INTRODUCTION:

Nitrogen-containing heterocycles are broadly dispersed in nature and are basic to life, assuming an indispensable job in the digestion of every single living cell. 4(3H)- Quinazolinones have risen as a significant class of nitrogen containing heterocycles that have pulled in critical manufactured intrigue on account of their pharmacological and remedial properties, for example, antibacterial, antifungal, antimalarial, antihypertensive, anticonvulsant, for treatment Parkinsonism, antihistaminic and nearby sedative, pain relieving, mitigating antiviral and anticancer activities ^1-10. Few quinazolinones have been accounted for as strong chemotherapeutic operators in the treatment of tuberculosis. For instance, 3-aryl-6,8-dichloro-2H-1,3-benzoxazine-2,4(3H)-diones and 3-arylquinazoline-2,4(1H,3H)-diones were recommended as antimycobacterial agents¹¹ and as antitubercular agents ¹².

The antihyperlipidemic activities of these molecules were also investigated¹³. A new series of 3-[(dialkylamino) methyl]-2-substituted-4(3H)-quinazolinones were screened for anti-inflammatory activity and were showed their significant anti-inflammatory activity is higher that of standard¹⁴. A series of 6-substituted 2-ethyl-3-[substituted benzothiazol-2-yl]-4(3H)-quinazolinones have been showed most prominent anticonvulsant activity with low side effects compared with the reference drug Phenytoin sodium in MES test and Diazepam in scPTZ test.¹⁵

The easy generation of complex molecular diversity through broadly applicable, cost-effective, practical and sustainable synthetic methods in a straightforward fashion along with the importance of these motifs in medicinal chemistry, received significant attention from researchers engaged in drug design and heterocyclic methodology development. There are a few strategies for the cyclisation on basis of 4(3H)-quinazolinones^16-17. Nitrogen-containing heterocycles are the most bountiful and vital frameworks that happen pervasively in an assortment of engineered drugs, bioactive characteristic items, pharmaceuticals and agrochemicals^18-20. The nearness of N-heterocycles as a basic auxiliary theme in an assortment of naturally dynamic substances has invigorated the improvement of new methodologies and advances for their blend. Quinazolinone is part of about 200 commonly found alkaloids that belong to various groups of plants and microorganisms. The first quinazoline alkaloid isolated was vazicine (peganin 1) in 1888 ²¹. The first quinazolinone synthesized in the late 1860s from anthranilic corrosive and cyanogens to give 2-cyanoquinazolinone ²². Some of biologically active compounds containing 4-(2H)-quinazolinones moiety were shown in below (fig.1).

Fig.1: Biologically active compounds containing 4-(2H)-quinazolinone moiety

Among this class of compounds, 3-substituted 4(3H)-quinazolinones are notable since they are available in an enormous group of items with expansive organic molecules. Hence, their union has gotten impressive consideration. A few customary arrangement strategies required refluxed temperature and long response time (3 days) ²³. Recently, new improvements for the blend of 3- substituted 4(3H)-quinazolinones by a three-segment, one-pot buildup of anthranilic corrosive, amines, and ortho esters within the sight of different impetuses, for example, NaHSO₄ or Amberlyst-15 ²⁴, Yb(III)-resin ²⁵, Yb(OTf)₃²⁶_, Bi(TFA)₃-[nbp]FeCl₄] ionic liquid²⁷, La(NO₃)₃. 6H₂O p-toluenesulfonic acid²⁸, Keggin-type heteropolyacid under microwave irradiation²⁹, SnCl₄.4H₂O ³⁰, and SiO₂-FeCl₃ ³¹ have been accounted for. Be that as it may, a portion of these techniques are related with specific downsides, for example, long response times, low yields, cruel response conditions, troublesome work-up and utilization of earth poisonous reagents or media. Be that as it may, these conventional and microwave procedures are related with different downsides, similar to the reaction conditions, accessibility of reagents and chemical hazards.

The aim of our work is to optimize the production method using a new catalyst.

