single crystal diffractometers (CuK_α radiation, λ = 1.54178 Ǻ) and a STOE STADI P powder diffractometer (CoK_α1 radiation, λ = 1.788965 Ǻ, miniPSD detector) at 295 K.

Structure solution and refinement. The diffraction data for all substances were measured under ambient conditions (T = 295 K). Although the angle of the unit cell for compound 2 is equal to 90° within the standard deviation intensities of several tested hkl and –hkl reflections differed by at least one order of magnitude. Thus, it was suggested that its unit cell has monoclinic symmetry, which was later confirmed by the refinement. Crystals of 3 grew as stacking of extremely thin plates and were not suitable for single crystal diffraction experimentation. The obtained powder samples were ground in an agate mortar under liquid nitrogen to prevent amorphization. The collected single crystal data were corrected for Lorenz and polarization factors. An empirical absorption correction was applied. The structures were solved by the SIR2002 program package [43] and refined with JANA2000 [44]. All non-hydrogen atoms were refined successively in isotropic and anisotropic approximations of the atomic displacement parameters (ADP). Unexpectedly, two oxygen atoms in the Schiff base moiety of compound 2 were found but their ADP were about twice higher than for other atoms in the molecule (Scheme 1, 2A and 2B). Their occupancy refinement converged approximately to 0.6 and 0.4 for O2 and O21, respectively and in the final refinement their sum was constrained to 1 and the ratio appeared to be 0.630(5):0.370(5).

All hydrogen atoms in compound 1 were obtained from difference Fourier synthesis and refined independently. In compound 2 hydrogen positions in the aromatic moiety were calculated and refined in the restrained mode. The successive difference Fourier synthesis revealed only one hydrogen atom near C12 and two small peaks near O2 and O21 atoms at distances of about 1 Å. No meaningful electron density was found near the N2 and N3 atoms. It was suggested that the last hydrogen atom was linked to the O2 and O21 atoms with corresponding occupancies. In the final refinement all hydrogen atoms in structures 2 were refined independently. The description and the results of the single crystal experiments are given in Supplementary Information (Table S1); interatomic distances and selected bond angles are summarized in Supplementary Information (Tables S2 and S3).

The orthorhombic cell parameters of 3 were determined by the ITO [39,45] indexing program incorporated in the STOE diffractometer program package. Le Bail refinement confirmed the correctness of indexing and the choice of the space group. The structure of 3 was solved by the direct space method—parallel tempering realized in the FOX program [46]. The number of molecules and the number of general positions in the Pbca space group required the positioning of the Ni atom in the inversion center. The ligand group was introduced as a rigid body using the data obtained for structure 2. The solution converged with the positioning of the O2 and N3 atoms 1.7–2.0 Å apart from Ni forming its common square-planar configuration. For the refinement, the ligand was separated in three rigid bodies: quinazolinone, salicylicaldehyde and cyclopropane. The positions of the atoms within each group were fixed as well as the ADP. Preliminary investigation with a G670 Huber camera revealed significant differences in the intensity of 200 reflections for different orientations of the sample. Thus, preferred orientation refinement was introduced as well as strain broadening by tensor formalism. At the final stage isotropic ADP were refined for Ni and common ones within each rigid body group. Finally the N3–C12 distance (the distance between the two main groups) appeared to be close to that in structure 2 (Supplementary Information Tables S2–S4). The distance from the quinazolinone to the cyclopropyl ring (C7–C9) was rather large, probably due to some disorder in the cyclopropyl orientation. The description and the results of the structural experiment are given in Supplementary Information (Table S2) and the interatomic distances and selected bond angles are summarized in Supplementary Information (Table S3).

3.4. Computational Details

The geometries of molecules, transition states, and intermediates were fully optimized by means of the density functional theory (DFT) with the PBE functional calculations [47]. The full electron basis sets L1 and L2 were used, where L1 stands for double set size and L2 for triple set size. The numbers of contracted and primitive functions used in L1 are respectively {2,1}/{6,2} for H, {3,2,1}/{10,7,3} for C, N, and O. The numbers of contracted and primitive functions used in L2 are respectively {3,2,1}/{8,4,2} for H, {4,3,2,1}/{12,8,4,2} for C, N, and O [48]. Stationary points on the potential energy surface (PES) were identified by analyzing Hessians. The thermodynamic functions (Gibbs free energies, G) at 298.15 K were calculated using the approximation of the restricted rotator and harmonic oscillator. The ¹H NMR spectra were calculated using a gauge including atomic orbitals (GIAO) [49,50] in the complete electronic TZ2P basis. The atomic charges were calculated according to Hirschfeld [51]. The topological analysis was performed in the frame of Bader’s theory [52]. All calculations were performed using the MBC100k cluster at the Joint Supercomputer Center (JSCC) (Moscow, Russia) with the use of the PRIRODA04 program written by Laikov [53].

