Synthesis, spectral, anti-diabetic, anti-inflammatory, antioxidant, and molecular docking investigations of acridine derivatives

doi:10.21203/rs.3.rs-4016445/v1

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Synthesis, spectral, anti-diabetic, anti-inflammatory, antioxidant, and molecular docking investigations of acridine derivatives

https://doi.org/10.21203/rs.3.rs-4016445/v1

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Every synthesised molecule was assessed for IR, ¹H, ¹³C NMR, and mass spectral analysis approaches to validate the new acridine derivatives we synthesized for this work's conventional method. Biological studies like anti-inflammatory and anti-oxidant activities with DPPH radical scavenging activity, anti-diabetic properties, and molecular docking were examined. The anti-diabetic properties of acridine derivatives indicate that compounds 2 and 7 exhibit greater activity compared to the typical acarbose one, with IC50 values of 26 and 25, respectively. According to in-vitro investigations on anti-inflammatory effect, compounds 4 and 6 have larger inhibition percentages than the other compounds. The oxidoreductase tuberculosis protein is tightly docked with the synthesised moieties. Compound 7 exhibits the highest inhibition constant of 608.73 µM.

Biological sciences/Chemical biology

Physical sciences/Chemistry

Acridine

NMR

Mass

Anti-diabetic

Anti-oxidant

Anti- inflammatory

Molecular docking

Acridine is one of the several pharmacologically active scaffolds of interest in synthetic and medicinal chemistry. The chemical structures of acridines and quinoline and anthracene are similar. One of the carbon atoms in the middle ring has been replaced by nitrogen in the tricyclic ring structure.[1–4] Acridine compounds have a wide range of pharmacological actions, including anti-Alzheimer, anti-cancer, antibacterial, antitubercular, antimalerial, antiviral, and anti-protozoal activities.[5–8] It was discovered that the technique was better than the previous one-pot method, with higher yields and a wider range of the reaction.[9–11] Fluorometric and electrophoresis methods were used to investigate these chemicals' ability to bind DNA. Target chemicals intercalate DNA with pronounced AT-preferential binding, according to the data. These compounds' cytotoxic effectiveness against the human colon cancer cell line (HT29) was investigated and contrasted with that of standard medications. chemical was determined to be highly potent cytotoxic chemical.[12–15]

The DNA and interaction inhibition of these drugs, as well as their cytotoxic growth and inhibition of various human tumours In vitro, the acridine chromophore demonstrated notable cytotoxicity against the development of human tumour cells. Compound was the most derivative; in mice with human breast cancer MX-1 xenografts, it showed 60% suppression of tumour volume at a dosage of 20 mg/kg.[16–18]. When the substance was tested in vitro against human lymphoblastic leukaemia, it was discovered to have a considerable cytotoxic effect. The cytotoxicity of a compound can be influenced by its substituent position and spacer length, as demonstrated by the structure activity relationship study.[19, 20] Creation of hybrid agents between platinum and acridine that have carboxylic acid ester groups. In comparison to cisplatin, the most active derivative showed up to three times the activity in ovarian cancer (OVCAR-3).

The compound showed activity that was around 75- and 150-fold higher, respectively, than that of cisplatin against pancreatic (PANC-1) and non-small cell lung cancer (NSCLC, NCI-H460) cell lines.[21, 22] assessed each compound's in-vitro anticancer activity against four different human cancer cell lines: liver (Hep G2), lung (NCl H-522), and breast (T47D). Compounds appeared to be more efficient than others since they inhibited all cancer cell lines at 10 µM concentration; however, one drug (colon HCT-15) had an IC50 value of 2.4 µM.[23–26].

2.1. Synthetic route of acridine derivatives

A cyclo-condensation of a combination of 5,5-dimethylcyclohexane-1,3-dione, substituted benzaldehyde, NH₄OAc in ethanol medium. Refluxing the reaction mixture at ethanol's boiling point 78 ºC allowed thin layer chromatography, which used benzene and ethyl acetate as eluent to monitor the reactions completion. Chloroform was used to remove the reaction mixture, and column chromatography was used to purify the remaining substance. The schematic representation of synthetic pathway of acridine derivatives (1–7) is depicted in Scheme 1.

2.2. Measurements

Using a Bruker 400 MHz NMR spectrometer, the ¹H and ¹³C spectra of the synthesised compounds in DMSO were captured. The central line of DMSO and TMS were used to record the NMR spectra as internal standards. Using KBr pellets, infrared spectrum were captured on a JASCO FT-IR-5300 Spectrometer within the 4000–400 cm^− 1 array.

2.3. Activity of Antioxidant

Assay for DPPH radical scavenging

DPPH for the free of charge, and the synthesised moieties were evaluated for radical scavenging activity in accordance with the previously reported protocol.[27] To summarise, a 0.0001M solution of DPPH in DMSO was made, and then 10mL of the obtained solution was added to 100ml of the solutions of all chemicals in DMSO at varied concentrations (200, 400, 600, 800, and 1000 mg/ml). After giving the solutions a good shake, they were left to stand at room temperature for thirty minutes. In a UV-VIS spectrophotometer, the absorbance at 516 nm is measured using ascorbic acid as a reference. If the absorbance value is low, there will be an exceptionally high free radical scavenging activity. We computed the scavenging DPPH radical activity using the supplied formula.

