Novel Fluorescent Benzothiazolyl-Coumarin Hybrids as Anti-SARS-COVID-2 Agents Supported by Molecular Docking Studies: Design, Synthesis, X-ray Crystal Structures, DFT, and TD-DFT/PCM Calculations

Abstract

This study revealed the design and preparation of new 3-(benzo[d]thiazol-2-yl)-2H-chromen-2-one derivatives 9a–h. The structures of the synthesized products were elucidated by their spectroscopic data and X-ray crystallography for compounds 9a and 9d. The prepared new compounds were measured for their fluorescence, and a good result indicated that the emission efficiency was decreased by increasing the electron-withdrawing groups from the unsubstituted compound 9a to the highly substituted derivative 9h (2 Br heavy atoms). On the other hand, the B3LYP/6-311G** theoretical level of theory was used to optimize the quantum mechanical calculations of the geometrical characteristics and energy of the novel compounds 9a–h under study. The electronic transition was investigated using the TD-DFT/PCM B3LYP approach, which uses time-dependent density functional calculations. Moreover, the compounds exhibited nonlinear optical properties (NLO) and a small HOMO–LUMO energy gap, which makes them easy to polarize. Furthermore, the acquired infrared spectra were compared with the expected harmonic vibrations of the substances 9a–h. On the other hand, binding energy analyses of compounds 9a–h with human corona virus nucleocapsid protein Nl63 (PDB ID: 5epw) were predicted using molecular docking and virtual screening tools. The results showed a promising binding and how these potent compounds were inhibiting the COVID-19 virus. Compound 9h was the most active anti-COVID-19 agent among all the synthesized benzothiazolyl-coumarin derivatives, as it forms five bonds. The presence of the two bromine atoms in its structure was responsible for the potent activity.

1. Introduction

Coumarins constitute a major class of synthetic and naturally occurring compounds and distinct therapeutic platforms that display a wide range of biological and therapeutic properties.¹ Several major synthetic molecules bearing the coumarin skeleton have been learned in the recent past and are in several stages of drug improvement.² Coumarins have been well studied as a distinct construct for mapping novel agents that have great attractiveness and specificity for diverse molecular targets of antiviral agents.³ Although limited studies on coumarin derivatives tested against SARS-CoV2 have been described, and reported that the compounds show good binding affinity, there are not many cross-sectional studies on coumarins that can help discover a single key compound for interaction with different targets, which are in authority for the human entry and replication of SARS-CoV2.⁴ Moreover, coumarins are the most important class of fluorophores and they have been studied extensively as fascinating tools for biological applications, especially for live cell imaging.⁵ Then, we have synthesized some new coumarin derivatives that have found their use as laser dyes used in medicine.⁶ Major efforts have been focused on emerging effective synthetic methods for coumarin derivatives.⁷⁻⁹

Benzothiazole and its derivatives are significant heterocyclic aromatic compounds. The benzothiazolyl moiety is giving rise to a category of compounds with several applications in medication and in nonlinear optics.¹⁰ Heterocyclic molecule-based benzothiazole derivatives exhibit strong fluorescence and luminescence in the solid state and in solutions.¹¹ Recently, we synthesized novel heterocyclic derivatives substituted with a benzothiazole moiety that showed important fluorescence and significant biological activities.¹²⁻²⁰ Among the compounds with valuable optical properties and biological activities are the substituted coumarins containing benzothiazole residue.²¹ In this regard, emerging more competent methods for synthesizing this structure for a useful pathway to motivated chemical collections of coumarins containing benzothiazole residue would be extremely required. Having succeeded in our concern about the green synthesis of fluorescent coumarins and benzothiazoles, we report here a novel one-pot synthesis of benzothiazolyl-coumarin hybrids through the reaction of N-[2-(benzo[d]thiazol-2-yl)acetyl]benzohydrazide with salicylaldehyde derivatives. In carrying out these determinations, we demonstrated an efficient procedure and studied the photophysical properties and docking studies on the anti-COVID 19 of the novel synthesized benzothiazolyl-coumarin hybrids, and we present here the details of these studies.

Utilizing spectroscopic methods, the structures of compounds 9a through 9h have been distinguished. The optimized molecular structure of the generated compounds was achieved by employing the DFT approach within the B3LYP/6-311G** basis set. The experimental work is adopted for the computer analysis of substances utilizing density functional theory. To explore the ground state attributes, such as optimization structure, geometrical parameters, reactivity parameters, and 3D-plots of the molecule electrostatic potential maps, theoretical calculations using the density functional theory (DFT) at the basis set B3LYP/6-311G** will be implemented (MEP). TD-DFT will be used to explore the genesis of electronic spectra and the make-up of the frontier molecular orbitals in the polarizable continuous solvation model (PCM). Bond angles, bond lengths, dihedral angles, electronic dipole moments, and first-order hyperpolarizability, among other quantum chemical parameters, have all been calculated for the compounds 9a–h. Natural bond orbital analysis (NBO), in addition to the global reactivity descriptors, was applied. Anisotropy of polarizability (α), mean first-order hyperpolarizability (Δα), mean polarizability (⟨β⟩), and total static dipole moment (μ_tot.) were determined and compared to urea as a control. Additionally, the electronic and infrared spectra were identified. A bacterial infection called the new coronavirus pneumonia (COVID-19) results in an infectious acute respiratory disease.²² The nucleic acid of the novel coronavirus is described as stranded positive RNA. Among its structural proteins are the spike protein (S), protein envelope (E), membrane protein (M), and phosphoprotein nucleocapsid.²³ The 5epw COVID-19 virus and the produced drugs were predicted to bind via molecular docking. The important objective of this study is to demonstrate consistency between the measured and computed findings.

2. Results and Discussion

2.1. Chemistry

The present study described the novel synthesis of new 3-(benzo[d]thiazol-2-yl)-2H-chromen-2-one derivatives 9a-h based on thiazole ring system compound 5 through Scheme 1. A simple method was used to prepare the desired novel compounds, where N′-(2-(benzo[d]thiazol-2-yl)acetyl)benzohydrazide compound 5 was heated in a reflux system for about 3 h with salicylaldehyde derivatives 6a–h in the presence of ethanol absolute and ammonium acetate to afford the coumarin derivatives 9a–h. Figure 1 presents the preferred mechanism of the reaction for the formation of the target products 9a–h. Moreover, the structures of these novel series were elucidated by X-ray single crystal structures for compounds 9a and 9d, which were presented in (Figures 2 and 3).^24,25 The reaction did not proceed via the cyclization and elimination of water molecules from the intermediate 7a–h to obtain 8a–h. But it proceeds by the cyclization of 7a–h and removes one molecule of benzohydrazide (PhCONHNH₂) to form the final products 9a–h by using the ammonium acetate in ethanol as a cyclization condition. The formation of the coumarin products 9a–h and not the N-substituted quinoline products 8a–h was suggested to be attributed to the fact that structures 9a–h were the thermodynamically controlled products due to less steric hindrance which obtained as a sole compound, and consequently more stable than the kinetically controlled products 8a–h.

Scheme 1. Synthesis of 3-(Benzo[d]thiazol-2-yl)-2H-chromen-2-one Derivatives 9a–h.

Figure 1.

Schematic diagram representing the mechanism of synthesis of the target compounds 9a–h.

Figure 2.

X-ray single crystal structure of the compound 9a. Reproduced with permission of the International Union of Crystallography under the,open-access license.²⁴

Figure 3.

