An Efficient and Green Microwave-Assisted Synthesis of Some Novel 1,3,4-Thiadiazinan- ones and their Molecular Docking, Computational and Biological Study Analysis

doi:10.21203/rs.3.rs-2084464/v1

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An Efficient and Green Microwave-Assisted Synthesis of Some Novel 1,3,4-Thiadiazinan- ones and their Molecular Docking, Computational and Biological Study Analysis

https://doi.org/10.21203/rs.3.rs-2084464/v1

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Among the vast number of structurally diverse alkaloids, 1,3,4-thiadiazinan-5-one and its analogues have also been targeted for the exploitation of modern synthetic techniques, possibly due to their good pharmacological properties. This study aims to synthesize 1,3,4-thiadiazinan-5-one by using an efficient and green reaction of aryl aldehyde, hydrazine substituted derivatives and thioglycolic acid. The synthesized compound’s chemical composition is characterized by the use of data from the elementary analysis, IR, Mass, ¹H and¹³C-NMR spectroscopy. Thiadiazinan-5-one derivatives analogue of the 3D-Crystal Protein Target Structure (PDB ID: 4COF) is conducted using Schrodinger Maestro 12.1 computation approach. The findings show no interaction of the hydrogen bond with 4COF protein based on the compound 2A docking. Overall, these 1A to 3Dcompounds are used in drug design and development studies as a chemical compound synthesis. The compounds 3D, 1B, 2D and 3B can also be considered as anti-epilepsy molecules based on the In-silico study. The descriptors for reactivity have been measured using frontier orbital molecular energy of hardness, electrophilicity index and energy gap.

Microwave

Anti-epilepsy

hydrazine

Thioglycolic acid and GABA(A)R-beta-3-homopentamer

The combination of 1,2,4-triazoles and 1,3,4-thiadiazines is said to have been widely used in medicine ^{[1, 2]}. Triazolo derivatives have been described to have a wide variety of pharmacologically significant effects, known as antifungal^[3], antibacterial^[4], antiviral^[5], anthelmintic^[6], antitumor^[7], anti-inflammatory^[8], anti-tuberculosis^[9], diuretics^[10] and anticancer^[11] agents^[12]. These compounds have also been provided considerable attention due to its important inhibitors of matrix metalloproteinase. They illustrate excellent tonic and hypertensive breathing endurance. These can be used to pancreatic cancers and acquired immunodeficiency syndrome (AIDS)^[13]. Thiadiazepines are known for their antimicrobial, antifungaland metalloproteinase inhibitory properties. Recently, it was shown that 1,4,5-dibenzolo thiadiazepines exhibit effective neuroprotective expertise against neurodegenerative illnesses without having anticholinergic effects. ^[14–17].

GABAergic neurotransmission abnormalities or dysfunctions are idea to be found inloads of neurological and neuropsychiatric illnesses ^[18–20]. The relaxation of GABA`s outcomes are mediated via way of means of the ionotropic GABAA receptors (GABAARs), which belong to the Cys-loop superfamily of ligand-gated ion channels. GABAARs are pentameric membrane proteins that cowl an anion-selective pore ^{[21, 22]}. The receptors are made up of nineteenwonderful subunits (α1 6, β1 3, γ1 3, δ, ε, θ, π, and ρ1 3), forming one-of-a-kind hetero- or homopentameric receptor combinations. The quantity of synaptic GABAARs has a 2α, 2β, and 1γ subunit widespread stoichiometry, with the bulk of receptors being α1βγ2, α2βγ2, and α3βγ2 receptors ^[23]. In a subset of receptors, however, the -subunit succeeds the -subunit. The -subunits containing GABAARs (α4β2δ, α6β2δ and α1β2δ) are broadly speaking discovered in peri- or paraventricular areas ^[24]. GABAARs containing 3 subunits that gathers as homo- or pseudo-homomers and also are called GABACRs ^[25].

