Ionic liquid mediated four-component synthesis of novel phthalazinone based indole-pyran hybrids as cytotoxic agents

2.1 Chemistry: General procedure for the synthesis of novel phthalazinone based indole-pyran hybrids 5a-j

Dimethyl phthalate 1 (1 eq, 1.94 g, 10 mmol), cyanoacetohydrazide 2 (1 eq, 0.99 g, 10 mmol), 1H-indole-3-carbaldehydes 3 (1 eq, 10 mmol) and malononitrile (1 eq, 0.66 g, 10 mmol)/ ethyl 2-cyanoacetate 4a-4b (1 eq, 1.13 g, 10 mmol) were added into [BMIM]BF₄ (8 eq, 18.08 g, 80 mmol) and heated at 75–80 °C for 60–120 min. Thin layer chromatography was employed to monitor the course of the reaction. After the reaction is complete, the reaction mass was brought to room temperature and cold water was added. The resulting mixture was stirred for 30 min and the crude solid was separated by filtration followed by recrystallization from ethanol solvent. The recrystallized solid was dried at 60–65 °C overnight to afford pure novel phthalazinone based indole-pyran hybrids 5a-j.

2.2 2-Amino-6-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-4-(1H-indol-3-yl)-4H-pyran-3,5-dicarbonitrile 5a

Yield: 85 %; IR (KBr) cm⁻¹: 3385 (broad, —NH), 2189 (—CN), 1644 (C⚌O); ¹H NMR (DMSO‑d₆, 400 MHz): δ 4.8 (s, 1H, —CH), δ 7.0–8.2 (m, 11H, Ar-H, and NH₂), δ 11.5 (s, 1H, —NH), δ 12.2 (s, 1H, —NH); ¹³C NMR (DMSO‑d₆, 100 MHz): δ 43.1, 52.5, 63.2, 111.8, 114.1, 115.6, 115.9, 116.6, 122.5, 124.0, 127.2, 127.7, 128.2, 128.3, 135.5, 146.2, 153.4, 155.3, 160.5, 162.2, 166.2 172.2, 177.2; [M+H⁺]: 423.

2.3 2-Amino-6-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-4-(1-methyl-1H-indol-3-yl)-4H-pyran-3,5-dicarbonitrile 5b

Yield: 84 %; IR (KBr) cm⁻¹: 3405 (broad, —NH), 2187 (—CN), 1658 (C⚌O); ¹H NMR (DMSO‑d₆, 400 MHz): δ 3.6 (s, 3H, —CH₃), δ 4.8 (s, 1H, —CH), δ 7.0–8.3 (m, 11H, Ar-H, and NH₂), δ 11.4 (s, 1H, —NH); ¹³C NMR (DMSO‑d₆, 100 MHz): δ 34.1, 43.1, 52.2, 63.1, 110.9, 114.1, 116.0, 118.6, 119.1, 120.7, 122.3, 124.1, 125.1, 127.4, 128.2, 128.3, 139.2, 146.2, 148.4, 153.4, 163.2, 166.8, 172.0, 177.2; [M+H⁺]: 436.

2.4 2-Amino-6-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-4-(1-ethyl-1H-indol-3-yl)-4H-pyran-3,5-dicarbonitrile 5c

Yield: 83 %; IR (KBr) cm⁻¹: 3408 (broad, —NH), 2188 (—CN), 1659 (C⚌O); ¹H NMR (DMSO‑d₆, 400 MHz): δ 1.3 (t, 3H, —CH₃), 4.2 (q, 2H, —CH₂), δ 4.9 (s, 1H, —CH), δ 7.0–8.2 (m, 11H, Ar-H, and NH₂), δ 11.6 (s, 1H, —NH); ¹³C NMR (DMSO‑d₆, 100 MHz): δ 12.2, 41.3, 43.2, 53.1, 64.2, 111.9, 115.2, 116.1, 118.7, 119.0, 120.8, 122.1, 123.2, 124.5, 127.6, 128.3, 128.4, 138.3, 145.3, 148.5, 153.3, 162.4, 166.7, 172.1, 177.3; [M+H⁺]: 451.