X-ray single crystal structure of the compound 9d. Reproduced with permission of the International Union of Crystallography under the open-access licence.¹⁰⁰

The structures for the entire synthesized product were confirmed by their spectral data and mass spectrometry. For compound 9a, the disappearance of the two NH groups and the CH₂ moiety which was present in compound 5 in its ¹H NMR spectrum confirmed the structure which revealed only 9 signals, a multiplet at δ 7.46–8.21 ppm due to the appearance of two C₆H₄ moieties, a singlet at δ 9.26 ppm due to the presence of CH-pyran ring. The ¹³C NMR spectrum also approved the structure by the appearance of 16 signals for the aromatic carbons, pyran ring [116.7–153.8 ppm], C=N moiety [159.9 ppm], and C=O group [160.1 ppm]. Moreover, the molecular formula C₁₆H₉NO₂S was in agreement with the molecular ion peak, which appeared at m/z 279. The ¹H NMR spectrum of 9b confirmed its structure via the presence of a multiplet at δ 7.48–8.20 ppm for C₆H₄ and C₆H₃ moieties. Moreover, the appearance of the singlet at δ 9.20 ppm approved the pyran ring.

The mass spectra of 9b and 9c confirmed their structures and approved their respective molecular formulas, C₁₆H₈ClNO₂S and C₁₆H₈BrNO₂S, by displaying a molecular ion peak [M⁺] at m/z 313 and [M⁺ + 1] at m/z 359, which corresponds to their base peak, respectively. For compound 9d, the presence of the signal at δ 2.40 ppm for the CH₃ group in its ¹H NMR spectrum and the signal at δ 20.8 ppm in the spectrum of ¹³C NMR elucidated the structure. ¹H NMR of 9e revealed the absence of a CH₂ signal and the appearance of the two groups C₆H₄ and C₆H₃ as multiplet in the range of 7.50–8.74 ppm. Moreover, the presence of the signal at δ 9.05 ppm for the CH- approved the formation of the pyran ring system.

In addition, the appearance of the molecular ion peak [M⁺] at m/z 293 which corresponds to its base peak confirmed the proposed structure. GC–MS analysis of 9e approved its structure by indicating the molecular ion peaks [M⁺ + 2] m/z 326, [M⁺ + 1] m/z 325, and [M⁺] m/z 324. The structure of compound 9f was elucidated by the ¹H NMR spectrum due to the appearance of the two ethyl groups, the triplet in the range at δ 1.09–1.19 ppm for two moieties of CH₃ and quartet at δ 3.33–3.54 ppm for the two CH₂ groups. The structures of compounds 9g and 9h were confirmed by their spectral data and their mass spectra where all the resulting data elucidated their structures.

2.2. Fluorescence Measurement

The absorption spectra of the examined coumarin derivatives have been recorded in chloroform. In general, the samples were highly soluble in CHCl₃ and usually possess broad absorption bands in the UV-Visible region. As seen in Figure 4, the absorption spectrum of 9a exhibited a pronounced peak at 364.5 nm. When changing to other derivatives, almost the same spectral profiles were observed with a considerably small shift (1–2 nm). This finding suggests small changes for the substituted electron-withdrawing groups (Br^–, NO₂, and Cl^–) on the optical absorption behavior of the examined materials.

Figure 4.

Steady-state absorption spectra of the examined materials in CHCl₃.

Fluorescence spectra were also studied using an excitation wavelength of 375 nm. From Figure 5, we can notice that the emission spectrum of 9a exhibited a strong emission band with a maximum of 462 nm, with a shoulder at 440 nm. When changing into other coumarin derivatives, we can see clearly a significant decrease in the fluorescence intensity accompanied by little change in the spectral profiles. For example, the emission spectrum of 9c (where the Br atom was substituted on the coumarin ring) exhibited a considerable decrease in the emission intensity with a maximum emission band at 455 nm, which is approximately a blue shift of about 7 nm compared to that of 9a. When changing into 9h, where the coumarin derivative was substituted with two Br atoms, one could see that the emission band at 461 nm was further decreased. This finding was in good agreement with the effect of the Br atom (as heavy atom effect and its electron-withdrawing behavior) on decreasing the emission efficiency and increasing the population of the triplet excited states. Figure 6 presents the illumination of the examined materials with 365 nm light. Table 1 lists the maximum of the absorption and emission bands, in addition to the molar absorption coefficient in CHCl₃.

Figure 5.

Steady-state fluorescence spectra of the examined materials in CHCl₃; λ_ex = 375 nm.

Figure 6.

Illumination of the examined materials with 365 nm light.

Table 1. Maximum Absorption, Emission Bands and Extinction Coefficient (ε) of the Novel Prepared Compounds^a.

compound number	λmax.(abs.) (nm)	shift (nm) compared to 9a	extinction coefficient (ε) M–1 cm–1	λmax.(Flu.) (nm)
9a	364.5(M*), 380(S*)		24,378	462(M), 440(S)
9b	370(M), 384(S), 406(S)	5.5	21,113	455.5(M), 423(S)
9c	371(M), 385(S), 407(S)	6.5	20,864	455.5(M), 424(S), 489(S)
9d	370(M), 350(S), 385(S)	5.5	16,019	451(M), 468.5(S)
9e	366.5(M)	2	22,332	462.5(M), 435(S)
9g	373(M), 353(S), 408(S)	8.5	21,118	460.5(M), 499(S), 438(S)
9h	372.5(M), 355(S), 388(S), 409 (S)	8	24,534	461(M), 491(S), 434(S)

^aM* = main band, S* = shoulder band).

2.3. DFT Calculation

Using the DFT technique, the electronic ground state structures of compounds 9a–h were obtained. The outcomes of the optimizations, which were validated at the B3LYP/6-311G** theoretical level, are shown in Figure 7. Except for 9f, which is noncoplanar, compounds 9a through 9h are coplanar as the dihedral angles were between 0 and 180 (Table 2). Both HOMO and LUMO molecular orbitals, shown in Figure 8, confirm this. While the LUMO was delocalized over the other portions of the molecules, 9b (Cl), 9d (CH₃), 9e (diethyl), 9g (two chlorine atoms), and 9h, the HOMO molecular orbitals were localized over all eight compounds with the exception of 9e (NO₂) (two bromine atoms). Since there was little interaction between the many subsystems in each molecule, this can be seen in the UV spectra. The eight molecules are localized on certain subsystems by both HOMO and LUMO molecular orbitals, as depicted in Figure 8. Table 2 gives a list of the geometrical characteristics of compounds 9a–h in the gaseous form. Figure 7 shows the classification schemes. The eight moieties in compounds 9a–h and eight different bond lengths or angles are contrasted in Table 2. Figure 8 displays the graphical performance of the HOMO and LUMO orbitals for gaseous 9a–h compounds at the B3LYB/6-311G** level of theory. It was important to keep in mind that these molecular orbitals were typically restricted to certain regions of the molecules rather than being expanded to cover the entire molecule. Additionally, Table 3 includes the calculated HOMO and LUMO energy values, as well as the energy difference between HOMO and LUMO (E_g) for the compounds under study. The analyzed description compounds’ computed E_g increases in the order 9f < 9g < 9h < 9e < 9c = 9b < 9d < 9a, indicating that compound 9f has the highest reactivity while compound 9a has the lowest reactivity. The ability to lose electrons, or I.P., was equal to -EHOMO; as a result, the values of I.P. are 9f < 9d < 9a < 9c < 9b < 9h < 9g < 9e. On the other side, the relationship E.A = E_LUMO links E_LUMO to the compound’s electron affinity (E.A). Table 3 demonstrates that the order of electron affinity values is 9f < 9d < 9a < 9c < 9b < 9h < 9g < 9e, indicating that compound 9e has the strongest propensity to receive electrons. An effective indicator of a molecular system’s chemical reactivity, kinetic stability, and biological activity was the energy difference between its border molecular orbitals (HOMO and LUMO). The difference between [E_LUMO – E_HOMO] was what determines the energy gap (E_g).

Figure 7.

Optimized geometry, numbering system, and vector of dipole moment for the studied 9a–h compounds using B3LYP/6-311G**.