An explicit perceptible region of space known to mankind in which at least one thermodynamic loop occurs is a thermodynamic framework. The system conduct depends on the individual components and its compatibility with the containment. Quantum compound boundaries are accounted for in structure-movement interactions (SAR) to provide promising organic activity interaction effects. At the sub-atomic level, a particle's reactivity is exceeded by sub-atomic orbitals of the outskirts (FMO), precisely the highest sub-atomic orbital involved (HOMO) and the least vacant sub-atomic orbital involved HOMO and LUMO. The FMO principle suggests that an atom's HOMO and LUMO play key roles in intermolecular communications.

In this report, it was agreed to explore the microwave expedition as a means of improving the contraction mechanism adaptability. Many studies suggesting a large variety of pharmacological activities have been published. It was a hypothesis of interest to unite the oxazine moieties required by synthesis after prudently pursuing the literature survey, which may enhance the drug activity of compounds to a certain degree or possess some biological activities mentioned above. Our research work included the synthesis of numerous new 1,3,4-thiadiazinan-5-one heterocyclic derivatives and the characterization of derivatives by the comfort of Mass spectrum, FTIR, ¹H and¹³C NMR spectrum of the derivatives obtained by molecular docking simulations were determined and discussed for the prepared molecules.

The open-capillary technique was used to determine melting points that were not adjusted. All of the reactions took place under microwave irradiation.The elemental and spectral analysis confirmed the chemical compositions of the obtained compounds. With the Shimadzu spectrometer, UV spectra have been recorded. Upon on FTIR-8300 Shimadzu spectrophotometer, IR spectra are registered on Bruker DPX (200 MHz) and Jeol GSX (400 MHz) instruments, possibly the¹³C and¹H NMR spectra were recorded, with TMS as that of the internal standard. The mass spectrum was observedon the instruments Jeol JMS-DX 3030 HF and GCMSQP 5000 Shimadzu. Thin-layer chromatography (TLC) done with Merck silica gel GF-254aluminium sheets of 0.25 mm thickness, using production process: ether: chloroform, squared the clarity of the components. The spot was observed under UV light along with its absorption. By standard methods, reagents and solvents were purified.

2.1. General method for the Synthesis of 2-substituted-4-diphenyl-1,3,4-thiadiazinan-5-one

The formation of thiadiazinan-5-one red-orange solid mass derivatives with outstanding yields was assisted by equimolar preparations of aromatic aldehydes, Phenyl hydrazineand thioglycolic acid and added ethanol with microwave irradiation for 2–3 minutes (85–92%). In Scheme 1, various 2-substituted-4-phenyl-1,3,4-thiadiazinan-5-ones have been synthesized and described.

2.2. Preparation of 2-substituted-1,3,4-thiadiazinan-5-one

Substituted aromatic aldehydes, thioglycolic acid, hydrazine derivatives (1:1:1) and added C₂H₅OH were treated with microwave irradiation for 2–3 minutes. The synthesis of the red-orange thiadiazinan-5-one derivative solid mass has been confirmed. 2-substituted-1,3,4-thiadiazin-5-one varieties were synthesized and described in Scheme 2.

2.3. Synthesis of 2-substituted-4-(2,4-dinitro phenyl)-1,3,4-thiadiazinan-5-one

A mixture of substituted aryl aldehydes, 2,4-dinitrophenyl hydrazine with thioglycolic acid, and added ethanol is obtained by microwave irradiation of a mixture of substituted aryl aldehydes, 2,4-dinitrophenyl hydrazine with thioglycolic acid, and added ethanol for 4 minutes. The raw material was found to be reddish brown, indicating that it is a thiadiazinan-5-one derivative. Scheme 3 shows various 2-substituted-4-(2,4-dinitro phenyl)-1,3,4-thiadiazinan-5-ones that have been produced.