2.5 2-Amino-4-(5-chloro-1H-indol-3-yl)-6-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-4H-pyran-3,5-dicarbonitrile 5d

Yield: 81 %; IR (KBr) cm⁻¹: 3388 (broad, —NH), 2187 (—CN), 1654 (C⚌O); ¹H NMR (DMSO‑d₆, 400 MHz): δ 4.8 (s, 1H, —CH), δ 7.0–8.2 (m, 10H, Ar-H, and NH₂), δ 11.5 (s, 1H, —NH), δ 12.2 (s, 1H, —NH); ¹³C NMR (DMSO‑d₆, 100 MHz): δ 42.3, 53.7, 63.2, 110.0, 111.4, 113.5, 114.8, 115.6, 121.3, 124.1, 128.1, 128.9, 129.2, 129.4, 135.6, 145.1, 152.3, 155.2, 161.4, 162.4, 171.3, 176.5; [M⁺]: 456 and [M⁺²]: 458.

2.6 2-Amino-4-(5-bromo-1H-indol-3-yl)-6-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-4H-pyran-3,5-dicarbonitrile 5e

Yield: 81%; IR (KBr) cm⁻¹: 3382 (broad, —NH), 2182 (—CN), 1658 (C⚌O); ¹H NMR (DMSO‑d₆, 400 MHz): δ 4.7 (s, 1H, —CH), δ 7.1–8.2 (m, 10H, Ar-H, and NH₂), δ 11.6 (s, 1H, —NH), δ 12.1 (s, 1H, —NH); ¹³C NMR (DMSO‑d₆, 100 MHz): δ 43.1, 52.8, 62.1, 111.1, 111.4, 114.6, 114.9, 115.9, 120.3, 123.2, 127.1, 128.8, 129.3, 129.9, 135.7, 145.2, 152.5, 155.5, 161.5, 162.8, 171.4, 176.6; [M⁺]: 500 and [M⁺²]: 502.

2.7 Ethyl 2-amino-5-cyano-6-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-4-(1H-indol-3-yl)-4H-pyran-3-carboxylate 5f

Yield: 83 %; IR (KBr) cm⁻¹: 3404 (broad, —NH), 1720 (C⚌O); ¹H NMR (DMSO‑d₆, 400 MHz): δ 1.3 (t, 3H, –CH₃), δ 4.3 (q, 2H, –CH₂), δ 4.9 (s, 1H, –CH), δ 6.8–7.9 (m, 11H, Ar-H, and NH₂), δ 11.5 (s, 1H, —NH), δ 12.1 (s, 1H, —NH); ¹³C NMR (DMSO‑d₆, 400 MHz): δ 13.9, 43.1, 55.2, 61.5, 63.4, 111.8, 114.0, 114.2, 116.7, 122.5, 124.0, 127.3, 127.4, 127.7, 131.3, 146.3, 153.4, 155.3, 159.0, 165.7, 172.1, 177.2; [M+H⁺]: 470.

2.8 Ethyl 2-amino-5-cyano-6-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-4-(1-methyl-1H-indol-3-yl)-4H-pyran-3-carboxylate 5g

Yield: 84 %; IR (KBr) cm⁻¹: 3411 (broad, —NH), 1716 (C⚌O); ¹H NMR (DMSO‑d₆, 400 MHz): δ 1.3 (t, 3H, —CH₃), δ 3.8 (s, 3H, —CH₃), δ 4.3 (q, 2H, —CH₂), δ 4.9 (s, 1H, —CH), δ 6.9–7.9 (m, 11H, Ar-H, and NH₂), δ 11.6 (s, 1H, —NH); ¹³C NMR (DMSO‑d₆, 400 MHz): δ 14.1, 34.1, 41.4, 58.1, 62.5, 63.2, 111.0, 118.4, 119.1, 123.5, 124.1, 127.5, 128.6, 128.8, 133.2, 133.3, 142.1, 143.2, 145.0, 148.4, 152.5, 153.3, 158.1, 165.7, 172.0, 177.2; [M+H⁺]: 484.