Table 2. Selected Geometric Bond Lengths, Bond Angles, and Dihedral Angles of the Optimized 9a–h Using B3LYP/6-311G**.

compound	bond lengths (Å)		bond angles		dihedral angles
9a	C18–O19	1.407	C17–O19–C18	124.412	C13–C14–C18–O20	0.000
	C18–O20	1.192	O19–C18–O20	116.604	N11–C13–C14–C15	0.000
	C18–C14	1.484	O19–C18–C14	115.255	N11–C13–C14–C18	0.000
	C13–C14	1.465	C13–C14–C18	119.026	S12–C13–C14–C18	180.000
	C4–S12	1.748	S12–C13–C14	119.697	S12–C13–C14–C15	0.000
	C13–N11	1.290	N11–C13–C14	125.967	C4–S12–C13–C14	180.000
	C3–C4	1.414	N11–C13–S12	38.982	C6–C4–S12–C13	180.000
	C2–C3	1.401	C3–N11–C13	112.385	C2–C3–N11–C13	180.000
9b	C18–O19	1.408	C17–O19–C18	124.351	C13–C14–C18–O20	0.000
	C18–O20	1.191	O19–C18–O20	121.330	N11–C13–C14–C15	180.000
	C18–C14	1.485	O19–C18–C14	115.216	N11–C13–C14–C18	0.000
	C13–C14	1.466	C13–C14–C18	118.955	S12–C13–C14–C18	180.000
	C4–S12	1.748	S12–C13–C14	119.763	S12–C13–C14–C15	0.000
	C13–N11	1.290	N11–C13–C14	125.829	C4–S12–C13–C14	180.000
	C3–C4	1.414	N11–C13–S12	114.409	C6–C4–S12–C13	180.000
	C2–C3	1.401	C3–N11–C13	112.339	C2–C3–N11–C13	180.000
9c	C18–O19	1.409	C17–O19–C18	124.366	C13–C14–C18–O20	0.000
	C18–O20	1.192	O19–C18–O20	116.572	N11–C13–C14–C15	180.000
	C18–C14	1.484	O19–C18–C14	115.207	N11–C13–C14–C18	0.000
	C13–C14	1.466	C13–C14–C18	118.991	S12–C13–C14–C18	180.000
	C4–S12	1.747	S12–C13–C14	119.731	S12–C13–C14–C15	0.000
	C13–N11	1.290	N11–C13–C14	125.852	C4–S12–C13–C14	180.000
	C3–C4	1.414	N11–C13–S12	114.417	C6–C4–S12–C13	180.000
	C2–C3	1.4015	C3–N11–C13	112.335	C2–C3–N11–C13	180.000
9d	C18–O19	1.405	C17–O19–C18	124.329	C13–C14–C18–O20	0.000
	C18–O20	1.193	O19–C18–O20	116.664	N11–C13–C14–C15	180.000
	C18–C14	1.484	O19–C18–C14	115.265	N11–C13–C14–C18	0.000
	C13–C14	1.465	C13–C14–C18	119.030	S12–C13–C14–C18	180.000
	C4–S12	1.748	S12–C13–C14	119.691	S12–C13–C14–C15	0.000
	C13–N11	1.290	N11–C13–C14	125.993	C4–S12–C13–C14	180.000
	C3–C4	1.414	N11–C13–S12	114.316	C6–C4–S12–C13	180.000
	C2–C3	1.401	C3–N11–C13	112.403	C2–C3–N11–C13	180.000
9e	C18–O19	1.417	C17–O19–C18	124.476	C13–C14–C18–O20	0.000
	C18–O20	1.189	O19–C18–O20	116.236	N11–C13–C14–C15	180
	C18–C14	1.484	O19–C18–C14	115.154	N11–C13–C14–C18	0.000
	C13–C14	1.4659	C13–C14–C18	118.882	S12–C13–C14–C18	180
	C4–S12	1.747	S12–C13–C14	119.863	S12–C13–C14–C15	0.000
	C13–N11	1.291	N11–C13–C14	125.602	C4–S12–C13–C14	180.000
	C3–C4	1.415	N11–C13–S12	114.535	C6–C4–S12–C13	180.000
	C2–C3	1.402	C3–N11–C13	112.257	C2–C3–N11–C13	180.000
9f	C18–O19	1.412	C17–O19–C18	124.330	C13–C14–C18–O20	2.813
	C18–O20	1.195	O19–C18–O20	116.547	N11–C13–C14–C15	––148.804
	C18–C14	1.473	O19–C18–C14	115.271	N11–C13–C14–C18	31.707
	C13–C14	1.464	C13–C14–C18	118.576	S12–C13–C14–C18	–148.749
	C4–S12	1.749	S12–C13–C14	119.403	S12–C13–C14–C15	30.740
	C13–N11	1.290	N11–C13–C14	125.862	C4–S12–C13–C14	––178.502
	C3–C4	1.415	N11–C13–S12	114.734	C6–C4–S12–C13	–179.552
	C2–C3	1.401	C3–N11–C13	112.047	C2–C3–N11–C13	157.680
9g	C18–O19	1.414	C17–O19–C18	124.404	C13–C14–C18–O20	0.000
	C18–O20	1.189	O19–C18–O20	116.426	N11–C13–C14–C15	180.000
	C18–C14	1.483	O19–C18–C14	115.021	N11–C13–C14–C18	0.000
	C13–C14	1.466	C13–C14–C18	118.934	S12–C13–C14–C18	180.000
	C4–S12	1.747	S12–C13–C14	119.856	S12–C13–C14–C15	0.000
	C13–N11	1.290	N11–C13–C14	125.670	C4–S12–C13–C14	180.000
	C3–C4	1.415	N11–C13–S12	114.475	C6–C4–S12–C13	180.000
	C2––C3	1.402	C3–N11–C13	112.307	C2–C3–N11–C13	180.000
9h	C18–O19	1.412	C17––O19–C18	124.530	C13–C14–C18–O20	0.000
	C18–O20	1.190	O19–C18–O20	116.481	N11–C13–C14–C15	180.000
	C18–C14	1.484	O19–C18–C14	115.078	N11–C13–C14–C18	0.000
	C13–C14	1.465	C13–C14–C18	118.966	S12–C13–C14–C18	180.000
	C4–S12	1.748	S12–C13–C14	119.820	S12–C13–C14–C15	0.000
	C13–N11	1.290	N11–C13–C14	125.716	C4–S12–C13–C14	180.000
	C3–C4	1.414	N11–C13–S12	114.463	C6–C4–S12–C13	180.000
	C2–C3	1.402	C3–N11–C13	112.308	C2–C3–N11–C13	180.000

Figure 8.

HOMO and LUMO charge density maps of the studied 9a–h compounds using B3LYP/6-311G**.

Table 3. Total Energy, the Energy of HOMO and LUMO, Energy Gap, Ionization Energy (I, eV), Electron Affinity (A, eV), Absolute Electronegativities, (χ, eV), Absolute Hardness (η, eV), Global Softness (S, eV^–1) Chemical Potential (V, eV^–1) of 9a–h Compounds Using B3LYP/6-311G**.

parameter	9a	9b	9c	9d	9e	9f	9g	9h
ET, a.u.	–1218.75	–1678.37	–3792.29	–1258.075	–1423.30	–1430.71	–2137.98	–6365.82
EHOMO, a.u.	–0.2327	–0.2382	–0.2377	–0.2305	–0.2466	–0.2086	–0.2431	–0.2422
ELUMO, a.u.	–0.0988	–0.1068	–0.1063	–0.0971	–0.1154	–0.0803	–0.1127	–0.1116
Eg, eV	3.6425	3.5764	3.5759	3.6300	3.5685	3.4937	3.5481	3.5541
I, eV	6.3321	6.4821	6.4693	6.2734	6.7096	5.6774	6.6143	6.5898
A, eV	2.6896	2.9057	2.8934	2.6433	3.1410	2.1837	3.0662	3.0357
χ, eV	4.5109	4.6939	4.6813	4.4583	4.9253	3.9306	4.8403	4.8128
η, eV	1.9769	1.7882	1.7879	1.8150	1.7843	1.7468	1.7741	1.7771
S, eV	0.2745	0.2796	0.2797	0.2755	0.2802	0.2862	0.2818	0.2814
V, eV	–4.5109	–4.6939	–4.6813	–4.4583	–4.9253	–3.9306	–4.8403	–4.8128