Table 1

Physical data of 1,3,4-thiadiazinan-5-one derivatives
Compound	R	R’	Yield %	M.P ⁰C
1A	H	H	83	161
1B	NO₂	H	80	157
1C	H	Cl	77	152
1D	H	OH	76	151
1E	OMe	OH	68	142
2A	H	H	87	158
2B	NO₂	H	72	149
2C	H	OH	83	162
2D	OMe	OH	84	146
3A	H	H	77	158
3B	H	OH	81	164
3C	H	Cl	72	161
3D	NO₂	H	86	159

2.4. Experimental Section

The significant biological activity of thiadiazines, as well as the effect of their derivatives on the board spectrum, has piqued interest in recent years. Thiadiazinan-5-one is used in the development of conventional thiadiazinan-5-one derivatives, which makes it important in the pharmaceutical industry. We were fascinated by the synthesis of 1,3,4-Thiadiazinan-5-one on the concept of microwave irradiation, which attracted our interest in the synthesis of nitrogen and sulphur-containing heterocycles. We used microwave technology to make thiadiazinan-5-one derivatives in this study, which was a novel synthesis approach.

The spectral and analytical study proved the structures of the 1,3,4-thiadiazinan-5-one 1A-E. As an example for the discussion, the FT-IR compound spectrum(1D) indicates that characteristic frequencies of absorption occurred at 1640 cm^− 1 due to C = N stretching vibrations. The absorption band due to the C-N stretching vibration is approximately 1111 cm^− 1. N-N stretching vibrations are assigned to the absorption band at 1406 cm^− 1. At 1724 and 1567 cm^− 1 respectively, the carbonyl group and C-S were observed. In CDCl₃/Chloroform, the ¹H NMR spectra of the compound (1D), as well as its derivatives, have been recorded using TMS as the internal standard. Peaks at δ 3.30 ppm referring to methylene proton have been found in the ¹H NMR range of substituted 1,3,4-thiadiazinan-5-one (1D). In both compounds, aromatic protons from different environments were present as multiplets in the δ range of 7.01–7.41 ppm. Signals occurred in the range of δ 121.0-133.1 ppm in ¹³C NMR spectra in the aromatic carbons of different environments present in both compounds. A signal at δ 31.9 ppm confirmed the presence of methylene carbon. In the presence of carbonyl carbon at δ 174.2 ppm, At m/z 284.3 (C₁₅H₁₂N₂O₂S), the Mass spectrum of 1D revealed the pseudo molecular ion peak. Anal. Calcd for C₁₅H₁₂N₂O₂S: C, 63.38; H, 4.23; N, 9.86; O, 11.27; S, 11.26. Found: C, 64.25; H, 3.83; N, 8.72; O, 12.32; S, 10.88.

¹H, ¹³C NMR spectroscopy and mass spectrometry confirmed the structures of isolated products 2A-D. The FT-IR compound spectrum (2A) as an example for discussion) shows characteristic frequencies of absorption that occurred at C = N were observed at 1658 cm^− 1. At 1121cm^− 1, the N-NH stretching vibration was reported. At 1392 cm^− 1, the FT-IR bands detected were designated for C-N vibration stretching modes. The ¹H NMR spectrum of 2A exhibited arising from the methylene group δ 3.79 ppm. The NH protons showed a singlet at δ 8.20 ppm. The aromatic protons of the ring system showed a multiplet in the region 7.23–7.33 ppm. The ¹³C NMR spectrum of 2A exhibited only one signal at 170.6 ppm for the carbonyl carbon of thiadiazinan-5-one ring respectively and only one signal at 38.7 ppm for the methylene protons. The mass spectra of compound 2A displayed the molecular ion peak at the appropriate m/z value 192 (C₉H₈N₂OS). Anal. Calcd for C₉H₈N₂OS: C, 56.25; H, 4.17; N, 14.58; O, 8.33; S, 16.67. Found: C, 56.94; H, 3.72; N, 14.06; O, 9.20; S, 16.08.