To achieve this aim, new series of 3-substituted 4-(2H)-quinazolinones were synthesized from anthranilic acid, amine and orthoester and physical and chemical properties were investigated using modern methods. In this communication, we report a novel protocol for the selective synthesis of 3-substituted quinazolin-4(3H)-ones by using Bi(OTf)₃ as effective catalyst. Bi(OTf)₃ can be considered as a new and efficient Lewis‐acid‐type catalyst for a number of reactions involving various Lewis bases as substrates. The relatively low cost and high catalytic efficiency of Bi(OTf)₃ makes it similar to rare‐earth triflates. The small number of publications reporting catalysis by Bi(OTf)₃ compared to that of rare‐earth triflates indicates that the dawn of the use of Bi(OTf)₃ in organic synthesis has just begun. There is no doubt that Bi(OTf)₃ will emerge as a new, powerful and environmentally friendly Lewis acid catalyst for synthetic methodologies needed for green chemistry.

MATERIALS AND METHODS:

All solvents were purified before use. Compounds were observed for their purity by thin-layer chromatography (TLC) on silica gel G plates with spots checked by iodine vapors.

The NMR spectra were recorded by using a 400 MHz Bruker Avance spectrometer at 400.1 and 100.6 MHz and spectra (¹H NMR and ¹³C NMR) were recorded by using tetramethylsilane (TMS) in the solvent of CDCl₃-d or DMSO-d6 as the internal standard (¹H NMR: TMS at 0.00 ppm, CDCl₃ at 7.26 ppm, DMSO at 2.50 ppm and¹³C NMR: CDCl₃ at 77.16 ppm, DMSO at 40.00 ppm). Chemical shifts are reported in ppm units use of δ scale.

For receptor-oriented flexible docking, the Autodock 4.2 software package was used. Ligands were prepared using the MGL Tools 1.5.6 program. The Ligand optimization was performed using the Avogadro program. To perform calculations in the Autodock 4.2 program the output formats of the receptor and ligand data were converted to a special PDBQT format. In previous studies, a similar software package was used ^32-35. The active macromolecule centers of the tyrosine kinase receptor EGFR (PDB ID: 4HJO, 1М17) and human cytochrome P450 CYP1A1 (PDB ID: 6DWM) from the Protein Data Bank (PDB) were used as a biological targets for docking. The receptor maps were made in MGL Tools and AutoGrid programs. Water molecules, ions, and the ligand were removed from the PDB file ID: 6DWM, 4HJO, 1М17.

The choice of crystallographic models of PDB ID: 4HJO and tyrosine kinase PDB ID: 1M17 (Epidermal Growth Factor Receptor tyrosine kinase domain with 4-anilinoquinazoline inhibitor erlotinib) as a biological target for the study of the possible antitumor activity is due to the existing crystallographic model co-crystallized with a derivative of 4-anilinoquinazoline. Erlotinib, tyrosine kinase inhibitors ^36-37 used to block EGFR (epidermal growth factor receptor) signalling in cancer, are thought to bind only the active conformation of the EGFR-TKD (tyrosine kinase domain). Computational and crystallographic studies have shown that a crystallographic model with erlotinib (PDB ID: 4HJO) indicates binding to active and inactive EGFR-TKD conformations, which has the potential for use in mutated EGFR forms of cancer ³⁸. The crystal structure of the epidermal growth factor kinase domain EGFRK (PDB ID: 1M17) assumes a conformation that is similar to the phosphorylated active form of the kinase domain, which leads to significant intermolecular contacts³⁹.

Human cytochrome P450 1A1 (CYP1A1) is an extrahepatic enzyme involved in the monooxygenation of structurally diverse compounds ranging from natural products to drugs and protoxins. Because CYP1A1 has a role in human carcinogenesis, inhibiting its activity may potentially aid in cancer chemoprevention, whereas utilizing CYP1A1's oxidative activity could help selectively activate anticancer prodrugs. Such potential therapeutic purposes require detailed knowledge of CYP1A1's interactions with potential ligands. Known CYP1A1 ligands also vary substantially in size, and it has not been apparent from a single existing CYP1A1 structure how larger, structurally diverse ligands are accommodated within the enclosed active site. Here, two new X-ray structures with the natural product furanocoumarin bergamottin (at 2.85 Å resolution) and the lung cancer drug erlotinib (3.0 Å) revealed binding orientations consistent with the formation of innocuous metabolites and of toxic metabolites, respectively ⁴⁰.