The examined compounds’ calculated E_g rises in the following order: 9f < 9g < 9h < 9e < 9c = 9b < 9d < 9a, indicating that 9f has higher reactivity. In contrast to the other compounds, 9f has a lower E_g value, which suggests reduced stability and a strong impact from intramolecular charge transfer (ICT), causing the absorption spectra to shift to red. The chemical potential(V), electronegativity (χ), and chemical hardness (η) were other key parameters that can be estimated using E_LUMO and E_HOMO data. The previous formulas were used to calculate this parameter.²⁵ Additionally, molecule 9e was the one that can draw electrons from other compounds since compound 9e has a higher value than the other compounds (Table 3). Contrarily, compound 9a has a high value compared to the other compounds, indicating that it was exceedingly difficult for compound 9a to free the electrons, whereas the other compounds were excellent candidates for providing electrons to a different acceptor molecule (Table 3). When a molecule has a strong dipole moment, it typically exhibits a better asymmetry in the distribution of electronic charge and was more responsive to changes in its electronic molecular structure and electronic properties in the presence of an external electric field. Table 4 demonstrates that compound 9f has a greater dipole moment (μ) than compounds 9a, 9b, 9c, 9d, 9e, 9g, and 9h. As a result, this substance is more reactive.²⁵ As a result, molecule 9f is regarded as being tougher, more stable, and less reactive than the other compounds.²⁶

Table 4. Calculated Total Static Dipole Moment (μ), the Mean Polarizability ⟨α⟩, Anisotropy of the Polarizability Δα and the First-Order Hyperpolarizability ⟨β⟩ Configuration for the Studied 9a–h Compounds Using B3LYP/6-311G**.

property	urea	9a	9b	9c	9d	9e	9f	9g	9h
μ, D	1.3197	4.81	3.00	3.11	5.33	2.80	7.18	4.41	4.25
αxx, a.u.		–114.6496	–109.8714	–120.4715	–100.745	–139.0386	–104.3399	–140.4615	–147.793
αyy		–95.3368	–141.0058	–141.4887	–122.2247	–144.1432	–154.9419	–136.4922	–146.6
αzz		–125.5484	–137.3895	–143.0998	–131.8357	–138.621	–156.9323	–149.1995	–160.6092
αxy		14.6795	–7.0887	–14.981	–15.1173	23.784	8.2945	–13.7486	15.6319
αxz		0	0	0	0	0.0002	–1.4437	0	0
αyz		0	0	0	0	–0.0001	–2.1621	0	0
⟨α⟩ esu		–1.6575 × 10–23	–1.9180 × 10–23	–2.001 × 10–23	–1.7527 × 10–23	–2.0837 × 10–23	–2.0561 × 10–23	–2.1052 × 10–23	–2.2477 × 10–23
Δα, esu		3.9273 × 10–24	4.3709 × 10–24	3.24074 × 10–24	4.0861 × 10–24	0.78927 × 10–24	7.6510 × 10–24	1.6688 × 10–24	1.9937 × 10–24
βxxx		24.6047	69.5719	–44.8565	–32.8333	–286.4647	127.9035	–41.8301	–97.9189
βxxy		–2.4339	54.5691	34.9338	–1.9847	88.8396	6.139	14.6273	29.4554
βxyy		20.1024	23.1379	50.4007	–12.7835	–13.0514	21.4025	–36.7486	–34.7836
βyyy		19.7427	–28.4043	93.5795	–20.3349	–21.3484	–20.5929	96.3717	–77.2509
βxxz		0	0	0	0	0.0107	–15.1645	0	0
βxyz		0	0	0	0	–0.0057	18.4469	0	0
βyyz		0	0	0	0	–0.0024	–5.7016	0	0
βxzz		–8.0958	–16.1166	–35.8958	–3.2642	35.4651	16.4841	21.2778	–80.6862
βyzz		9.4774	5.8001	57.6008	12.3413	3.3721	9.0851	–13.9218	–59.2723
βzzz		0	0	0	0	–0.0018	4.4671	0	0
⟨β⟩, esu	0.1947 × 10–30	0.5115 × 10–30	0.7170 × 10–30	1.6291 × 10–30	0.43101 × 10–30	2.3619 × 10–30	1.44001 × 10–30	0.9739 × 10–30	2.0626 × 10–30

2.4. Nonlinear Optical Properties (NLO)

In determining the size and direction of its moment, consideration is also given to how the atomic charges propagate within molecule compounds. For the investigated 9a–h compounds as well as urea, the mean polarizability, anisotropy of the polarizability, dipole moment, and first-order hyperpolarizability were examined using the same level of analysis. The results are shown in Table 4. The experimental approximations of urea were also included in the table. Compounds 9a–h has estimated dipole moments of 4.81, 3.09, 3.11, 5.33, 2.80, 7.18, 4.41, and 4.25 D, respectively. All compounds have values higher than urea, with compound 9f having a higher dipole moment value than the other seven compounds. Atomic units (au) were used to describe the polarizabilities and first-order hyperpolarizabilities; the computed values have been converted into electrostatic units (esu) using correction factors of 0.1482 × 10^–24 esu for α and 8.6393 × 10^–33 esu for β. In NLO investigations, urea was a common prototype. Since there were no experimental standards for the NLO characteristics of the tested chemicals, urea²⁷ was used as the study’s reference. One of the main features of an NLO system was the extent of compounds 9a–h polarizability estimates range from 0.79 to 7.65 × 10^–24 (esu). The obtained values for compounds 9e and 9f were in descending order. The theoretically calculated analyses of β for the compounds reveal that compound 9e was 12 times more potent than urea, while those for compounds 9h, 9c, 9f, 9g, 9b, 9a, and 9d were, respectively, 11, 8, 7, 5, 4, 3, and 2 times more potent. All of the investigated compounds had greater first-order hyperpolarizability and polarizability values when compared to urea as a reference material, indicating that they were anticipated to be suitable candidates for NLO elements.

2.5. Molecular Electrostatic Potential Surfaces (MEP)

The MEP determines whether a proton positioned at any location surrounding the molecule finds the area of the molecule to be attractive or repulsive.²⁸ To optimize the geometry of the MEP surfaces, the DFT method (B3LYP) and basis set (6-311G**) were used, as shown in Figure 9. According to the color scheme for the MEP surface, red indicates an electron-rich, partially negative charge, blue an electron-deficient, partially positive charge, light blue an electron-deficient, slightly positive region, yellow an electron-rich, slightly positive region, and green a neutral (zero potential) region.²⁹ The 9a–h MEP plots for the compounds under investigation are distinguished by a positive zone (blue), which was situated at the corners. The N, O, Cl, Br, and S atoms of the whole compound moiety of 9a–h are what gives the region a negative charge. The regions with the negative potential were over the electronegative atoms (N, O, Cl, Br, and S atoms), and regions with negative electrostatic potential were typically linked to the lone pair of electronegative atoms, as can be determined from MEP of the examined compounds, as shown in Figure 9. While the largest positive regions were over the hydrogen atoms, the primary negative potentials were on the whole compounds. According to Figure 9, the carbon atoms appear to have no potential.

Figure 9.

Molecular electrostatic potential (A) and contours electrostatic potential (B) surfaces of the studied 9a–h compounds using B3LYP/6-311G**.