DPPH % inhibition = [A₀-A_t/ A₀] x100

Hydroxyl radical scavenging assay

The capability of the compounds to scavenge hydroxyl (OH•) radicals has been investigated by the Nash technique.[28] Ascorbic acid and Fe³⁺ have been converted into in vitro (OH•) radicals. The total amount of formaldehyde absorbed at 412 nm during the corrosion reaction with DMSO was used to measure the (OH•) radical recognition. The test tubes were filled with 0.5 mL of the 0.018% EDTA result, 1.0 mL of the Fe–EDTA result (0.12% FAS and 0.24% EDTA), and 1.0 mL of the DMSO (0.80% v/v DMSO in 0.1 M phosphate buffer, pH 7.2). After 0.5 mL of ascorbic acid (0.22%) was added to start the process, it was grown for 15 minutes at 80–90 ºC in a water bath. Following the incubation period, 1.0 mL of cool Cl₃CCOOH (17.5% w/v) was added to complete the response. Following the addition of 3.0 mL of Nash reagent to every tube, the tubes were permissible to stand at space temperature for 15 minutes. The quantity of colour generated during the reaction at 412 nm was measured using spectrophotometer in relation to a blank reagent.

Percentage of activity related to scavenging = [(A₀ - A_C)/A₀] x100

Superoxide radical scavenging assay

The MET-VitB2-NBT system was used to investigate a superoxide radical in an indirect manner.[29, 30] After adjusting, the aqueous mixture to a pH of 7.8 using a 0.067 M phosphate barrier, which contained 0.5 mL of VitB2, 1 mL of NBT (Nitro blue-tetrazolium), 1 mL of 0.05M MET (methionine), and chemicals at different quantities. They were made clearer by a bright lamp that provided constant light at 25 degrees Celsius. At 560 nm, the optical absorbance (A) of the outcome was determined under various illumination conditions. Every test was conducted three times, and the mean and standard deviation of the data are displayed.[31] Every test was conducted three times, and different complex concentrations were made in order to raise the concentration of the compounds to a level where about 50% of the compounds' scavenging activity could be seen. Furthermore, the subsequent formula was used to determine the proportion of scavenging activity = [(A₀ - A_C)/A₀] x 100 (The complexes relative nonexistence and existence are represented by the absorbances A₀ and A_C). The 50% of scavenging activity can be constructed using the percentage of scavenging activity results (IC₅₀).

2.4. Anti- inflammatory activity

The reaction contained 1% bovine albumin fraction solution and test extracts. A small amount of HCl was supplementary to the reactions pH at 37°C. Aspirin was utilised as a standard medication and the extracts were incubate for 20 min at 37°C, followed by 20 minutes at 51°C. After cooling, the turbidity was measured spectrophotometrically at 660 nm.

% of inhibition = (OD of Control - OD of Sample / OD of Control) X 100.

2.5. Research on molecular docking

Docking computations were performed using Docking Server. Using the MMFF94 force field, Docking Server was used to reduce the ligand molecules energy. The atoms of the ligand were partially charged with Gasteiger fields. Rotatable bonds were identified and non-polar hydrogen atoms were joined. To undertake docking analyses, the 4ICT - Oxidoreductase TB was utilised. The required hydrogen atoms, Kollman unified atom type charges, and solvation parameters were added using AutoDock tools. Affinity (grid) maps with grid points of 20×20×20 Å and a spacing of 0.375 Å were made using the Autogrid programme. AutoDock parameter set- and distance-dependent dielectric functions were used to calculate the electrostatic and Vander Waals terms, respectively. Docking simulations were performed using the Lamarckian genetic algorithm (LGA) and the Solis & Wets local search method. The starting orientation, position, and torsions of the ligand molecules were all chosen at random. Ten separate runs were used to produce each docking experiment, and each run was designed to terminate after a maximum of 250000 energy evaluations. 150 people were the target population. The search was conducted using quaternion and torsion steps of 5, together with a translational step of 0.2 Å.

3.1. Spectral analysis of the compounds (1-7)

3,3,6,6-tetramethyl-9-(p-tolyl)-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (1)

M.F.: C₂₄H₂₉NO₂; m.p.: 109 ^°C; Yield: 82 %; IR (cm^-1); 1606.09 (C=O); 3183.76 – 2875.13 (Aromatic C-H); 1651.53 (C=C); 3277.83-3433.56 (N-H). ¹H NMR ppm; d: 0.85 (s, 6H), 0.99 (s, 6H), 1.98 (s, 4H), 2.17 (s, 3H), 2.51 (s, 4H), 4.74 (s, 1H), 6.99 (dd, 4H), 9.34 (s, 1H). ¹³C NMR; d: 20.99, 26.83, 29.56, 32.56, 32.87, 40.32, 50.65, 112.11, 127.99, 128.62, 134.85, 144.68, 149.85, 195.21. Theoritical value of MS: m/z. 363.22 [M+].