The nucleus-independent chemical shifts (NICS) were computed for 1 at two points: at the ring center (0) and 0.10 nm above the ring center (+1) of the benzene and heterocyclic quinazolinone moieties. The NICS values for 2 were calculated for three points: (0, +1, and −1) at the ring center, 0.10 nm above, and 0.10 nm below the ring center of the benzene and heterocyclic quinazolinone moieties. The NICS values for 3 were found for three points: 0, +1, and −1 at the ring centers of the benzene (A), heterocyclic quinazolinone moieties (B) and of the nickel chelate cycle (C).

3.5. Antifungal Activity

The bread mold experiment was carried out against mold to investigate the antifungal properties of 1–3. The slices of wheat bread were treated with 0.2 mL of 1.5·10^–3 M solutions of corresponding compound in ethanol. After the solvent was evaporated in air the patterns were placed into a humidity camera for exposure at room temperature (23–25 °C). The samples were monitored for 7–21 days. The antifungal activity was estimated by the visual observation of the fungal growth.

The inhibitory activity of 1–3 in relation to a concrete plaster mold was also studied in the humidity chamber at 25 °C. The inhibitory effect was detected after 5–6 months.

4. Conclusions

New 2-cyclopropyl derivatives of 3-aminoquinazolin-4(3H)-one and nickel(II) chelate, bis[2-cyclopropyl-3-{[2-(hydroxy-κO)benzylidene]amino-κN}quinazolin-4(3H)-onato]nickel(II), were synthesized and characterized by XRD, IR, ¹H and ¹³C NNMR, and UV-VIS spectroscopy. Compounds 1 and 2 are monoclinic (space group P2₁/n). Unit cell parameters (a, b, c) are 9.2529; 4.7246; 22.3460 Å and 10.2811; 4.6959; 30.972 Å for 1 and 2, respectively. Two rotary conformers of 2-cyclopropyl-3-[(2-hydroxybenzilidene)amino]quinazolin-4((3H)-one coexist in the crystalline phase. Nickel(II) chelate compound crystallizes in an orthorhombic crystal system (space group Pbca). Unit cell parameters (a, b, c) for 3 are 26.5010; 14.8791; 8.904975 Å, respectively. Quantum chemical optimizations of the structures for new compounds were carried out. Potentially tridentate Schiff base 2-cyclopropyl-3-[(2-hydroxybenzilidene)amino]quinazolin-4((3H)-one, however, acts exclusively as a bidentate ligand to form nickel(II) chelate compound, the oxygen atom of C=O group taking no part in coordination. Schiff base 2 in the crystalline state exhibits two rotary isomers in a molar ratio of 1:3, among which only a minor component as a bidentate ligand can form compound 3 with Ni(II) ion. 2-Cyclopropyl derivatives of quinazolin-4(3H)-one were found to exhibit high antifungal activity against mold Mucor mucedo.

Author Contributions

Conceptualization, A.N.F., E.V.T. and A.N.Z.; methodology and data analysis, A.V.M., E.V.T. and A.N.Z.; writing—original draft preparation, A.V.M., V.A.T., I.P.G. and A.N.Z.; writing—review and editing, A.N.Z.; supervision and funding acquisition not applicable. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in the Supplementary Materials or on request from the corresponding author.

Acknowledgments

This study was fulfilled using a STOE STADI VARI PILATUS-100K diffractometer purchased by the MSU Development Program.

Conflicts of Interest

The authors declare no conflicts of interest.

Sample Availability

Samples of the compounds are available from the authors.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Figures, Schemes and Table

Figure 1. (a) Molecular structures of 3-R-2-cyclopropylaminoquinazolin-4(3H)-ones, R: NH2 (1), N=CH(2-hydroxyphenyl) (2) and Ni(II) chelate of 2, bis[2-cyclopropyl-3-{[2-(hydroxy-κO)benzylidene]amino-κN}quinazolin-4(3H)-onato]nickel(II) (3). (b) Molecular structures of Schiff base conformers 2A and 2B obtained by condensation of 3-amino-2-cyclopropylaminoquinazolin-4(3H)-one with salycilaldehyde.