2.6. TD-DFT Studies

In order to clarify the creation of electronic spectra, TD-DFT/PCM computations were carried out at the same level of theory as B3LYP/6-31G(d,p) utilizing the polarizable continuous solvation method, PCM, and TD-DFT/PCM. In PCM, the solvent (ethanol) is referred to as a material with no structure, while the solute (water) remains inside the cavity. The PCM approach uses the solvent’s dielectric constant and other macroscopic properties to show it. The model describing the molecular structures of the molecules 9a through 9h was authorized for TD-DFT calculations. Four bands at 373, 347, 281, and 257 nm, which correspond to HOMO → LUMO, HOMO–1 → LUMO, HOMO–4 → LUMO, and HOMO → LUMO+1 in that order, make up the theoretical spectrum of 9a. The transition at 373 nm is due to a 67.76% contribution from the HOMO → LUMO, (n-π*) transition,³⁰ whereas the second excitation band at 347 nm was due to a 67.42% contribution, HOMO–1 → LUMO, (n-π*) transition,³¹ the third excitation band at 281 nm was corresponding to 65.44% contribution, HOMO–4 → LUMO, the fourth band at 257 nm, was corresponding to 60.34% contribution, HOMO → LUMO+1, (π–π*) transition. Therefore, the only transition states that were admissible in ethanol with effective oscillator strengths (0.09–0.70) are S0 → S1, S0 → S2, S0 → S5, and S0 → S2 correspondingly. In Figure 10, it is explained how compound 9a’s FMO orbitals and transfer of electron density affect the electronic transitions. Compound 9b’s TD-DFT spectrum (Figure 10) shows six bands at wavelengths of 381, 357, 334, 280, 257, and 238 nm that are caused by the transitions HOMO → LUMO, HOMO–1 → LUMO, HOMO–2 → LUMO, HOMO–4 → LUMO, HOMO–5 → LUMO, and HOMO → LUMO+2. While the second excitation band at 357 nm corresponds to a 66.67% contribution from the HOMO–1 → LUMO, (n−π*) transition,³⁰ the transition at 381 nm matches a 67.05% contribution from the HOMO → LUMO (n−π*) transition.³⁰ The fourth band at 280 nm relates to 63.75% contribution, HOMO–4 → LUMO, (π-π*) transition, and the third excitation band at 334 nm was connected to 68.55% contribution, HOMO–2 → LUMO. The HOMO–5 → LUMO, (π–π*) transition is credited with 65.11% of the contribution to the fifth band at 257 nm. The transition HOMO → LUMO+2, (π–π*) transition was identical to 57.92% for the sixth one at 238 nm. The only permissible transition states with large oscillator strengths (0.07–0.65) were the vertical excitation energy states S0 → S1, S0 → S2, S0 → S3, S0 → S5, S0 → S6, and S0 → S3, respectively. Five bands at 382, 358, 338, 280, and 257 nm, which were correspond to the HOMO → LUMO, HOMO–1 → LUMO, HOMO–2 → LUMO, HOMO–4 → LUMO, and HOMO → LUMO+1 in that sequence, characterize the theoretical spectrum of chemical 9c. The transition at 382 nm was due to a 67.40% contribution from the HOMO → LUMO (n−π*) transition,³⁰ whereas the second excitation band at 358 nm was due to a 66.71% contribution, HOMO–1 → LUMO, (n−π*) transition,³⁰ the third excitation band at 338 nm was corresponding to a 67.98% contribution, HOMO–2 → LUMO, (π–π*) transition, The fourth transition at 280 nm matches a contribution of 63.75%, HOMO–4 → LUMO, (π–π*) transition and the fifth transition at 257 nm matches a contribution of 56.74%, HOMO → LUMO+1, (π–π*) transition. The only transition states that are appropriate and have effective oscillator strengths (0.08–0.66) were the vertical excitation energy states S0 → S1, S0 → S2, S0 → S3, S0 → S5, and S0 → S2. In Figure 11, the orbitals of the FMO and the transfer of the electron density of compound 9c, which are relevant to the electronic transitions, are explained. Five bands at 376, 336, 282, 257, and 234 nm, which correspond to the HOMO → LUMO, HOMO–2 → LUMO, HOMO–4 → LUMO, HOMO → LUMO+1, and HOMO–2 → LUMO+1 in that sequence, characterize the theoretical spectrum of compound 9d. The transition at 376 nm was due to a 68.28% contribution from the HOMO → LUMO (n−π*) transition,³⁰ whereas the second excitation band at 336 nm was due to a 65.01% contribution, HOMO–2 → LUMO, (π–π*) transition, the third excitation band at 282 nm, was corresponding to 65.36% contribution, HOMO–4 → LUMO (π–π*) transition. The fourth band at 257 nm corresponds to a contribution of 60.20%, HOMO → LUMO+1, (π −π *) transition, and the fifth band at 234 nm to a contribution of 48.37%, HOMO–2 → LUMO+1, (π–π *) transition. The only suitable transition states with practical oscillator strengths (0.08–0.721) were the vertical excitation energy states S0 → S1, S0 → S3, S0 → S5, S0 → S2, and S0 → S4, respectively. Figure 10 explains how compound 9d FMO orbitals and transfer of electron density affect the electronic transitions. Three bands at 383, 364, and 289 nm, which stand for HOMO → LUMO, HOMO–2 → LUMO, and HOMO–2 → LUMO+1, respectively, define the theoretical spectrum of 9e. The HOMO → LUMO (n−π *) transition contributes 63.42% to the transition at 383 nm, the HOMO–2 → LUMO (n−π*) transition contributes 58.48% to the second excitation band at 364 nm, and the HOMO–2 → LUMO+1 (π–π*) transition contributes 64.71% to the third excitation band at 289 nm. Therefore, the only transition states that were suitable with effective oscillator strengths (0.21–0.48) in ethanol were S0 → S1, S0 → S3, and S0 → S4, respectively. Figure 10 shows how compound 9e’s FMO orbitals and transfer of electron density affect the electronic transitions. Compound 9f’s TD-DFT spectrum (Figure 10) shows two bands at 408 and 400 nm because of the transitions HOMO → LUMO and HOMO–2 → LUMO. While the second excitation band at 400 nm corresponds to a 15.25% contribution from the HOMO–2 → LUMO, (n-π*) transition,³⁰ the transition at 408 nm matches a 68.06% contribution from HOMO → LUMO (n−π*) transition.³⁰ The only allowed transition states with large oscillator strengths (0.12–1.05) are the vertical excitation energy states S0 → S1 and S0 → S3, respectively. Five bands at 386, 366, 287, 261, and 241 nm, which correspond to HOMO → LUMO, HOMO–1 → LUMO, HOMO–4 → LUMO, HOMO → LUMO+1, and HOMO → LUMO+2, make up the theoretical spectrum of compound 9g. The transition at 386 nanometers corresponds to a 64.53% contribution from the HOMO → LUMO (n-π*) transition,³⁰ whereas the second excitation band at 366 nm is due to a 64.31% contribution, HOMO–1 → LUMO, (n−π*) transition,³⁰ the third excitation band at 287 nm, was corresponding to a 66.54% contribution, HOMO–4 → LUMO, (π–π*) transition. The fourth transition at 261 nm corresponds to 61.93% contribution, HOMO → LUMO+1, (π–π*) transition, and the fifth transition at 241 nm matches to 53.96% contribution, HOMO → LUMO+2, (π–π*) transition. The only acceptable transition states with practical oscillator strengths (0.07–0.56) were the vertical excitation energy states S0 → S1, S0 → S2, S0 → S5, S0 → S2, and S0 → S3, respectively. Figure 10 shows how the compound 9g’s FMO orbitals and transfer of electron density affect the electronic transitions. Four bands at wavelengths 386, 350, 294, and 264 nm that correspond to HOMO → LUMO, HOMO–2 → LUMO, HOMO–3 → LUMO, and HOMO → LUMO+1 make up the theoretical spectrum of compound 9h. The transition at 386 nm corresponds to a 65.13% contribution from the HOMO → LUMO, (n−π*) transition,³⁰ whereas the second excitation band at 350 nm was due to a 67.19% contribution, HOMO–2 → LUMO, (π–π*) transition,³⁰ the third excitation band at 294 nanometers was corresponding to a 68.05% contribution, HOMO–3 → LUMO (π–π*) transition and the fourth transition, HOMO → LUMO+1, (π–π*) transition, at 264 nm, amounts to 58.95% contribution. The only appropriate transition stages with useful oscillator strengths (0.08–0.59) are the vertical excitation energy states S0 → S1, S0 → S3, S0 → S4, and S0 → S2, respectively. Figure 10 shows how the compound 9h’s FMO orbitals and transfer of electron density affect the electronic transitions. In addition, Table 5 explains the calculated values for the functional groups present in the compounds and compared their values with the observed values. All the theoretical values were in agreement with the observed values.