9-(4-methoxyphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H) -dione (2)

M.F.: C₂₄H₂₉NO₃; m.p.: 110 ^°C; Yield: 86 %; IR (cm^-1); 1606.93 (C=O); 3073.42 – 2954.71 (Aromatic C-H); 1640.88 (C=C); 3200.62-3442.58 (N-H). ¹H NMR, ppm; d: 0.86 (s, 6H), 1.0 (s, 6H), 1.97 (s, 4H), 2.46 (s, 4H), 3.89 (s, 3H), 4.74 (s, 1H), 6.68 (d, J = 8.8 Hz,2H), 7.02 (d, J = 8.8 Hz, 2H), 9.27 (s, 1H). ¹³C NMR; d: 26.20, 29.57, 32.30, 32.59, 40.52, 50.72, 63.17, 112.17, 113.84, 128.96, 139.96, 149.57, 156.84, 194.96. Theoritical value of MS: m/z. 379.21 [M+].

9-(4-bromophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (3)

M.F.: C₂₃H₂₆BrNO₂; m.p.: 110 ^ºC; Yield: 84 %; IR (cm^-1); 1609.10 (C=O); 3175.38 – 3058.08 (Aromatic C-H); 1656.21 (C=C); 3254.46-3449.11 (N-H). ¹H NMR, ppm; d: 0.86 (s, 6H), 1.0 (s, 6H), 1.96 (s, 4H), 2.43 (s, 4H), 4.76 (s, 1H), 7.11 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 9.38 (s, 1H). ¹³C NMR; d: 26.92, 29.51, 32.61, 33.27, 40.51, 50.60, 111.47, 118.94, 130.37, 130.91, 146.96, 150.04, 194.96. Theoritical value of MS: m/z. 427.11 [M+].

9-(3-hydroxy-4-methoxyphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydro acridine-1,8 (2H,5H)-dione (4)

M.F.: C₂₄H₂₉NO₄; m.p.: 112 ^ºC; Yield: 79 %; IR (cm^-1); 1610.77 (C=O); 3191.78 – 2959.69 (Aromatic C-H); 1644.20 (C=C); 3288.83-3436.62 (N-H). ¹H NMR, ppm; d: 0.83 (s, 6H), 1.0 (s, 6H), 2.02 (s, 4H), 2.42 (s, 4H), 3.66 (s, 3H), 4.79 (s, 1H), 6.61 (s, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 12.0 Hz, 1H), 7.04 (s, 1H), 9.32 (s, 1H). ¹³C NMR; d: 26.89, 29.57, 32.59, 33.15, 40.52, 50.69, 55.18, 110.77, 111.77, 114.35, 120.42, 129.03, 149.03, 149.91, 159.12, 194.96. Theoritical value of MS: m/z. 395.21 [M+].

9-(3-methoxyphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (5)

M.F.: C₂₄H₂₉NO₃; m.p.: 113 ^ºC; Yield: 76 %; IR (cm^-1); 1616.38 (C=O); 3189.53 – 2957.17 (Aromatic C-H); 1643.55 (C=C); 3280.46-3434.89 (N-H). ¹H NMR, ppm; d: 0.87 (s, 6H), 1.0 (s, 6H), 1.96 (s, 4H), 2.45 (s, 4H), 3.88 (s, 3H), 4.73 (s, 1H), 6.68 (d, J = 8.8 Hz,2H), 7.04 (d, J = 8.8 Hz, 2H), 9.28 (s, 1H). ¹³C NMR; d: 27.03, 29.32, 32.58, 40.57, 50.77, 55.97, 111.92, 112.17, 115.91, 118.56, 129.96, 140.57, 145.90, 146.0, 149.44, 160.54, 194.95. Theoritical value of MS: m/z. 379.21 [M+].

3,3,6,6-tetramethyl-9-(3,4,5-trimethoxyphenyl)-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (6)

M.F.: C₂₆H₃₃NO₅; m.p.: 116 ^ºC; Yield: 82 %; IR (cm^-1); 1607.81 (C=O); 3170.89 – 2953.78 (Aromatic C-H); 1641.62 (C=C); 3275.33-3496.73 (N-H). ¹H NMR, ppm; d: 0.91 (s, 6H), 1.02 (s, 6H), 2.06 (s, 4H), 2.51 (s, 4H), 3.65 (s, 3H), 3.66 (s, 6H), 4.79 (s, 1H), 6.42 (s, 2H), 9.33 (s, 1H). ¹³C NMR; d: 26.81, 29.61, 33.10, 40.55, 50.72, 56.09 (C-21, 22), 60.15 (C-23), 105.36, 111.73, 135.94, 143.24, 149.96, 152.63, 195.10. Theoritical value of MS: m/z. 439.24 [M+].