The structure of the 1,3,4-thiadiazinan-5-one 3A-E was confirmed by spectral and analytical data. FT-IR spectra of compound (3A) as taken as an example for discussion) showed an absorption band at 1633 cm^− 1 assigned to C = N stretching vibration and the C-N showed the strong band at 1394 cm^− 1 and the N-N showed the strong band at 1111 cm^− 1. The ¹H NMR of compound 3a showed a multiplet at δ 7.11–7.52 for aromatic protons and a methylene peak showed at δ 3.92 ppm. The ¹³C NMR of compound 3A showed peaks at δ 125.7, 126.5, 127.1, 128.7, 129.2, 130.4, 131.1 and also showed the presence of C = O band around δ 174.2 ppm. The mass spectrum of the compound 3A showed the molecular ion peak at m/z 358 (C₁₅H₁₀N₄O₅S) confirms the molecular weight. Anal. Calcd for C₁₅H₁₀N₄O₅S: C, 50.28; H, 2.79; N, 15.64; O, 22.35; S, 8.94. Found: C, 50.86; H, 3.08; N, 14.72; O, 23.54; S, 7.80.

All of the computational experiments have been conducted using the Schrodinger Suite. Schrodinger is a software suite that is used to model systems of small molecules and macromolecules.

3.1. Ligand preparation

The ligands (small molecules) 1B, 1C, 1D, 1E, 2A, 2B, 2C, 2D, 3A, 3B, 3C and 3D were synthesized drawn using Chem draw (8.0) and saved in. mol format. These derivatives of Thiadiazinan-5-one satisfy Lipinski's rule of 5. After hydrogen bonds were introduced, the save ligands were later imported and reduced using the 'Prepare ligands' procedure.

3.2. Preparation of Protein Molecule

The GABA(A)R-beta-3-homopentamer (4COF) assay X-ray crystal structure of a gamma-aminobutyric acid receptor, as seen in Fig. 1, was retrieved in .pdb file format from the RCSB protein data bank. Using the 'Prepare Protein' protocol from the Schrodinger Suite programme, the protein molecules were prepared. From the protein report provided by the programme, active site residues were selected.

3.3. Molecular Docking

For the analysis of the relationship (hydrogen bond) between the configuration of a GABA(A)R-beta-3-homopentamer (4COF) and molecules 1A to 3D, the 'flexible docking' procedure of the Schrodinger suite was adopted 2D diagram of 1a-3d compounds interactions with 4COF are shown in Fig. 2 .

GABA(A)R-beta-3-homopentamer In-silico screening of compounds against human gamma-aminobutyric acid receptors (4COF). The molecular docking of the compounds within the human gamma-aminobutyric receptor active sites was carried out using the Schrodinger Suite versatile docking system. The recent research has extended the molecular diversity of GABAA(R) receptor and transporter targeting ligands, which could promote the research in terms of effectiveness, potency and selectivity of different pharmacological profiles. The results of molecular docking score, glide score, glide energy glide emode, interaction with hydrogen bond and distance were tabulated in the table. Compounds 1A, 1B, 2C, 2D and 1E showed a better GABA(A)R-beta-3-homopentamer (4COF) docking and glide score relative to other compounds. Glide energy and glide emode with GABA(A)R-beta-3-homopentamer (4COF) were seen relative to other compounds in the docking findings of 1B, 1C, 3B, 3D and 3C. Effects of molecular docking showed that the compounds formed a stable complex within the 4COF protein's active site. In the strong interactions of GABA(A)R-beta-3-homopentamer (4COF) with the 3D compound, the highest glide energy (-33) and glide emode (-43.693) were established. Molecular docking tests have however shown that compound (3D) can be considered a better inhibitor with greater GABA(A)R-beta-3-homopentamer action (4COF). In the strong interactions of GABA(A)R-beta 3-homopentamer (4COF) with the 3B compound, the second-highest glide energy (-29.513) and glide emode (-37.522) was established. In the effective interactions of GABA(A)R-beta-3- homopentamer (4COF) with 1B compound, the third-highest glide energy (-27.334) and glide emode (-35.192) were observed Poses with best interactions of molecule 1a -3d respectively in 4COF are shown in Fig. 3.