Figure 10.

Frontier molecular orbitals involved in the electronic absorption transitions of the compounds 9a–h calculated at TD-B3LYP/6-31G(d,p) level of theory.

Figure 11.

2D and 3D plots of the interaction between the ligands 9a–h with the active site of the receptor of COVID-19 (PDB ID: 5epw).

Table 5. Calculated and Observed Values for the IR Spectral Data of All the Prepared Compounds 9a–h.

compound number	IR values
9a	IR (KBr, cm–1): υ 3048, 3028, 3170a (CH-aromatic), 1715, 1677a (C=O), 1557, 1588a (C=N) and 1602, 1479, 1615a, 1479a (C=C).
9b	IR (KBr, cm–1): υ 3050, 3030, 3020a (CH-aromatic), 1723, 1676a (C=O), 1553, 1586a (C=N) and 1605, 1476, 1612a, 1479a (C=C).
9c	IR (KBr, cm–1): υ 3048, 3201a (CH-aromatic), 1724, 1675a (C=O), 1552, 1586a (C=N) and 1605, 1476, 1608a, 1479a (C=C).
9d	IR (KBr, cm–1): υ 3062, 3057a (CH-aromatic), 2918, (CH3), 1710, 1681a (C=O), 1582, 1588a (C=N) and 1619, 1485, 1624a, 1498a (C=C).
9e	IR (KBr, cm–1): υ 3058, 3204a (CH-aromatic), 1731, 1706a (C=O), 1529, 1525a (C=N) and 1609, 1482, 1616a, 1471a (C=C).
9f	IR (KBr, cm–1): υ 3050, 3061a, (CH-aromatic), 1701, 1682a (C=O), 1514, 1518a (C=N) and 1621, 1411, 1640a, 1402a (C=C).
9g	IR (KBr, cm–1): υ 3075, 3203a (CH-aromatic), 1730, 1675a (C=O), 1546, 1584a (C=N) and 1601, 1475, 1603a, 1494a (C=C).
9h	IR (KBr, cm–1): υ 3058, 3203a (CH-aromatic), 1732, 1673a (C=O), 1546, 1583a (C=N) and 1603, 1471, 1592a, 1487a (C=C).

^aTheoretical values.

2.7. Molecular Docking and Antiviral Activity

Molecular docking was essential for the creation of computer medications. The MOE2019 program was used to determine the likely modes of binding for the Nl63 human corona virus’s most active site.³¹ The major structural element of the vision that was involved in viral replication, assembly, and immunological control was known as the nucleocapsid (N) protein (PDB ID: 5epw). It was essential for the viral life cycle because they prevent viral infection by interfering with N protein’s typical oligomerization or RNA-binding capabilities, small anti-corona virus medicines were increasingly interested in the binding sites on N protein. Before the necessary PDBQT files could be made, water molecules linked to DNA base pairs were taken out and polar hydrogen atoms were supplied in place of them to make proteins. The energy of the target structures was decreased before docking. For docking runs, only the docked ligands’ lowest energy conformers, as well as the default settings, were permitted. Molecular docking was used to simulate the identification of molecules. Molecular docking aims to achieve ideal confirmation for both the drug (ligand) and the protein in order to lower the free energy of the entire system (ligand). The pair-wise interaction energies of complicated proteins or ligands were taken into account in this study to simulate the actual docking process. Rotatable bonds were first described by combining nonpolar hydrogen atoms.

Figure 11 displays both the reported 2D plots and a three-dimensional docked image of the ligands (9a–h) with 5epw. Two-dimensional maps of the linkages in the ligand–protein complexes for the 9a–h are given in Figure 11, with dashed lines denoting hydrogen bonds. The study simulates the actual docking cycle, and Table 6 contains the energy interaction between the ligand and protein. The binding surfaces of the chemicals under study and their complexes with proteins were found to be predominately composed of pi–pi, pi–hydrogen, and hydrogen donor/acceptor bonds. It is important to remember that negative binding affinities of greater than −5.0 indicate that these events were highly likely to take place. The ligands (9a–h) bind to the protein of the 5epw by hydrogen bonds and pi–hydrogen linkages. The pi–H-donor or pi–pi bonds between the ligands and receptors were generated by the free ligands with the amino acid residues and have the following distances: 3.19–4.4; −0.0–4.3 kcal/mol. The moderate binding energy score of unbound ligands (S = −5.22 to 6.78 kcal/mol) is notable. We might also suggest a connection between the 5epw receptor and the receptors for the ligands (9a–h) based on those discoveries. By increasing the energy of ligands (9a–h) interactions, this partnership might induce programmed cell death in viral cells. It appears that the binding energy of 9a–h decreased when the data was analyzed. This shows that the binding energy of 9a–h is decreased during the corona viral mutation. The most popular technique for verifying the binding affinity of 9a–h uses binding energies. The mutation lowers the ligands’ binding energy to the receptor, increasing their propensity for binding to the receptor. The accessibility of multiple active hydrogen bonding sites that were open is one characteristic of the ligands and their complexes. Thanks to this research, which also contributes to the production of other inhibitory chemicals, they may now actively hinder protein binding. The results demonstrate that the corona virus’ mutant 5epw-Viral protein was successfully inhibited by the ligands (9a–h).

Table 6. Calculations of the Docking Interaction Data between the Compounds 9a–h with the COVID-19 Receptor’s Active Site (PDB ID: 5epw).

system	binding score (kcal/mol)	receptor	interaction	distance (Å)	E (kcal/mol)
9a-5epw
6-ring		N ILE 304	pi–H	4.12	–2.2
6-ring	–5.22	CD1 ILE 304	pi–H	3.98	–0.8
6-ring		6-ring TRP 236	pi–pi	3.88	–0.0
9b-5epw
O 28	–5.50	NH2 ARG 253	H-acceptor	3.44	–1.8
6-ring		6-ring PHE 250	pi–pi	3.96	–0.0
9c-5epw
6-ring	–5.32	N ILE 304	pi–H	4.17	–1.7
5-ring		CB ILE 304	pi–H	4.21	–1.2
9d-5epw
6-ring	–5.33	N ILE 304	pi–H	4.39	–1.7
6-ring		CD1 ILE 304	pi–H	4.44	–0.7
9e-5epw
O 16		NH1 ARG 253	H-acceptor	3.19	–1.5
O 16	–5.83	NH2 ARG 253	H-acceptor	2.86	–4.3
6-ring		6-ring PHE 250	pi–pi	3.94	–0.0
9f-5epw
6-ring	–6.78	CG ARG 235	pi–H	4.25	–0.7
6-ring		6-ring PHE 250	pi–pi	3.88	–0.0
9g-5epw
6-ring		N ILE 304	pi–H	4.31	–1.0
6-ring	–5.47	CD1 ILE 304	pi–H	3.86	–1.0
6-ring		6-ring TRP 236	pi–pi	3.75	–0.0
9h-5epw
6-ring		N ILE 304	pi–H	4.44	–1.1
6-ring		CB ILE 304	pi–H	4.35	–0.6
6-ring	–5.54	CD1 ILE 304	pi–H	3.89	–1.0
6-ring		5-ring TRP 236	pi–pi	3.96	–0.0
6-ring		6-ring TRP 236	pi–pi	3.76	–0.0

In the order 9h > 9a = 9e = 9g > 9b = 9c = 9d = 9f, the ligands 9b–9d and 9f make two bonds, 9a, 9e, and 9g create three bonds, and 9h forms five bonds. The possibility of creating novel COVID-19 antiviral medications was supported by these facts. The chemicals under study have modest (η) values, which demonstrate that they can transfer charge to COVID-19 (PDB ID: 5-epw), as shown by the theoretical study results. As a result, the compounds’ increased reactivity toward COVID-19 (PDB ID: 5-epw) was demonstrated by their higher global electrophilicity index values and lower global nucleophilicity index values (5-epw).