9-(3,4-dimethoxyphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8 (2H,5H)-dione (7)

M.F.: C₂₅H₃₁NO₄; m.p.: 113 ^ºC; Yield: 83%; IR (cm^− 1); 1609.80 (C = O); 3200.65–3273.24 (Aromatic C-H); 1632.17 (C = C); 3446.31 (N-H). ¹H NMR, ppm; δ: 0.85 (s, 6H), 1.01 (s, 6H), 1.99 (s, 4H), 2.50 (s, 4H), 3.83 (s, 6H), 4.78 (s, 1H), 7.15 (d, J = 8.4Hz, 1H), 7.22 (d, J = 8.4Hz, 1H), 7.31 (s, 1H), 9.40 (s, 1H). ¹³C NMR; δ: 26.38, 29.50, 33.14, 40.44, 50.89, 56.1 (C-22, 23), 111.54, 112.7, 114.6, 128.01, 129.92, 130.45, 146.52, 150.12, 195.07. Theoritical value of MS: m/z. 409.52 [M+].

3.2. Anti-diabetic activity

A class of metabolic illnesses known as diabetes mellitus is characterised by persistently elevated blood sugar levels. Inhibiting the enzymes responsible for breaking down carbs into monosaccharides, which is the primary factor in elevated blood glucose, is one treatment strategy for reducing hyperglycemia. Therefore, creating substances that block the activity of enzymes that hydrolyze carbohydrates may be a helpful strategy for managing diabetes. The results suggest that compounds 2 and 7 have higher activity than compared to standard acarbose one and the IC₅₀ values are 26 and 25 are shown in (Table 1). The compounds 2 and 7 are used with a proper diet and control high blood sugar in people with type diabetes and compound 4 has moderated activity were observed and lower diabetic activity observed at remaining moieties was shown in Fig. 1. Therefore, its likely that the biomolecules increased the synthetic drugs ability to prevent diabetes. The aforementioned findings, however, imply that artificial acridine derivatives may be more efficient ant-diabetic particles in blocking the enzymes that break down carbohydrates, and this could prove to be a useful strategy for the treatment of diabetes.

Table 1

Anti-diabetic activity of acridine derivatives **(1–7)**
Concentration of the Sample (mg/ml)	1	2	3	4	5	6	7	% of inhibition of Acarbose
20	25.2	35.6	15.0	39.8	36.5	32.8	40.2	33.54
40	36.8	46.5	25.9	53.7	52.6	56.3	52.6	44.20
60	48.2	56.2	39.5	65.3	69.7	60.2	64.9	55.13
80	59.8	67.2	52.5	78.2	85.2	73.3	77.6	65.76
100	70.5	77.0	64.2	91.6	99	86.5	89.2	79.43
IC₅₀ value	37	26	48	30	37	36	25	32.34

3.3. Inhibitory action against inflammation

An established source of inflammation is albumen denaturation. Protein denaturation causes the production of autoantigen in certain cases of arthritic disease. Electrostatic hydrogen, hydrophobic, and disulfide bonding are all altered throughout the denaturation process. The typical anti-inflammatory medication aspirin was used, as indicated by Table 2 and Fig. 2. 100µg/ml, 200µg/ml, 300µg/ml, 400µg/ml, and 500µg/ml were agreed upon protein denaturation concentrations. The comparison of compounds 4 and 6 shows better activity the compared to standard aspirin. compound 4 the % of cytotoxicity for 100 µg/ml as 48%, 200 µg/ml as 61%, 300 µg/ml as 73.5%, 400 µg/ml as 86.5 and 500 µg/ml as 70.6% and compound 6 the % of cytotoxicity for 100 µg/ml as 40%, 200 µg/ml as 50%, 300 µg/ml as 60%, 400 µg/ml as 70% and 500 µg/ml as 80%. For all other drugs with lesser activity, these inhibition values are compared to those of aspirin. When the isolated compounds concentrations are 100, 200, 300, 400, and 500 µg/ml and its percentage of cytotoxicity values are compared with aspirin, albumen denaturation significantly changes. According to in-vitro investigations on anti-inflammatory effect, the compound's inhibition % using the albumen denaturation method is indicated. Compounds 4 and 6 have larger inhibition percentages than the other chemicals.

Table 2

Anti-inflammatory activity of acridine derivatives **(1–7)**
Concentration of the Sample (µg /ml)	(% of Protein Denaturation)							Aspirin
Concentration of the Sample (µg /ml)	1	2	3	4	5	6	7	Aspirin
100	40	30	37	48	30.0	40.0	30.4	40
200	54	40	48	61	40.5	50.0	41.5	50.5
300	68.5	50	60	73.5	50.0	60.0	52.5	60.0
400	82.5	60.0	72.0	86.5	60.2	70.0	64.2	70.0
500	97	70.0	82.0	98.5	70.6	80.0	75.0	80.5
IC₅₀ value	151	150	135	90	150	100	165	100

3.4. Anti – Oxidant activity by DPPH scavenging assay method

A common test for determining antioxidant activity, DPPH radical scavenging activity assessment provides a quick way to check the radical scavenging capabilities of particular substances. The absorption maxima of a freshly made DPPH solution are observed at 517 nm. Reduced absorbance is the result of the antioxidant in the standard molecule quenching the DPPH free radical and converting it to dark 1,1'-diphenyl-1-picrylhydrazine or a substituted analogue of hydrazine. As a result, it will encourage quick drops in absorption, giving the substance more powerful antioxidant action. Acridine derivatives DMSO solutions % activity was measured and contrasted with ascorbic acid, the internal standard.