The following docking parameters were determined: the maximum RMS tolerance for the conformational cluster analysis – 2 Å; the free energy coefficient for torsional degrees of freedom – 0.2983; the cluster tolerance – 2 Å; the external grid energy – 1000; the maximum initial energy – 0; the maximum number of retries – 10 000; the number of individuals in the population – 150; the maximum number of energy evaluations – 2500000; the maximum number of generations – 27000; the number of top individuals to survive to the next generation – 1; the rate of gene mutation – 0.02; the rate of crossover – 0.8; the crossover mode – arithmetic; the α-parameter of Gauss distribution – 0; the β-parameter of Gauss distribution – 1. The visual analysis of complexes of substances in the active center of the tyrosine kinase receptor (PDB ID: 6DWM, 4HJO, 1М17) was performed using the Discovery Studio Visualizer program.

RESULTS AND DISCUSSION:

It was discovered that the reaction could be done under extremely basic response conditions within the sight of Bi (OTf)₃ which gives the ideal 3-substituted quinazolinone derivatives in great yield. Вismuth (III) triflate can productively catalyze a one-pot cyclisation of 3-substituted quinazolinones through a three-part buildup of anthranilic acid, amine and orthoester. Synthesis was carried ассоrding Scheme 1:

Scheme 1

We discovered that the high yields of the target compounds were achieved by introducing the equimolar amounts of the reagents at temperature 60 °without solvent.

All the products were identified by spectral (¹H NMR, ¹³C NMR) and analytical data.

For the synthesized compounds, a computer prediction of antitumor activity was carried out. Based on the results of molecular docking the following data were calculated: the scoring function indicating the enthalpy contribution to the value of the free energy of binding (Affinity DG) for the best conformational positions (Table. 1); the values of the free energy of binding and binding constants (EDoc kcal/mol and Ki mM (millimolar)) for a specific conformational position of the ligand; they allow assessing the stability of complexes formed between ligands and the corresponding receptor (Table. 2).

Table 1: Affinity DG values for best conformational positions of the test compounds in combination with the biotargets (PDB ID: 4HJO, 1М17, 6DWM)

Ligand	Afinity DG, kcal/mol
Ligand	4HJO	1М17	6DWM
4 a	-8,2	-8,3	-9,3
4 b	-8,5	-7,8	-10,4
4 c	-8,7	-8,1	-10,6
4 d	-8,1	-7,9	-10,3

Table 2: Values of the free energy of binding and binding coefficients of the test antitumor agents in combination with the biotargets (PDB ID: 4HJO, 1М17, 6DWM)

Ligand	4HJO		1М17		6DWM
Ligand	EDoc kcal/mol	Ki uM micromolar	EDoc kcal/mol	Ki uM micromolar	EDoc kcal/mol	Ki uM micromolar
4 a	-6.06	36.37 uM	-5.73	63.60 uM	-6.24	26.87 uM
4 b	-5.51	91.70 uM	-5.72	63.74 uM	-6.13	32.04 uM
4 c	-5.80	56.33 uM	-6.11	33.04 uM	-6.35	22.31 uM
4 d	-5.40	89.60 uM	-5.71	63.53 uM	-6.09	32.24 uM

Table 3: Values of interatomic distances, categories and types of intermolecular interactions of the molecule 4 c in the active sites of the biotargets (PDB ID: 4HJO, 1М17, 6DWM)