3. Conclusions

The present study explained the novel synthesis of benzothiazolyl-coumarin derivatives 9a–h. The structures of the later products were confirmed by spectroscopic data and mass spectrometry. In addition, the X-ray analysis was measured for compounds 9a and 9d, which elucidated the structures of all the prepared compounds. The molecular structures of the ligands 9a–h were optimized using the basis set B3LYP/6-311G**. The compounds have pronounced NLO properties and a small HOMO–LUMO energy gap, making them easily polarizable. The polarizabilities and hyperpolarizabilities of the complexes indicate that they are strong candidates for NLO material. The respected electronic transition was investigated using the TD-DFT/PCM approach B3LYP, which uses time-dependent density functional computations. The ligands 9a–h with the COVID-19 viral receptor (PDB ID: 5epw) underwent molecular docking and binding energy investigations, which demonstrated that they effectively inhibit COVID-19.

4. Experimental Section

Uncorrected melting points were measured on a Gallenkamp melting point apparatus. By using an FTIR plus (460) IR spectrophotometer (Shimadzu, Japan), the IR spectra (KBr discs) were recorded. Also, by using a BRUKER-400 spectrometer operating at 400 MHz (for ¹H) and 100 MHz (for ¹³C), in DMSO-d₆ (ppm) with Si(CH₃)₄ as an internal standard at Faculty of Pharmacy, Ain Shams University, Egypt. The mass spectra were run in the Microanalytical Center at Cairo University. In commercially available grade purity, the reagents and solvents were obtained. The 2-hydroxybenzaldehyde derivatives 6a–h were commercially purchased from Alfa Aesar, Acros Organics, and Sigma-Aldrich Companies.

4.1. Synthetic Methods

Compounds 3, 4, and 5 were prepared according to our literature procedures.^17,19,32

4.1.1. General Method for the Synthesis of 3-(Benzo[d]thiazol-2-yl)-2H-chromen-2-one Derivatives (9a–h)

To a solution of compound 5 (3.11 g, 0.01 mol), salicyaldehyde 6a (1.22 g, 0.01 mol), 5-chloro salicylaldehyde 6b (1.56 g, 0.01 mol), 5-bromo salicylaldehyde 6c (2.01 g, 0.01 mol), 5-methyl salicylaldehyde 6d (1.36 g, 0.01 mol), 5-nitro salicylaldehyde 6e (1.67 g, 0.01 mol), 4-(diethylamino)-2-hydroxybenzaldehyde 6f (1.93 g, 0.01 mol), 3,5-dichloro salicylaldehyde 6g (1.91 g, 0.01 mol), and 3,5-dibromo salicylaldehyde 6h (2.79 g, 0.01 mol) in ethanol (30 mL) and ammonium acetate (0.77 g, 0.01 mol) were added. The reaction mixture refluxed for about 3 h, and then the resultant precipitates were collected by filtration and recrystallized from ethanol.

4.1.1.1. 3-(Benzo[d]thiazol-2-yl)-2H-chromen-2-one (9a)

Pale canary yellow crystals; yield: 94% (2.63 g); m.p. 228–230 °C; IR (KBr, cm^–1): υ 3048, 3028 (CH-aromatic), 1715 (C=O), 1557 (C=N) and 1602, 1479 (C=C). ¹H NMR (400 MHz DMSO-d₆) δ: 7.46–8.21 (m, 8H, 2C₆H₄), 9.26 (s, 1H, CH-pyran ring). ¹³C NMR (100 MHz, DMSO-d₆) δ: 116.7, 119.2, 119.8, 122.7, 123.0, 125.7, 125.9, 127.2, 130.7, 134.2, 136.4, 142.5, 152.4, 153.8 (aromatic carbons, pyran ring), 159.9 (C=N), and 160.1 (C=O). MS (EI): m/z (%) 281 [M⁺ + 2] (0.44), 280 [M⁺ + 1] (0.96), 279 [M⁺] (4.06), 278 [M⁺ – 1] (0.12), 277 [M⁺ – 2] (0.17), and 105 (100.00). Anal. calcd for C₁₆H₉NO₂S (279.31): C% 68.80; H% 3.25; N% 5.01; S% 11.48. Found: C% 68.70; H% 3.33; N% 5.12; S% 11.60.

4.1.1.2. 3-(Benzo[d]thiazol-2-yl)-6-chloro-2H-chromen-2-one (9b)

Faint yellow crystals; yield: 93% (2.92 g); m.p. 246–248 °C; IR (KBr, cm^–1): υ 3050, 3030 (CH-aromatic), 1723 (C=O), 1553 (C=N) and 1605, 1476 (C=C). ¹H NMR (400 MHz DMSO-d₆) δ: 7.48–8.20 (m, 7H, C₆H₄, C₆H₃), 9.20 (s, 1H, CH-pyran ring). ¹³C NMR (100 MHz, DMSO-d₆) δ: 118.7, 120.7, 121.0, 122.8, 123.1, 126.1, 127.3, 129.4, 129.5, 133.5, 136.5, 141.1, 152.4, 152.5 (aromatic carbons, pyran ring), 159.5 (C=N), and 159.8 (C=O). MS (EI): m/z (%) 315 [M⁺ + 2] (38.41), 314 [M⁺ + 1] (21.44), 313 [M⁺] (100.00), 312 [M⁺ – 1] (4.31), and 311 [M⁺ – 2] (0.26). Anal. calcd for C₁₆H₈ClNO₂S (313.76): C% 61.25; H% 2.57; N% 4.46; S% 10.22. Found: C% 61.50; H% 2.40; N% 4.20; S% 10.50.

4.1.1.3. 3-(Benzo[d]thiazol-2-yl)-6-bromo-2H-chromen-2-one (9c)

Faint yellow crystals; yield: 92% (3.30 g); m.p. 271–273 °C; IR (KBr, cm^–1): υ 3048, (CH-aromatic), 1724 (C=O), 1552 (C=N), and 1605, 1476 (C=C). ¹H NMR (400 MHz DMSO-d₆) δ: 7.48–8.32 (m, 7H, C₆H₄, C₆H₃), 9.19 (s, 1H, CH-pyran ring). ¹³C NMR (100 MHz, DMSO-d₆) δ: 117.3, 119.0, 121.0, 121.2, 122.8, 123.2, 126.2, 127.3, 132.5, 136.3, 136.5, 141.1, 152.4, 152.9 (aromatic carbons, pyran ring), 159.5 (C=N), and 159.9 (C=O). MS (EI): m/z (%) 360 [M⁺ + 2] (20.86), 359 [M⁺ + 1] (100.00), 358 [M⁺] (22.24), 357 [M⁺ – 1] (95.08), and 356 [M⁺ – 2] (2.87). Anal. calcd for C₁₆H₈BrNO₂S (358.21): C% 53.65; H% 2.25; N% 3.91; S% 8.95. Found: C% 53.77; H% 2.20; N% 3.70; S% 9.10.