Compound 3 has the highest level of antioxidant activity when compared to ascorbic acid, with an IC₅₀ value of 0.15 mg/ml. The strongest molecules have methoxy and hydroxyl groups as substituents, and even at extremely low concentrations, they exhibit good antioxidant action. Cytotoxicity of compound 3 for 200 mg/ml as 56.8%, 400 mg/ml as 68.0%, 600 mg/ml as 80.9%, 800 mg/ml as 93.1% and 1000 mg/ml as 100.9%, respectively. All the inhibition values are compared with Ascorbic acid for 200, 400, 600, 800 and 1000 mg/ml concentrations. Hence, this assay provided in sequence on the reactivity of the samples with a constant free radical. In the process of examining the anti-oxidant activity technique, the compounds ability to inhibit the DPPH scavenging assay was investigated. Compound 3 exhibits the highest level of antioxidant activity out of all seven chemicals. The graphical representation of percentage inhibition at different concentrations (Table 3) of compounds 1–7 are shown in Fig. 3.

Table 3

The *in vitro* antioxidant activities of acridine derivatives **1–7** by DPPH method
Concentration of the Sample (mg/ml)	1	2	3	4	5	6	7	Ascorbic acid
200	26.6	39.8	56.8	21.5	12.0	24.5	14.6	35.4
400	39.8	55.0	68.0	33.2	24.6	38.2	31.5	46.13
600	52.3	71.0	80.9	43.9	36.3	52.3	49.2	57.53
800	66.0	87.0	93.1	53.6	48.8	66.4	66.9	68.87
1000	79.0	99.0	100.9	63.8	60.4	80.9	70.4	80.33
IC₅₀ value	0.4	0.32	0.15	0.35	0.5	0.43	0.47	0.28

3.5. Molecular docking studies compounds (1–7)

3.5.1. Score for docking energy

The cancer protein (PDB CODE: 4ICT) is used in the insilico molecular docking research to investigate compounds 1–7. The calculated free energy of binding, estimated inhibition constant, total intermolecular energy, electrostatic energy, van der Waals + hydrogen bond + desolv energy, and interaction surface are shown in Table 4. The synthesised moieties are firmly docked with the oxidoreductase tuberculosis protein (Fig. 4). The compound 4 & 6 shows the lowest inhibition constant 1.22 µM and the compound 7 shows the highest inhibition constant 608.73 µM. The other compounds (1, 2, 3, 5) are showing the inhibition constants 308.73, 396.19, 233.71, 389.32, 82.60, 608.73 and 225.12 µM respectively. All of the compounds (1–7) are clearly shown to enter the protein cavities active binding region by the 2D ligand–protein pictures (Fig. 5). A variety of compounds, including asparagine, methionine, threonine, phenylalanine, leucine, arginine, and other amino acids present in proteins, interact with the amino acids of the protein (Table 5).

Table 4

Docking energy score of the compound **1–7**
Entry	Rank	Estimated Free Energy of Binding kcal/mol	Estimated Inhibition Constant, Ki µM	Vander wall + Hydrogen bond + desolv Energy kcal/mol	Electrostatic Energy kcal/mol	Total Inter molecular Energy kcal/mol	Interaction Surface
1	1	-8.88	308.73	-9.20	+ 0.02	-9.18	619.287
2	1	-8.73	396.19	-9.40	+ 0.01	-9.39	631.752
3	1	-9.05	233.71	-9.34	-0.00	-9.34	585.673
4	1	-8.07	1.22	-8.81	+ 0.03	-8.78	648.362
5	1	-8.74	389.32	-9.31	-0.01	-9.32	609.068
6	1	-8.07	1.22	-9.12	+ 0.04	-9.08	696.246
7	1	-8.48	608.73	-9.34	+ 0.08	-9.26	646.623