4HJO			1М17			6DWM
Distance, À	Category	Types	Distance, À	Category	Types	Distance, À	Category	Types
3,54	Hydrogen Bond	Carbon Hydrogen Bond	4,57	Electrostatic	Pi-Cation	3,68	Hydrophobic	Pi-Sigma
4,76	Electrostatic	Pi-Anion	4,21	Hydrophobic	Alkyl	3,83	Hydrophobic	Pi-Pi Stacked
3,66	Hydrophobic	Pi-Sigma	4,11	Hydrophobic	Pi-Alkyl	3,67	Hydrophobic	Pi-Pi Stacked
3,93	Hydrophobic	Pi-Sigma	5,48	Hydrophobic	Pi-Alkyl	4,89	Hydrophobic	Pi-Pi T-shaped
3,94	Hydrophobic	Pi-Sigma	5,30	Hydrophobic	Pi-Alkyl	4,73	Hydrophobic	Pi-Pi T-shaped
4,61	Hydrophobic	Alkyl	5,36	Hydrophobic	Pi-Alkyl	3,50	Hydrophobic	Amide-Pi Stacked
4,04	Hydrophobic	Alkyl	5,37	Hydrophobic	Pi-Alkyl	5,18	Hydrophobic	Alkyl
3,87	Hydrophobic	Alkyl	5,12	Hydrophobic	Pi-Alkyl	5,18	Hydrophobic	Pi-Alkyl
4,87	Hydrophobic	Pi-Alkyl	5,47	Hydrophobic	Pi-Alkyl
4,21	Hydrophobic	Pi-Alkyl	4,88	Hydrophobic	Pi-Alkyl
5,36	Hydrophobic	Pi-Alkyl	4,81	Hydrophobic	Pi-Alkyl
5,20	Hydrophobic	Pi-Alkyl	4,73	Hydrophobic	Pi-Alkyl
4,78	Hydrophobic	Pi-Alkyl
5,19	Hydrophobic	Pi-Alkyl

Fig 2. The Ligand 4 с superposition and the diagram of intermolecular interactions in the complex with the biotargets PDB ID: 4HJO (а), 1М17 (b), 6DWM (c)

Molecule 4 c forms a сhelate complex with the tyrosine kinase receptor (PDB ID: 4HJO) due to the carbon bond and the π-anionic interaction between the quinazoline ring and the phenyl moiety and the Asp831 residue. (Fig. 2).The Chelate 3 complex is facilitated by π-σ bonds between aromatic components and residues and Thr766, Val702, Leu820. The complex 4 c with tyrosine kinase (PDB ID: 1M17) is formed due to the π-cation interaction with the lysine residue Lys721. Stabilization of complexes is stimulated by π-Alk and Alk intermolecular interactions with amino acid residues Leu820, Leu764, Leu694, Lys721, Ala719, Val702, Met742.

Molecule 4 c forms a сhelate complex with the enzyme system CYP1A1 (PDB ID: 6DWM) due to π-σ, π-π, π-amide, π-Alk and Alk intermolecular interactions between the components of the molecule and amino acid residues Gly316, Phe224, Phe258, P , Ile386 (Fig. 2).

Taking into account the detailed analysis of the location of the molecules tested in the active site of receptors, the formation of a number of intermolecular interactions between them, negative values of scoring functions and calculated values of binding constants it can be concluded that the tested molecules have an affinity for these specified biological target targets. The obtained data can be used in planning experimental screening for antitumor activity.

General Procedure for the synthesis of 3-Substituted Quinazolinone derivatives 4(a-d):

Bi(OTf)₃ (0.05 mmol, 1 mol %) was added to a solution of anthranilic acid 1 (10 mmol), amine 2 (12 mmol) and orthoester 3 (12 mmol) in ethanol (10mL). The mixture was stirred at 60°C for 4 hrs, the progress of the reaction was checked by TLC. After completion, the reaction mixture was allowed to cool to room temperature and water (20 mL) was added. The solid product 4 was obtained through simple filtering. The resulting precipitates were dried and recrystallized from ethanol. Target compounds 4.a-c were crystallized from organic solvents and obtained with the yields of 79-90%.