One of the most essential forms of interaction shown by protein and ligand molecules is hydrogen bonding. Compound 3D revealed hydrogen bond interaction in the 4COF protein with TYR 157, TYR 97, PHE 200, TYR 205 and GLU 155 amino acids, respectively. At a distance of 1.92 A0, the Nitro group (3D) of the compound showed a hydrogen bond interaction with TYR 157. Compound 2D revealed hydrogen bond interaction in the 4COF protein with TYR 157, GLY 158, TYR 97 and LEU 99 amino acids, respectively. At a gap of 1.72 and 2.21 A⁰, the hydroxy and nitrogen group (2D) of the compound showed hydrogen bond contact with TYR 157 and TYR 97. In the 4COF protein, compound 1B showed a hydrogen bond connection with the amino acids TYR 207, TYR 97 and ARG 207, respectively. At a distance of 2.22 A0, the Nitro group of the compound (1B) demonstrated hydrogen bond contact with TYR 97. Compound 2A does not demonstrate any hydrogen bond interaction with the 4COF protein based on the docking results. Overall, in drug design and production trials, this 1A to 3D compounds are eligible for chemical compound synthesis. Thus the compounds 3D, 1B, 2D and 3B can be considered as anti-epilepsy action molecules based on the In-Silico study.

Table 2

Docking results for synthesized compounds
Compound	glide energy	XP GScore	glide emodel	glide gscore	Docking score
1A	-24.472	-2.952	-31.347	-2.952	-2.952
1B	-27.334	-2.967	-35.192	-2.967	-2.967
1C	-24.637	-2.851	-31.706	-2.851	-2.851
1D	-26.76	-2.816	-33.924	-2.816	-2.816
1E	-23.295	-2.829	-27.983	-2.829	-2.829
2A	-18.774	-2.59	-22.517	-2.59	-2.59
2B	-21.638	-2.749	-25.573	-2.749	-2.749
2C	-20.931	-2.887	-25.057	-2.887	-2.887
2D	-20.428	-3.099	-22.567	-3.099	-3.099

4.1 HOMO - LUMO

A fine model for understanding the chemical stability of molecules is the FMO hypothesis concerning both HOMO and LUMO. An explanation of energy distribution and energy behavior is given through the help of HOMO and LUMO energies for ligands and complexes, along with the description of optical and electronic properties. The LUMO orbital embraces electrons and its energy is related to electronic affinity (EA) in molecular interactions, while the HOMO orbital serves electron donors and its energy is related to the potential for ionization (IP). In molecular electrotransport, the HOMO-LUMO energy difference describes the interaction between the final charge transfers within the molecules. In order to eliminate electrons from the low HOMO position, a molecule with a large boundary orbit distance (HOMO-LUMO energy gap) needs to have low chemical reactivity and high kinetic stability since adding electrons to the high LUMO position is energetically undesirable.A large HOMO-LUMO deviation is correlated with high molecular stability, high aromaticity, and low reactivity in chemical reactions; however a slight HOMO-LUMO deviation is associated with anti-aromaticity. It is the ability to donate and receive electrons that is determined by the HOMO energy and LUMO energy. HOMO energy is elevated for reactions involving electrophiles and LUMO energy is low for reactions involving nucleophiles. According to Table 3, HOMO and LUMO data for different energy ranges can be determined for the molecule shown in Fig. 4. The molecule shows both electrophilic and nucleophilic regions of attraction. The shortest distance LUMO-HOMO is associated with high reactivity. In contrast, the energy gap of + 0.1253 eV for 1B is soft and the least stable (more reactive) at the amplitude of HOMO-LUMO, while the gap for 2D is hard and more stable (+ 0.2595 eV).

4.2. Global descriptors

Molecular stability and reactivity are discussed using the DFT approach. Our efforts to use FMOs, HOMO, and LUMO energies useful in quantum chemical calculations to determine the energy, structure, and reactivity characteristics of complexes have provided information on IP, EA, electronegativity, electrophilicity index, hardness, softness, and chemical potential.