Table 5

Decomposed Interaction Energies in kcal/mol
Compods.	hydrogen bonds	halogen-bond	hydrophobic	other
1	GLN385 (-1.2573) ASN74 (-0.9144)		PRO285 (-0.9662) PHE280 (-0.8706) LEU73 (-0.6762) LEU284 (-0.5828) LEU76 (-0.428) MET62 (-0.4137) VAL78 (-0.3306)	ASP282 (-0.6671) ARG386 (-0.563) THR77 (-0.1388) THR65 (0.2073) ARG72 (0.3668)
2	GLN385 (-0.6131)		VAL78 (-0.3758) PHE280 (-0.199) TRP182 (0.2673) PHE168 (1.0579) ALA233 (2.1254)	THR229 (-13.420) ARG386 (-0.3351) THR77 (-0.1851)
3	GLN385 (-0.1836)	VAL228 (0.2221)	LEU76 (-7.2311) PHE168 (-1.7201) VAL78 (-0.0728) TRP182 (-0.0408)	THR229 (-0.8394) ASN85 (-0.4424) ALA233 (-0.3009) VAL83 (-0.0316)
4	ASN74 (-0.8605)		PRO285 (-1.121) VAL83 (-1.0904) PHE168 (-1.0653) PHE280 (-0.9097) LEU76 (-0.5962) MET62 (-0.4668) LEU284 (-0.4253)	GLN385 (-1.4494) ASP282 (-0.7831) LEU73 (-0.6386) ARG386 (-0.5482) VAL78 (-0.4569) THR77 (-0.3865) THR65 (0.6626) ARG72 (0.8387)
5	GLN385 (-0.7845)		PHE168 (-1.2887) VAL78 (-0.794) LEU76 (-0.3584) ALA233 (-0.2039) PHE280 (-0.1686)	THR229 (-1.9478) ARG386 (-0.2879) THR77 (-0.2475)
6	GLN385 (-1.6676) ASN74 (-0.6021) THR77 (-0.1802)		PRO285 (-1.0586) PHE168 (-0.9425) VAL83 (-0.9309) PHE280 (-0.8805) LEU284 (-0.5639) VAL78 (-0.3722) LEU76 (-0.3325) MET62 (-0.17)	ASP282 (-0.7814) ARG386 (-0.6977) LEU73 (-0.3964) ALA233 (-0.2701) THR65 (-0.1846) ARG72 (-0.0384)
7	THR77 (-0.2999) ASN74 (-0.6422)		PHE168 (-1.1161) PHE280 (-0.9463) PRO285 (-0.9002) VAL83 (-0.707) VAL78 (-0.6173) LEU284 (-0.4429) MET62 (-0.2992) LEU76 (-0.23)	GLN385 (-1.7297) ASP282 (-0.6986) ARG386 (-0.5267) LEU73 (-0.3897) THR65 (-0.3791) ARG72 (-0.3177)

3.5.2. Ligand-Protein hydrogen bond

Every substance (1–7) that forms hydrogen bonds with the chosen proteins amino acids The compounds (1, 2, 5, 6) have a nitrogen atom that forms bonds with asparagine, glutamine, and threonine, with respective bond lengths of 3.76, 3.21, 3.34, and 2.91 Å. The hydrogen bonds between the oxygen atoms of compounds 1, 6, and 7 and asparagine, threonine, and laminin have bond lengths of 3.27, 3.52, 3.10, 2.96, and 3.60 Å. Compound 1 has both nitrogen and oxygen atoms in a hydrogen bond with asparagine and glutamine, with bond lengths of 3.49 and 3.76 Å, respectively (Table 6). Figure 6 displays the graphs of the hydrogen bonding between ligands and proteins. When it comes to the tuberculosis protein, all of the drugs are more active in insilico molecular docking investigations.