Scheme 1. Formation of 2-cyclopropyl-4H-benzo[d][1,3]oxazin-4-one by the reaction of 2-[(cyclopropylcarbonyl)amino]benzoic acid and acetic acid anhydride.

Scheme 2. Formation of 1 by the reaction of 2-cyclopropyl-4H-benzo[d][1,3]oxazin-4-one with N2H4·H2O.

Figure 2. Crystal structure of 3-amino-2-cyclopropylquinazolin-4(3H)-one (1) (Hydrogen atoms are not shown except those at nitrogen atom).

Figure 3. Betaine-like molecular structure of 1.

Figure 4. Crystal structure of 3-amino-2-cyclopropylquinazolin-4(3H)-one Schiff base 2A and 2B (hydrogen atoms are not shown except those at oxygen atoms).

Figure 5. Intermolecular and intramolecular hydrogen bondings in the crystalline structure of 2.

Figure 6. Configuration of phenyl moiety in the crystal structure of 2.

Figure 7. View of bonding critical points and charges on O1 and N2 in 1.

Figure 8. View of the unit cell of 1.

Figure 9. View of crystal packing of 2.

Figure 10. Diffuse reflectance spectra of free ligand 2 (1), Ni(OAc)2 (2), and 3 (3).

Figure 11. Crystal structure of 3.

Figure 12. Molecular structure of 3 optimized by a quantum chemistry calculation (red is oxygen atoms, weight is hydrogen atoms, gray is carbon and nitrogen atoms).

Figure 13. Antifungal activity of 1-3 against black mold (Mucor mucedo) on white bread samples treated with 1 (1), 2 (2), 3 (3) (mold-free areas of the samples were treated with a corresponding compound). Sample 4 was untreated with any of the compounds under consideration. The surface concentration of the corresponding inhibitors supported on each sample was equal to 3 × 10−6 mol/cm2.

Figure 14. Antifungal activity of 1 and 2 against plaster mold. Areas 1 and 2 were treated with 1 μM ethanolic solutions of compound 1 and Schiff base 2, respectively to prepare surface concentrations of 1 and 2 approximately equal to 1 μmol/cm2. Mold growth is observed within the untreated area of the plaster.

Figure 15. Antifungal activity of Ni(II) chelate in relation to the concrete plaster mold. The upper area was treated with 1 μM ethanolic solution of compound 3 to obtain a surface concentration of 3 equal to 1 μmol/cm2. The lower area is inhibitor free.

Table 1

Isotropic NICS values (ppm) calculated at center (0); at 0.10 nm above (+1) and at 0.10 nm below (−1) the center of the benzene (A), heterocyclic quinazolinone (B) moieties, and metal chelate cycle (C).

Moiety	Point	Compound
		1	2	3
A	0	−8.002	−2.963	−4.639
	1	−10.091	−8.086	−10.564
	−1			−7.957
B	0	−1.295	−8.896	−8.527
	1	−4.107	−9.982	−15.976
	−1			−14.875
C	0			−0.0200
	1			−3.890
	−1			−3.445

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/inorganics12120304/s1, Figure S1: O-π and N-π interactions of neighboring molecules in solid 1; Figure S2: O-π and N-π interactions of of neighboring molecules in solid 2; Figure S3: View of 1 (a and b are the end and face views, respectively) in symmetric conformation (1A) of hydrogen atoms of the amino group and calculated proton shifts (ppm), energy (E) and Gibbs’s free energy (G); Figure S4: View of 1 in asymmetric conformations of hydrogen amino atoms: 1B is enol form and 1C is twisted form of the amino group and calculated proton shifts (ppm), energy (E) and Gibbs free energy (G) and optimized geometric parameters for 1C; Figure S5: Quantum chemical calculations of energy (E), Gibbs free energy (G), proton chemical shifts (ppm), and charges (Q) on O1 and N2 atoms of 2A and 2B conformers of 2; Table S1: Crystal data, data collection and refinement for C₁₁H₁₁N₃O, C₁₈H₁₅N₃O₂, and Ni(C₁₈H₁₅N₃O₂)₂; Table S2: Selected interatomic distances (Å) and angles (°) in C₁₁H₁₁N₃O; Table S3: Selected interatomic distances (Å) and angles (°) in C₁₈H₁₅N₃O₂; Table S4: Selected interatomic distances (Å) and angles (°) in Ni(C₁₈H₁₄N₃O₂)₂ (data are corrected by Berar factor 3.386); Additional crystallographic information on the structure refinement is available from the Cambridge Structure Database, CCDC 1844355, 1844356 and 1853675.