The IP and EA are calculated as follows: IP = -EHOMO and EA = -ELUMO. Table 3 shows information about ionization potential and electronic negativity.According to the Koopman theorem, the following are descriptors of global reactivity:

Chemical potential (µ) = - \(\frac{(\mathbf{I}\mathbf{P}+ \mathbf{E}\mathbf{A})}{2}\)

Hardness (η)= \(\frac{(\mathbf{I}\mathbf{P}- \mathbf{E}\mathbf{A})}{2}\)

Softness (S) = 1/ η

Electronegativity (χ) = \(\frac{(\mathbf{I}\mathbf{P}+ \mathbf{E}\mathbf{A})}{2}\)

Electrophilicity index(ω) = 𝜇 ² /2η

Based on thermodynamic properties, the global index of electrophilicity (*) determines the energy trend that is desired when electron addition saturation is achieved via chemical synthesis. As a result of electrons flowing from a donor molecule to its acceptor molecule, molecules lose energy. In addition, it also determines the chemical reactivity of a system and is expressed as follows, where µ represents the global chemical hardness and µ represents the electronic chemical potential that controls how charge is transferred in the ground state within the system. Chemically reactive organic compounds are more reactive than those with lower chemical potential.Compound 2C is the most responsive, while compound 3C is the most un-receptive. Also, S is the worldwide delicate quality that is utilized to gauge the electron move bearing. Likewise, electronegativity (χ) is a proportion of the fascination in a covalent obligation of a particle to electrons; subsequently, compound 3C has higher electronegativity (χ) and shows a high stream of charge. Moreover, the discoveries acquired recommend that compound 3C (NO₂) is a weighty electrophile, while compound 1E (OH) is a nucleophile.

Electron-donating gatherings add to an ascent in the energy levels of the limit orbitals, while the converse outcome is had by electron-giving gatherings. To raise the energy proportions from the most really electron-pulling out bunch (- NO₂) to the most intensely electron-giving gathering (OH). The least IP is found in the OH substituent (compound 1E) and is consequently the most nucleophilic species. The LUMO-HOMO energy gap values mirror the atom's synthetic conduct. Because of the great electron acknowledgment capacity of the electron acceptor bunch, the abatement in the HOMO-LUMO energy gapshows the conceivable charge move association that happens in the concentrated on compounds [1–7]. In light of this the soundness of the investigated compounds is 2D > 2C > 3D > 1A > 1E > 3C > 1B. The determined outcomes show that the steadiest and the most un-stable are intensifies 1 and 7, individually. In examination, the more noteworthy HOMO-LUMO energy contrast for intensifies 1–7 brings down the energy hole as follows: 2D > 2C > 3D > 1A > 1E > 3C > 1B, and the compound reactivity diminishes in the contrary request: 2D < 2C < 3D < 1A < 1E < 3C < 1B < 1B (see Table 4). In this work, energy levels increment to the most grounded electron gift bunch (- OH) in the request for the most grounded electron withdrawal bunch (- NO₂). The electrons are stifled by an electron-pulling out bunch and the HOMO and LUMO energies are decreased accordingly. Normally, an electron gift bunch works through an involved orbital of nonbonding. This is like HOMO enthusiastically. In this way, it affects HOMO than on LUMO (basically in organic molecules).

Table 3

Data for LUMO, HOMO and LUMO-HOMO gap (ΔE) for 1,3,4-thiadaizinan-5-one derivatives
Compound	HOMO	LUMO	Gap (ΔE)	IP	EA
1A	-0.2149	-0.0606	0.1543	0.2149	0.0606
1B	-0.2298	-0.1045	0.1253	0.2298	0.1045
1E	-0.2063	-0.0524	0.1539	0.2063	0.0524
2C	-0.2155	-0.0514	0.2207	0.2155	0.0514
2D	-0.2087	-0.0507	0.2595	0.2087	0.0507
3C	-0.2430	-0.1146	0.1284	0.2430	0.1146
3D	-0.2521	-0.0506	0.2015	0.2521	0.0506