Spectral data for selected compounds:

3-Phenylquinazolin-4(3H)-one: (4a) ¹H NMR (400 MHz, CDCl₃): δ 8.38 (ddd, J = 8.0, 1.5, 0.7 Hz, 1H), 8.14 (s, 1H), 7.89 –7.73 (m, 2H), 7.61–7.48 (m, 4H),7.47-7.38(m, 2H). ¹³C NMR (100 MHz, CDCl3): δ 160.63, 147.76, 145.98, 137.38, 134.47 129.53, 129.02 127.54, 127.36 127.06, 126.91 122.32.

3-(4-Methoxyphenyl)quinazolin-4(3H)-one (4b): ¹H NMR (400 MHz, CDCl3): δ 8.37 (dd, J1 = 0.4 Hz, J2 = 8.0 Hz, 1H), 8.11(s, 1H), 7.80-7.77 (m, 2H), 7.55 (t, J = 6.4 Hz, 1H), 7.34 (d, J = 9.1Hz, 2H), 7.06(d, J = 8.8 Hz, 2H), 3.87 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 160.02148.00, 147.45, 146.58 134.66, 131.26 128.27, 127.72, 127.65, 127.29, 122.47, 114.96, 55.74.

3-p-Tolylquinazolin-4(3H)-one (4c): ¹H NMR (400 MHz, CDCl3): δ 8.37 (d, J = 8.0 Hz, 1H), 8.12(s, 1H), 7.82-7.49 (m, 2H), 7.59(t, J = 7.2 Hz, 1H), 7.36-7.28 (m, 4H), 2.43 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 161.02, 148.04, 146.42, 139.37, 135.05, 134.63, 130.37, 127.68 127.31, 126.85 122.54, 21.35.

3-(4-(Trifluoromethyl)phenyl)quinazolin-4(3H)-one (4d): ¹H NMR (400 MHz, CDCl₃): δ 8.35(ddd, J = 8.0, 1.5, 0.6 Hz, 1H), 8.11(s, 1H), 7.87 –7.71(m, 4H), 7.64–7.51 (m, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 160.27, 147.62 145.07, 140.35 134.85, 131.19, 128, 127.65 127.47, 127.13 126.77, 123.50, 122.07.

CONCLUSION:

New compounds 3-substituted quinazolinone derivatives were synthesized using a catalyst Bi(OTf)₃. The remarkable highlights of this synthetic technique are mild reaction conditions, great yields, improved rates, which make it a valuable procedure for the synthesis of 3-substituted quinazolinone derivatives. For the synthesized compounds, a computer prediction of antitumor activity was carried out. In silico prediction showed that these compounds are promising due to their inhibitory activity towards antitumor targets PDB ID: 4HJO, 1M17, 6DWM. The inhibitory activity of the tested molecules can be realized by forming complexes between them; their stability is provided mainly due to the energetically favorable geometric arrangement of the ligands in the active centers of these acceptors, the formation of hydrogen bonds between them, and intermolecular electrostatic and donor-acceptor interactions. As a consequence, the thermodynamic probability of such binding is confirmed by negative values of the evaluation function (Affinity DG, kcal / mol), calculated values of the free binding energy EDoc (kcal / mol), and binding constants Ki (mM / mol). μM). The data obtained can be used in planning experimental screening for antitumor activity.

ACKNOWLEDGEMENT:

Authors are exceptionally appreciative to our Research Supervisor Dr. P. Thriveni for giving us required facilities and inspiration for fulfillment of the research work. We additionally broaden our appreciation towards BRNS, BARC, Mumbai for money related help and IICT, Hyderabad for giving us offices of IR Spectra, ¹H NMR for portrayal of integrated compounds. The authors gratefully acknowledge the financial support from the National University of Pharmacy.

CONFLICT OF INTEREST:

The authors have declared no conflict of interest.

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Received on 26.10.2020 Modified on 18.03.2021

Research J. Pharm.and Tech 2022; 15(2):559-565.

DOI: 10.52711/0974-360X.2022.00091