References

1. Ajani, O.O.; Aderohunmu, D.V.; Umeokoro, E.N.; Olomieja, A.O. Quinazoline pharmacophore in therapeutic medicine. Bangladesh. J. Pharmacol.; 2016; 11, pp. 716-733. [DOI: https://dx.doi.org/10.3329/bjp.v11i3.25731]

2. Jafari, E.; Khajouei, M.R.; Hassanzadeh, F.; Hakimelahi, G.H.; Khodarahmi, G.A. Quinazolinone and quinazoline derivatives: Recent structures with potent antimicrobial and cytotoxic activities. Res. Pharm. Sci.; 2016; 11, pp. 1-14. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27051427]

3. Parkanyi, C.; Schmidt, D. Synthesis of 5-chloro-2-methyl-3-(5-methyl thiazole-2-yl)-4(3H)-quinazolinone and related compounds with potential biological activity. J. Heterocycl. Chem.; 2000; 37, pp. 725-729. [DOI: https://dx.doi.org/10.1002/jhet.5570370409]

4. Rohokale, R.S.; Kshirsagar, U.A. Advanced Synthetic Strategies for Constructing Quinazolinone Scaffolds. Synthesis; 2016; 48, pp. 1253-1268. [DOI: https://dx.doi.org/10.1055/s-0035-1560413]

5. Devi, K.A.; Sarangapani, M.S. Synthesis and Antimicrobial activity of some Quinazolinones Derivatives. Int. J. Drug Dev. Res.; 2012; 4, pp. 324-327.

6. Atia, A.J.K.; Al-Mufrgaiy, S.S. Synthesis and antibacterial activities of new 3-amino-2-methyl-quinazolin-4(3h)-one. Am. J. Chem.; 2012; 2, pp. 150-156. [DOI: https://dx.doi.org/10.5923/j.chemistry.20120203.09]

7. Kumar, P.; Shrivastava, B.; Pandeya, S.N.; Stables, J.P. ChemInform Abstract: Design, Synthesis and Potential 6 Hz Psychomotor Seizure Test Activity of Some Novel 2-(Substituted)-3-{[substituted]amino}quinazolin-4(3H)-one. Eur. J. Med. Chem.; 2011; 46, pp. 1006-1018. [DOI: https://dx.doi.org/10.1016/j.ejmech.2011.01.009]

8. Hemalatha, K.; Girija, K. Synthesis of some novel 2,3-disubstituted quinazolinone derivatives as analgesic and anti-inflammatory agents. Int. J. Pharm. Pharm. Sci.; 2011; 3, pp. 103-106.

9. Khan, M.T.H.; Khan, R.; Wuxiuer, Y.; Arfan, M.; Ahmed, M.; Sylte, I. Identification of novel quinazolin-4(3H)-ones as inhibitors of thermolysin, the prototype of the M₄ family of proteinases. Bioorg. Med. Chem.; 2010; 18, pp. 4317-4327. [DOI: https://dx.doi.org/10.1016/j.bmc.2010.04.083]

10. Tiwari, A.K.; Singh, V.K.; Bajpai, A.; Shukla, G.; Singh, S.; Mishra, A.K. Synthesis and biological properties of 4-(3H)-quinazolone derivatives. Eur. J. Med. Chem.; 2007; 42, pp. 1234-1238. [DOI: https://dx.doi.org/10.1016/j.ejmech.2007.01.002]

11. Alagarsamy, V.; Meena, S.; Vijayakumar, S.; Ramseshu, K.V.; Revathi, R. Synthesis and pharmacological investigation of some novel 2,3-disubstituted quinazolin-4(3H)-ones as analgetic and anti-inflammatory agents. Parmazie; 2003; 58, pp. 233-236. [DOI: https://dx.doi.org/10.1002/chin.200330182]

12. Siddappa, K.; Reddy, P.C. Synthesis, spectral and antimicrobial studies of some transition metal(II) complexes with schiff base 3-[(2-hydroxy-6-methoxyquinolin-3- ylmethylene)-amino]-2-methyl-3h-quinazoline-4-one. Int. J. Appl. Biol. Pharm. Tech.; 2012; 3, pp. 168-177.