Table 6

Ligand-Protein hydrogen bonds of compounds (**1–7)**
Compds.	hydrogen bonds	hydrophobic	pi-pi	other
1	N1 (7) - ASN74 [3.76] H5 (32) - ASN74 [3.27] O1 (19) - GLN385 [3.49]	C12 (13) - MET62 [3.56] C13 (14) - MET62 [3.81] C3 (3) - LEU73 [3.68] C16 (17) – LEU76 [3.57] C24 (27) - VAL78 [3.64] C14 (15) - PHE280 [3.61] C14 (15) - LEU284 [3.61] C7 (8) - PRO285 [3.28] C10 (11) - PRO2€85 [3.01]		O2 (20) - MET62 [3.59] C17 (18) - THR65 [2.96] C11 (12) - THR65 [3.78] C12 (13) - THR65 [3.36] C11 (12) - ARG72 [3.64] C16 (17) - ARG72 [3.20] C17 (18) - ARG72 [2.83] H5 (32) - LEU73 [2.42] N1 (7) - LEU73 [3.41] H5 (32) - ASN74 [3.81] C10 (11) - ASN74 [3.86] C16 (17) - ASN74 [3.77] C20 (23) - THR77 [3.75] C24 (27) - THR77 [3.13] C3 (3) - ASP282 [3.56] C15 (16) - ASP282 [3.32] N1 (7) - PRO285 [3.63] H5 (32) - PRO285 [3.53] C1 (1) - GLN385 [3.36] C19 (22) - GLN385 [3.11] C20 (23) - GLN385 [3.06] C21 (24) - GLN385 [3.66] C5 (5) - GLN385 [3.38] C6 (6) - GLN385 [3.12] C18 (21) - GLN385 [3.21] C22 (25) - GLN385 [3.73] C23 (26) - GLN385 [3.52] C1 (1) - ARG386 [3.48]
2	N1 (7) - GLN385 [3.21] H5 (33) - GLN385 [2.66]	C12 (13) - VAL78 [3.28] C13 (14) - VAL78 [3.72] C24 (28) - TRP182 [3.85] C1 (1) - ALA233 [3.50] C6 (6) - ALA233 [3.61] C23 (26) - ALA233 [3.90] C15 (16) - PHE280 [3.23]	C19 (22) - PHE168 [3.47] C20 (23) - PHE168 [3.19] C21 (24) - PHE168 [3.58]	C16 (17) - THR77 [2.95] O2 (20) - VAL78 [3.40] C22 (25) - THR229 [3.24] C23 (26) - THR229 [3.87] O1 (19) - ALA233 [3.52] H5 (33) - GLN385 [3.88] C16 (17) - GLN385 [3.59] C7 (8) - GLN385 [3.67] C10 (11) - GLN385 [3.45] C3 (3) - ARG386 [3.80]
3	O1(19)- GLN385 [3.15] O1 (19) - THR77 [3.34]	C15 (16) - LEU76 [3.14] C18 (21) - VAL78 [3.87] C21 (24) - VAL78 [3.90 C22 (25) - VAL78 [3.83] C23 (26) - VAL78 [3.82] C3 (3) - VAL78 [3.23] C4 (4) - VAL78 [3.51]	C22 (25) - PHE168 [3.70] C18 (21) - PHE168 [3.85] C23 (26) - PHE168 [3.49] C21 (24) - TRP182 [3.75]	Br1 (27) - VAL228 [3.80]
4	H5 (34) - ASN74 [3.49]	C1 (1) - MET62 [3.45] C6 (6) - MET62 [3.76] C14 (15) - LEU76 [3.39] C1 (1) - VAL83 [3.53] C24 (29) - PHE168 [3.47] C12 (13) - PHE280 [3.64] C16 (17) - PHE280 [3.43] C17 (18) - PHE280 [3.76] C16 (17) - LEU284 [3.36] C3 (3) - PRO285 [3.29] C4 (4) - PRO285 [3.60]	C20 (23) - PHE168 [3.84] C21 (24) - PHE168 [3.85]	O1 (19) - MET62 [3.71] C15 (16) - THR65 [2.93] C1 (1) - THR65 [3.63] C2 (2) - THR65 [3.89] C14 (15) - ARG72 [3.76] C15 (16) - ARG72 [2.92] H5 (34) - LEU73 [3.03] C24 (29) - THR77 [3.42] O4 (28) - VAL78 [3.78] O3 (27) - PHE168 [3.71] O4 (28) - PHE168 [3.69] C17 (18) - ASP282 [3.80] N1 (7) - PRO285 [3.80] H5 (34) - PRO285 [3.60] C12 (13) - GLN385 [3.41] C17 (18) - GLN385 [3.87] C22 (25) - GLN385 [3.43] C23 (26) - GLN385 [3.10] C7 (8) - GLN385 [3.66] C8 (9) - GLN385 [3.37] C13 (14) - GLN385 [3.32] C18 (21) - GLN385 [3.45] C12 (13) - ARG386 [3.27]
5	N1 (7) - GLN385 [3.34] H5 (33) - GLN385 [2.80]	C15 (16) - LEU76 [3.90] C24 (28) - VAL78 [3.62] C1 (1) - VAL78 [3.12] C6 (6) - VAL78 [3.65] C12 (13) - ALA233 [3.50] C13 (14) - ALA233 [3.61] C19 (22) - ALA233 [3.80] C17 (18) - PHE280 [3.22]	C22 (25) - PHE168 [3.44] C23 (26) - PHE168 [3.72] C21 (24) - PHE168 [3.62]	C14 (15) - THR77 [3.06] C24 (28) - THR77 [3.13] O3 (27) - VAL78 [3.73] O1 (19) - VAL78 [3.44] O3 (27) - PHE168 [3.67] C20 (23) - THR229 [3.33] O2 (20) - ALA233 [3.48] C14 (15) - GLN385 [3.89] C3 (3) - GLN385 [3.77] C4 (4) - GLN385 [3.90] C17 (18) - ARG386 [3.12]
6	H5 (37) - ASN74 [3.52] O5 (31) - THR77 [3.80] O5 (31) - GLN385 [3.84]	C1 (1) - MET62 [3.22] C6 (6) - MET62 [3.47] C14 (15) - LEU76 [3.45]	C21 (24) - PHE168 [3.72]	O1 (19) - MET62 [3.36] C1 (1) - THR65 [3.74] C15 (16) - THR65 [3.12] C15 (16) - ARG72 [3.07] H5 (37) - LEU73 [3.49] C26 (32) - THR77 [3.06] O3 (27) - PHE168 [3.40] O4 (29) - ALA233 [3.82] O2 (20) - PHE280 [3.65] C17 (18) - ASP282 [3.75] H5 (37) - PRO285 [3.87] C7 (8) - GLN385 [3.64] C8 (9) - GLN385 [3.71] C10 (11) - GLN385 [3.77] C12 (13) - GLN385 [3.87] C19 (22) - GLN385 [3.27] C20 (23) - GLN385 [3.65] C12 (13) - ARG386 [3.45]
7	O4 (29) - THR77 [3.01] H5 (35) - ASN74 [3.60]	C12 (13) - MET62 [3.37] C13 (14) - MET62 [3.77] C16 (17) - LEU76 [3.27] C24 (28) - VAL78 [3.89] C12 (13) - VAL83 [3.29] C24 (28) - PHE168 [3.66] C14 (15) - PHE280 [3.54] C15 (16) - PHE280 [3.86] C1 (1) - PHE280 [3.68] C14 (15) - LEU284 [3.44] C7 (8) - PRO285 [3.81] C10 (11) - PRO285 [3.50]	C21 (24) - PHE168 [3.72] C22 (25) - PHE168 [3.40]	O2 (20) - MET62 [3.81] C17 (18) - THR65 [2.83] C11 (12) - THR65 [3.89] C12 (13) - THR65 [3.79] C17 (18) - ARG72 [3.11] H5 (35) - LEU73 [3.32] C25 (30) - THR77 [3.30] C24 (28) - THR77 [3.39] O4 (29) - VAL78 [3.74] O3 (27) - VAL78 [3.87] O3 (27) - PHE168 [3.56] C15 (16) - ASP282 [3.76] H5 (35) - PRO285 [3.63] C1 (1) - GLN385 [3.34] C15 (16) - GLN385 [3.79] C3 (3) - GLN385 [3.76] C4 (4) - GLN385 [3.55] C5 (5) - GLN385 [3.33] C6 (6) - GLN385 [3.29] C18 (21) - GLN385 [3.55] C19 (22) - GLN385 [3.63] C23 (26) - GLN385 [3.83] C1 (1) - ARG386 [3.27]