4.1.1.4. 3-(Benzo[d]thiazol-2-yl)-6-methyl-2H-chromen-2-one (9d)

Faint yellow crystals; yield: 96% (2.82 g); m.p. 222–224 °C; IR (KBr, cm^–1): υ 3062, (CH-aromatic), 2918 (CH₃), 1710 (C=O), 1582 (C=N) and 1619, 1485 (C=C). ¹H NMR (400 MHz DMSO-d₆) δ: 2.40 (s, 3H, CH₃), 7.42–8.18 (m, 7H, C₆H₄, C₆H₃), 9.19 (s, 1H, CH-pyran ring). ¹³C NMR (100 MHz, DMSO-d₆) δ: 20.8 (CH₃), 116.5, 119.0, 120.0, 122.7, 123.0, 124.5, 125.9, 127.2, 128.6, 130.2, 135.2, 136.4, 142.4, 152.4 (benzene carbons, pyran ring), 160.0 (C=N), and 160.4 (C=O). MS (EI): m/z (%) 295 [M⁺ + 2] (7.22), 294 [M⁺ + 1] (23.07), 293 [M⁺] (100.00), 292 [M⁺ – 1] (4.25), and 291 [M⁺ – 2] (0.33). Anal. calcd for C₁₇H₁₁NO₂S (293.34): C% 69.61; H% 3.78; N% 4.77; S% 10.93. Found: C% 69.42; H% 3.90; N% 4.66; S% 10.99.

4.1.1.5. 3-(Benzo[d]thiazol-2-yl)-6-nitro-2H-chromen-2-one (9e)

Faint yellow crystals; yield: 96% (2.98 g); m.p. 278–280 °C; IR (KBr, cm^–1): υ 3058, (CH-aromatic), 1731 (C=O), 1529 (C=N), and 1609, 1482 (C=C). ¹H NMR (400 MHz DMSO-d₆) δ: 7.50–8.74 (m, 7H, C₆H₄, C₆H₃), 9.05 (s, 1H, CH-pyran ring). MS (EI): m/z (%) 326 [M⁺ + 2] (0.64), 325 [M⁺ + 1] (1.65), 324 [M⁺] (7.11), 323 [M⁺ – 1] (0.24), and 105 (100.00). Anal. calcd for C₁₆H₈N₂O₄S (324.31): C% 59.26; H% 2.49; N% 8.64; S% 9.89. Found: C% 59.40; H% 2.30; N% 8.80; S% 9.60.

4.1.1.6. 3-(Benzo[d]thiazol-2-yl)-7-(diethylamino)-2H-chromen-2-one (9f)

Orange crystals; yield: 92% (3.22 g); m.p. 182–184 °C; IR (KBr, cm^–1): υ 2968–2852 (CH₂CH₃), 1701 (C=O), 1514 (C=N), and 1621, 1411 (C=C). ¹H NMR (400 MHz DMSO-d₆) δ: 1.09–1.13, 1.15–1.19 (2t, 6H, 2CH₃, J = 7.2 Hz), 3.33–3.38, 3.49–3.54 (2q, 4H, 2CH₂, J = 7.2 Hz), 6.68–6.87; 7.41–7.59; 8.00–8.13 (m, 7H, C₆H₃, C₆H₄), 9.03 (s, 1H, CH-pyran ring). MS (EI): m/z (%) 351 [M⁺ + 1] (0.08), 350 [M⁺] (0.19), and 105 (100.00). Anal. calcd for C₂₀H₁₈N₂O₂S (350.43): C% 68.55; H% 5.18; N% 7.99; S% 9.15. Found: C% 68.73; H% 5.10; N% 8.10; S% 9.02.

4.1.1.7. 3-(Benzo[d]thiazol-2-yl)-6,8-dichloro-2H-chromen-2-one (9g)

Yellow crystals; yield: 95% (3.31 g); m.p. 258–260 °C; IR (KBr, cm^–1): υ 3075, (CH-aromatic), 1730 (C=O), 1546 (C=N), and 1601, 1475 (C=C). ¹H NMR (400 MHz DMSO-d₆) δ: 7.43–8.14 (m, 6H, C₆H₂, C₆H₄), 9.10 (s, 1H, CH-pyran ring). ¹³C NMR (100 MHz, DMSO-d₆) δ: 121.3, 121.5, 121.8, 122.6, 123.1, 126.2, 127.3, 128.5, 129.3, 132.7, 136.5, 140.7, 142.3, 152.1 (aromatic carbons, pyran ring), 160.0 (C=N), and 161.0 (C=O). MS (EI): m/z (%) 350 [M⁺ + 2] (12.04), 349 [M⁺ + 1] (52.91), 348 [M⁺] (18.53), 347 [M⁺ – 1] (73.38), 346 [M⁺ – 2] (4.28), and 69 (100.00). Anal. calcd for C₁₆H₇Cl₂NO₂S (348.20): C% 55.19; H% 2.03; N% 4.02; S% 9.21. Found: C% 55.30; H% 2.34; N% 3.80; S% 9.01.

4.1.1.8. 3-(Benzo[d]thiazol-2-yl)-6,8-dibromo-2H-chromen-2-one (9h)

Faint yellow crystals; yield: 93% (4.07 g); m.p. 283–285 °C; IR (KBr, cm^–1): υ 3058, (CH-aromatic), 1732 (C=O), 1546 (C=N), and 1603, 1471 (C=C). ¹H NMR (400 MHz DMSO-d₆) δ: 7.48–8.35 (m, 6H, C₆H₂, C₆H₄), 9.16 (s, 1H, CH-pyran ring). MS (EI): m/z (%) 439 [M⁺ + 2] (27.39), 438 [M⁺ + 1] (11.86), 437 [M⁺] (49.18), 436 [M⁺ – 1] (6.68), 435 [M⁺ – 2] (25.53), and 69 (100.00). Anal. calcd for C₁₆H₇Br₂NO₂S (437.11): C% 43.96; H% 1.61; N% 3.20; S% 7.34. Found: C% 43.70; H% 1.80; N% 3.10; S% 7.53.

4.2. Computational Details

Energy minimization analyses using the Gaussian-09W software program were carried out to determine the molecular conformation of the produced molecules.³³ The Lee–Yang–Parr (B3LYP) correlation functional method,³⁴ the split-valence double zeta basis set with two polarized basis functions (d,p), and the DFT/B3LYP at the 6-311G** with the B3LYP exchange-correlation functional attempt³⁵ was used to optimize the ground state geometrical structures of the compounds 9a through 9 h. For the atoms of C, H, N, O, Cl, Br, and S,³⁶⁻³⁸ respectively, the basis set 6-311G** was used. Every bond length, bond angle, and dihedral angle may decrease through geometry optimizations without restrictions, and the geometry of the systems under consideration was fully optimized in the gas phase. The optimization energy, geometrical parameters, and 3D representations of the molecular electrostatic potential maps (MEP), and reactivity parameters were only a few of the aspects that may be assessed using the DFT theory. The computed results were obtained using Gauss-View 5 software,³⁹ Chemcraft, and Avogadro programs. The optimal forms, frontier molecular orbitals, and 3D plots of the MEP maps were also visualized. The equations that were previously published^40,41 are used to obtain the quantum chemical properties of the compounds. To explain their optical characteristics, spin density difference map calculations were also carried out. The analysis of the x, y, and z components was done on the mean polarizability (⟨α⟩), anisotropy of the polarizability (Δα), first-order hyperpolarizability (⟨β⟩), and total static dipole moment (μ).⁴²⁻⁴⁴ To clarify the origin of electronic spectra, TD-DFT calculations were generated at the same level of theory (B3LYP/6-31G(d,p)) using the polarizable continuous solvation method PCM and TD-DFT/PCM.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.3c01085.

• All spectral analysis such as Mass, ¹H NMR, and ¹³C NMR spectra for the newly synthesized compounds (PDF)

The authors declare no competing financial interest.