13. Siddappa, K.; Mane, S.B. Harmacological activity of (e) 3-2-(1-(1-hydroxynaphthalen-2-yl) methyleneamino) phenyl) -2-methylquinazoline-4 (3h) -one schiff base and its transition metal complexes. Int. J. Pharm. Pharmaceut. Sci.; 2013; 5, pp. 725-732.

14. Sahu, S.K.; Azam, A.; Banerjee, M.; Acharrya, S.; Behera, C.C.; Si, S. Synthesis, Characterization and Biological Activity of 2-Methyl-3-aminoquinazolin-4(3H)-ones Schiff Bases. J. Braz. Chem. Soc.; 2008; 19, pp. 963-970. [DOI: https://dx.doi.org/10.1590/S0103-50532008000500023]

15. Gholap, A.V.A.; Maity, S.; Schulzke, C.; Maiti, D.; Kapdi, A.R. Synthesis of Cu-catalysed quinazolinones using a Csp3–H functionalisation/cyclisation strategy. Org. Biomol. Chem.; 2017; 15, pp. 7140-7146. [DOI: https://dx.doi.org/10.1039/C7OB01723E]

16. Khan, I.; Zaib, S.; Batool, S.; Abbas, N.; Ashraf, Z.; Iqbal, J.; Saeed, A. Quinazolines and quinazolinones as ubiquitous structural fragments in medicinal chemistry: An update on the development of synthetic methods and pharmacological diversification. Bioorg. Med. Chem.; 2016; 24, pp. 2361-2381. [DOI: https://dx.doi.org/10.1016/j.bmc.2016.03.031]

17. Zhou, Y.; Murphy, D.; Sun, Z.; Gregor, V.E. Novel parallel synthesis of N-(4-oxo-2-substituted-4H-quinazolin-3-yl)-substituted sulfonamides. Tetrahedron Lett.; 2004; 45, pp. 8049-8051. [DOI: https://dx.doi.org/10.1016/j.tetlet.2004.08.183]

18. Connolly, D.J.; Cusack, D.; O’Sullivan, T.P.; Guiry, P.J. Synthesis of quinazolinones and quinazolines. Tetrahedron; 2005; 61, pp. 10153-10202. [DOI: https://dx.doi.org/10.1016/j.tet.2005.07.010]

19. El-Hiti, G.A.; Smith, K.; Hegazy, A.S.; Alanazi, S.A.; Kariuki, B.M. Crystal structure of 3-amino-2-propylquinazolin-4(3H)-one. Acta Cryst.; 2015; E71, pp. o590-o591. [DOI: https://dx.doi.org/10.1107/S2056989015013134]

20. Coogan, M.P.; Hibbs, D.E.; Smart, E. Asymmetric transformation (deracemisation) of an atropisomeric bisheterocyclic amine. Chem. Commun.; 1999; 19, pp. 1991-1992. [DOI: https://dx.doi.org/10.1039/a905018c]

21. Kumar, K.S.; Ganguly, S.; Veerasamy, R.; De Clercq, E. Synthesis, antiviral activity and cytotoxicity evaluation of Schiff bases of some 2-phenyl quinazolinone-4(3)H-ones. Eur. J. Med. Chem.; 2010; 45, pp. 5474-5479. [DOI: https://dx.doi.org/10.1016/j.ejmech.2010.07.058] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20724039]

22. Xingwen, G.; Xuejian, C.; Kai, Y.; Lili, G.; Zhuo, C. Synthesis and Antiviral Bioactivities of 2-Aryl- or 2-Methyl-3-(substituted-Benzalamino)-4(3H)-quinazolinone Derivatives. Molecules; 2007; 12, pp. 2621-2642. [DOI: https://dx.doi.org/10.3390/12122621] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18259148]

23. Al-Amiery, A.A.H.; Al-Majedy, Y.K.; Abdulhadi, S.A.; Sadoon, A.H. Design, synthesis and bioassay of novel metal complexes of 3-amino-2-methylquinazolin-4(3H)-one. Afr. J. Pure Apl. Chem.; 2009; 3, pp. 218-227.