Table 4

Data for Chemical Potential, Hardness, Softness, Electrophilicity and Electronegativity for 1,3,4-thiadaizinan-5-one derivatives
Compound	Chemical Potential (µ)	Hardness (η)	Softness(S)	Electrophilicity (ω)	Electronegativity (χ)
1A	-0.1378	0.0771	12.965	0.1231	0.1378
1B	-0.1671	0.0626	15.962	0.2236	0.1671
1E	-0.1294	0.0769	12.993	0.1087	0.1294
2C	-0.1335	0.0820	12.189	0.1085	0.1335
2D	-0.1297	0.0789	12.661	0.1066	0.1298
3C	-0.1788	0.0642	15.572	0.2489	0.1788
3D	-0.1513	0.1008	9.923	0.1136	0.1513

4.3 Thermophysical properties

By doing a docking procedure, the free binding energy of the optimized molecules is determined. There will be the most extreme restricting partiality for the atom with the most un-restricting energy. By separating the energy from the principle particle, the limiting free energy of the planned atoms is acquired.Having a maximum binding affinity that means that molecules concentrate on computation is the strongest molecule for drug leads. Using the capability of the product, which will bind to the target molecule during the docking process, we can figure out the drug binding affinity and the second approach is to use the free energy measurements of Gibbs. A more successful medication can be considered dependent on this more negative value. Thermophysical characteristics such as total energy, entropy, free energy, and enthalpy are given in Table 5.

Table 5

Thermodynamic parameters for 1,3,4-thiadiazinan-5-one derivatives
Compound	Entropy (cal/mol/K) 298.15K 1.0atm	Enthalpy (kcal/mol) 298.15K 1.0atm	Free Energy (kcal/mol) 298.15K 1.0atm	Total Internal Energy (au) 298.15K 1.0atm	Total Enthalpy (au) 298.15K 1.0atm	Total Free Energy (au) 298.15K 1.0atm
1A	120.99	9.88	-26.19	-1161.51	-1161.50	-1161.56
1B	132.59	11.39	-28.13	-1366.00	-1366.00	-1366.06
1E	136.54	12.16	-28.54	-1351.22	-1351.22	-1351.28
2C	106.29	7.93	-23.75	-1005.75	-1005.75	-1005.80
2D	117.38	9.46	-25.53	-1120.24	-1120.24	-1120.30
3C	149.01	13.68	-30.74	-2030.10	-2030.09	-2030.16
3D	154.25	14.47	-31.51	-1774.99	-1774.99	-1775.06

5.1. Antibacterial activity

All the newly synthesized thiadiazinan-5-one were evaluated for antibacterial activity by serial diffusion technique against gram positive organism Staphylococcus aureus and gram negative organism, Escherichia coli.Norflaxin (bacteria). 10 µg/ml concentration of the newly synthesized compounds were prepared using chloroform as the solvent. Disc containing only chloroform was used as negative control. The results of antibacterial activity are listed in Table 06. Compound 2a showed good activity against E. coli and S. aureus in the range of 30 µg/ml. Compound 1a have shown low MIC value as compared to Norflaxin. Graphical representation of zone of inhibition of 1,3,4-thiadiazinan-5-one is shown in Fig. 5

Table 06

Antibacterial activity of 1a and 2a
Sample	Name of the Bacteria	Zone of inhibition (mm)						Standard (mm)
		Zone of inhibition (mm)						Norflaxin
		5 µg/ml	10 µg/ml	15 µg/ml	20 µg/ml	25 µg/ml	30 µg/ml	10 µg/ml
	E. Coli	0.1	0.1	0.1	0	0	0.1	0.5
1a	S. auereus	0	0	0	0	0	0	0.1
	P. valgaris	0	0	0	0	0	0	0.1
	E. Coli	0	0	0	0	0	1.8	1.5
2a	S. auereus	0	0.1	0.3	0.4	0.5	0.7	1.5
	P. valgaris	0	0	0	0	0	0.1	0.1