The findings of the anti-diabetic properties of acridine derivatives indicate that compounds 2 and 7 exhibit greater activity in comparison to the typical acarbose one, with IC₅₀ values of 26 and 25, respectively. When combined with a healthy diet, compounds 2 and 7 help persons with type diabetes manage their high blood sugar levels. Compound 4 showed decreased diabetic activity and moderate exercise. According to in-vitro investigations on anti-inflammatory effect, the compounds inhibition % using the albumen denaturation method is indicated. Compounds 4 and 6 have larger inhibition percentages than the other compounds. The oxidoreductase tuberculosis protein is tightly docked with the synthesised moieties. Compound 7 exhibits the highest inhibition constant of 608.73 µM, while compounds 4 and 6 display the lowest inhibition constant of 1.22 µM. The inhibition constants for the remaining compounds (1, 2, 3, 5, & 7) are 308.73, 396.19, 233.71, 389.32, and 608.73 µM.

Acknowledgement

One of the authors Dr. P. Punitha, Assistant Professor, Department of Chemistry, Srinivasa Subbaraya Government Polytechnic College, Puttur, Mayiladuthurai, is thankful to Sasthra University, Thanjavur for providing instrumental facility and Thruvalluvar University for providing biological studies.

Funding

No funding was received to assist with the preparation of this manuscript.

Authors and affiliations

Department of Chemistry, Annamalai University, Annamalainagar, Tamilnadu, India

Mr. Immani Ramachandra Rao

Department of Chemistry, Annamalai University, Annamalainagar, Tamilnadu, India

Department of Chemistry, Srinivasa Subbaraya Government Polytechnic College, Puttur, Mayiladuthurai, Tamilnadu, India.

Dr. P. Punitha

PG &Research Department of Chemistry, Government Arts College, C. Mutlur, Tamilnadu, India

Dr. B. Premalatha

Department of Chemistry, Andhra University, Visakhapatnam, India

Mr. Thota Siva Prasad

Corresponding author

“Correspondence to P. Punitha”

Ethics Declaration

This research doesn’t involve Human Participants and Animals.

Ethics Approval

Not applicable.

Consent to participate

All authors whose names appear on the submission:

Made substantial contributions to the acquisition, analysis, or interpretation of data; Drafted the work or revised it critically for important intellectual content; approved the version to be published; Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Consent for publication

All authors contributed to the study conception and design. All authors read and approved the final manuscript.

Availability of Data and Materials

All data’s are available in the manuscript.

Competing Interests

The authors declare no competing interests.

Author Contribution

Immani Ramachandra Rao, Writing – original draft, Data curation, Conceptualization, P. Punitha, Writing – review & editing. B. Premalatha, writing, data predicting, reviewing, editing, and approving the final draft. Thota Siva Prasad, Writing – original draft, Data curation.

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Synthesis, spectral, anti-diabetic, anti-inflammatory, antioxidant, and molecular docking investigations of acridine derivatives

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Abstract

Figures

1. Introduction

2. Experimental

2.1. Synthetic route of acridine derivatives

2.2. Measurements

2.3. Activity of Antioxidant

2.4. Anti- inflammatory activity

2.5. Research on molecular docking

3. Results and Discussion

3.2. Anti-diabetic activity

3.3. Inhibitory action against inflammation

3.4. Anti – Oxidant activity by DPPH scavenging assay method

3.5. Molecular docking studies compounds (1–7)

3.5.1. Score for docking energy

3.5.2. Ligand-Protein hydrogen bond

4. Conclusion

Declarations

References

Schemes

Additional Declarations

Supplementary Files

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