24. Raghavendra, N.M.; Thampi, P.; Gurubasavarajaswami, P.M.; Sriram, D. Synthesis, antitubercular and anticancer activities of substituted furyl-quinazolin-3(4H)-ones. Arch. Pharm. Chem. Life Sci.; 2007; 340, pp. 635-641. [DOI: https://dx.doi.org/10.1002/ardp.200700096] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17994604]

25. Alshammari, M.B.; Smith, K.; Hegazy, A.S.; Kariuki, B.M.; El-Hiti, G.A. Crystal structure of 2-ethylquinazoline4(3H)-thione. Acta Cryst.; 2014; E70, o953. [DOI: https://dx.doi.org/10.1107/S160053681401664X]

26. Borissova, A.O.; Lyssenko, K.A.; Gurinov, A.A.; Shenderovich, I.G. Energy Analysis of Competing Non-Covalent Interaction in 1:1 and 1:2 Adducts of Collidine with Benzoic Acids by Means of X-ray Diffraction. Z. Phys. Chem.; 2013; 2, pp. 775-790. [DOI: https://dx.doi.org/10.1524/zpch.2013.0400]

27. Prodius, D.; Wilk-Kozubek, M.; Mudring, A.-V. Synthesis, structural characterization and luminescence properties of 1-carboxymethyl-3-ethylimidazolium chloride. Acta Cryst.; 2018; C74, pp. 653-658. [DOI: https://dx.doi.org/10.1107/S2053229618005272]

28. Tafeenko, V.A.; Gurskiy, S.I. Disorder for the Sake of Order. Cryst. Growth Des.; 2016; 16, pp. 940-945. [DOI: https://dx.doi.org/10.1021/acs.cgd.5b01496]

29. Borissova, A.O.; Antipin, Y.M.; Karapetyan, H.A.; Petrosyan, A.M.; Lyssenko, K.A. Cooperativity effects of H-bonding and charge transfer in an L-nitroarginine crystal with Z’ > 1. Mendeleev Commun.; 2010; 20, pp. 260-262. [DOI: https://dx.doi.org/10.1016/j.mencom.2010.09.006]

30. Mironov, A.V.; Tafeenko, V.A.; Grebenkin, D.Y.; Oblezov, A.E. Hydrogen bonding in hydroxypyridium salts. Z. Kristallogr. Cryst. Mater.; 2018; 233, pp. 501-506. [DOI: https://dx.doi.org/10.1515/zkri-2017-2136]

31. Nakamoto, K. Infrared Spectra of Inorganic and Coordination Compounds; 2nd ed. Wiley: New York, NY, USA, 1970.

32. Pechler, K.G.R.; Matlok, F.; Gremlich, H.-U. A Collection of FT-IR Spectra. Merck/Bruker: Darmstadt/Karlsruhe, Germany, 1988.

33. Kemnitz, C.R.; Loewen, M.J. “Amide resonance” correlates with a breadth of C-N rotation barriers. J. Am. Chem. Soc.; 2007; 129, pp. 2521-2528. [DOI: https://dx.doi.org/10.1021/ja0663024] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17295481]

34. Pauling, L. The Nature of Chemical Bond; Cornell University Press: Ithaca, NY, USA, 1960.

35. Wheland, G.W. Resonance in Organic Chemistry; Wiley: Hoboken, NJ, USA, 1955.

36. Rotthaus, O.; Thomas, F.; Jarjayes, O.; Philouze, C.; Saint-Aman, E.; Pierre, J.-L. Valence tautomerism in octahedral and square-planar phenoxyl-nickel(II) complexes: Are imino nitrogen atoms good friends?. Chem. Eur. J.; 2006; 12, pp. 6953-6962. [DOI: https://dx.doi.org/10.1002/chem.200600258] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16810650]

37. Minkin, V.I.; Glukhovtsev, M.V.; Simkin, B.Y. Aromaticity and Antiaromaticity; Wiley: New York, NY, USA, 1994.

38. Von Ragué Schleyer, P.; Maerker, C.; Dransfeld, A.; Jiao, H.; van Eikema Hommes, N.J.R. Nucleus-Independent Chemical Shifts: A Simple and Efficient Aromaticity Probe. J. Am. Chem. Soc.; 1996; 118, pp. 6317-6318. [DOI: https://dx.doi.org/10.1021/ja960582d] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28872872]