5.2. Antifungal activity

The newly synthesized thiadiazin-5-one was evaluated for antifungal activity by serial diffusion technique against Aspergillum Niger, Aspergillum fumigatus, Klebesiella pneumonia. 10 µg/ml disc of Fluconazole (Aspergillum Niger, Aspergillum fumigatus); Norfloxin (Klebesiella pneumonia) (fungi) was used as the standard. Disc containing 10 µg/ml concentrations of the newly synthesized compounds as test and 10 µg/ml of chloroform was used as a negative control. The results of antifungal activity are listed in Table 07. Compound 1a and 2a have shown potent antifungal activity with MIC value in the range of 10 µg/ml against Aspergillum niger. Compound 2a showed good activity against Klebesiella pneumonia in the range of 10 µg/ml and moderate activity against Aspergillum fumigatus. Compound 1a have shown low MIC value against Aspergillum fumigatus and Klebesiella pneumonia as compared to fluconazole. Graphical representation of zone of inhibition of 1,3,4-thiadiazinan-5-one is shown in Fig. 6.

Table 07

Antifungal activity of 1a and 2a
Sample	Name of the Fungi	Zone of inhibition(mm)						Standard (mm)
		Zone of inhibition(mm)						Fluconazole
		5 µg/ml	10 µg/ml	15 µg/ml	20 µg/ml	25 µg/ml	30 µg/ml	10 µg/ml
1a	Aspergillum niger	1.5	1.8	2	2.1	2.2	2.3	1
	Aspergillum fumigatus	0	0	0	0	0	0.1	1.5
	Klebesiella pneumonia	0	0	0	0	0	0.1	1.5
2a	Aspergillum niger	1	1.7	1.8	1.9	2	2.1	1.2
	Aspergillum fumigatus	0	0	0	0	0.5	1	0.1
	Klebesiella pneumonia	0.1	1	1.3	1.5	1.7	1.8	0.1

In summary, one-pot, three-component combination in concrete and green synthetic strategy with great yields have laid out title compounds. This approach took a quick response period, a moderate condition with a reasonable workup convention and a technique that begins naturally. Thiadiazinan-5-one was then combined as a green dissolvable by buildup of subbed sweet-smelling aldehyde and subbed hydrazine within the sight of thioglycolic corrosive and ethanol. All target compounds were blended for just one stage, with 85% − 90% for all yields, separately. ¹H, ¹³C NMR and IR spectrum have been affirmed by the constructions of these original targets and portions of the intermediates. Using docking experiments; an effective technique of computational modeling focused on hydrogen bond interaction was reported. The docking analysis was conducted using "Schrodinger Maestro 12.1" for the compounds against 4COF. All target compounds exhibit significant binding energy and binding affinity with the amino acid. Yet compound 3D, relative to other compounds, has greater binding energy. All target compounds have been concluded as a powerful inhibitor of neurological disorders such as insomnia, anxiety, and epilepsy in the design of a new series of drugs, particularly for the GABAAR (4COF) protein.

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An Efficient and Green Microwave-Assisted Synthesis of Some Novel 1,3,4-Thiadiazinan- ones and their Molecular Docking, Computational and Biological Study Analysis

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Abstract

Figures

1. Introduction

2. Materials And Methods

2.1. General method for the Synthesis of 2-substituted-4-diphenyl-1,3,4-thiadiazinan-5-one

2.2. Preparation of 2-substituted-1,3,4-thiadiazinan-5-one

2.3. Synthesis of 2-substituted-4-(2,4-dinitro phenyl)-1,3,4-thiadiazinan-5-one

2.4. Experimental Section

3. Computational Section

3.1. Ligand preparation

3.2. Preparation of Protein Molecule

3.3. Molecular Docking

4. Fmo (Frontier Molecular Analysis)

4.1 HOMO - LUMO

4.2. Global descriptors

4.3 Thermophysical properties

5. Biological Studies Of Substituted 1,3,4-thiadiazinan-5-one Derivatives

5.1. Antibacterial activity

5.2. Antifungal activity

6. Conclusion

Declarations

References

Scheme

Additional Declarations

Supplementary Files

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