39. Waugh, J.S.; Fessenden, R.W. Nuclear Resonance Spectra of Hydrocarbons: The Free Electron Model. J. Am. Chem. Soc.; 1957; 79, pp. 846-849. [DOI: https://dx.doi.org/10.1021/ja01561a017]

40. Waghmare Sweeti, M.; Manchare Akanksha, M.; Shaikkh Avesh, Y.; Diksha Raut, G. Biological activity of quinazolinone derivatives: A review. Int. J. Curr. Pharm. Res; 2023; 15, pp. 15-18.

41. Wang, D.; Gao, F. Quinazoline derivatives: Synthesis and bioactivities. Chem. Cent. J.; 2013; 7, 95. [DOI: https://dx.doi.org/10.1186/1752-153X-7-95]

42. Rakesh, K.P.; Darshini, N.; Shubhavathi, T.; Mallesha, N. Biological Applications of Quinazolinone Analogues: A Review. Org. Med. Chem.; 2017; 2, OMCIJ.MS.ID.555585.

43. Burla, M.C.; Camalli, M.; Carrozzini, B.; Cascarano, G.; Giacovazzo, C.; Polidori, G.; Spagna, R. SIR2002: The program. A new direct-methods program, which has been designed to solve both small and large crystal structures, is described. J. Appl. Cryst.; 2003; 36, 1103. [DOI: https://dx.doi.org/10.1107/S0021889803012585]

44. Petricek, V.; Dusek, M.; Palatinus, L. Jana. The Crystallographic Computing System; Institute of Physics: Praha, Czech Republic, 2000.

45. Visser, J.W. A fully Aromatic Program for finding the Unit Cell from Powder Data. J. Appl. Crystallogr.; 1969; 2, pp. 89-95. [DOI: https://dx.doi.org/10.1107/S0021889869006649]

46. Favre-Nicolin, V.; Cerny, R. FOX, Free Objects for Crystallography: A Modular Approach to ab Initio Structure Determination from Powder Diffraction. J. Appl. Crystallogr.; 2002; 35, pp. 734-743. [DOI: https://dx.doi.org/10.1107/S0021889802015236]

47. Perdew, J.P.; Burke, K.; Ernzerhof, M. Generalized Gradient Approximation Made Simple. Phys. Rev. Lett.; 1996; 77, pp. 3865-3868. [DOI: https://dx.doi.org/10.1103/PhysRevLett.77.3865] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10062328]

48. Laikov, D.N. A new class of atomic basis functions for accurate electronic structure calculations of molecules. Chem. Phys. Lett.; 2005; 416, pp. 116-120. [DOI: https://dx.doi.org/10.1016/j.cplett.2005.09.046]

49. Schreckenbach, G.; Ziegler, T. Calculation of NMR Shielding Tensors Using Gauge-Including Atomic Orbitals and Modern Density Functional Theory. J. Phys. Chem.; 1995; 99, pp. 606-611. [DOI: https://dx.doi.org/10.1021/j100002a024]

50. Schreckenbach, G.; Ziegler, T. Calculation of NMR shielding tensors based on density functional theory and a scalar relativistic Pauli-type Hamiltonian. The application to transition metal complexes. Int. J. Quantum Chem.; 1997; 61, pp. 899-918. [DOI: https://dx.doi.org/10.1002/(SICI)1097-461X(1997)61:6<899::AID-QUA3>3.0.CO;2-R]

51. Hirshfeld, F.L. Bonded-Atom Fragments for Describing Molecular Charge Densities. Theoret. Chim. Acta; 1977; 44, pp. 129-138. [DOI: https://dx.doi.org/10.1007/BF00549096]

52. Bader, R.W.F. Atoms in Molecules: A Quantum Theory; Oxford University Press: Oxford, UK, 1990.

53. Laikov, D.N.; Ustynyuk, Y.A. PRIPODA-04: A Qiantem-Chemical Program Suite. New Possibilities in the Study of Molecular Systems with the Application Parallel Computing. Russ. Chem. Bull. Int. Ed.; 2005; 54, pp. 820-826. [DOI: https://dx.doi.org/10.1007/s11172-005-0329-x]