2.9 Ethyl 2-amino-5-cyano-6-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-4-(1-ethyl-1H-indol-3-yl)-4H-pyran-3-carboxylate 5h

Yield: 83 %; IR (KBr) cm⁻¹: 3422 (broad, —NH), 1700 (C⚌O); ¹H NMR (DMSO‑d₆, 400 MHz): δ 1.1 (t, 3H, —CH₃), δ 1.2 (t, 3H, —CH₃), δ 4.1 (q, 2H, —CH₂), δ 4.3 (q, 2H, —CH₂), δ 4.9 (s, 1H, —CH), δ 6.9–7.9 (m, 11H, Ar-H, and NH₂), δ 11.4 (s, 1H, —NH); ¹³C NMR (DMSO‑d₆, 400 MHz): δ 14.0, 15.3, 41.2, 41.8, 58.2, 62.6, 64.2, 111.6, 118.6, 118.2, 123.6, 124.3, 126.6, 128.7, 128.9, 132.3, 133.2, 142.0, 143.3, 145.1, 148.3, 152.6, 153.6, 158.2, 164.6, 172.1, 177.3; [M+H⁺]: 498.

2.10 Ethyl 2-amino-4-(5-chloro-1H-indol-3-yl)-5-cyano-6-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-4H-pyran-3-carboxylate 5i

Yield: 81 %; IR (KBr) cm⁻¹: 3410 (broad, —NH), 1701 (C⚌O); ¹H NMR (DMSO‑d₆, 400 MHz): δ 1.2 (t, 3H, —CH₃), δ 4.2 (q, 2H, —CH₂), δ 4.8 (s, 1H, —CH), δ 6.8–7.9 (m, 10H, Ar-H, and NH₂), δ 11.6 (s, 1H, —NH), δ 12.2 (s, 1H, —NH); ¹³C NMR (DMSO‑d₆, 400 MHz): δ 14.2, 43.2, 54.2, 62.5, 63.6, 111.9, 114.1, 114.5, 116.8, 121.4, 124.1, 126.4, 127.5, 127.8, 131.5, 145.5, 153.5, 155.5, 159.1, 164.8, 172.3, 177.5; [M⁺]: 503 and[M⁺²]: 505.

2.11 Ethyl 2-amino-4-(5-bromo-1H-indol-3-yl)-5-cyano-6-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-4H-pyran-3-carboxylate 5j

Yield: 80 %; IR (KBr) cm⁻¹: 3411 (broad, —NH), 1712 (C⚌O); ¹H NMR (DMSO‑d₆, 400 MHz): δ 1.3 (t, 3H, –CH₃), δ 4.1 (q, 2H, —CH₂), δ 4.9 (s, 1H, —CH), δ 6.8–7.9 (m, 10H, Ar-H, and NH₂), δ 11.6 (s, 1H, —NH), δ 12.1 (s, 1H, —NH); ¹³C NMR (DMSO‑d₆, 400 MHz): δ 14.5, 43.6, 54.3, 62.7, 63.8, 111.8, 114.2, 115.4, 116.7, 121.5, 124.5, 126.6, 127.8, 128.9, 131.6, 146.8, 153.6, 156.8, 159.3, 164.9, 172.5, 177.6; [M⁺]: 547 and [M⁺²]: 549.

2.12 Cytotoxicity assay

Three human cancer cell lines, i.e., MCF-7 (breast), A549 (lung) and Hela (cervical) cells, were used. Cell viability of these cancer cells in the presence of the novel phthalazinone based indole-pyran hybrids (5a-j) was assessed by using a colorimetric MTT assay (Sigma USA) (Mosmann 1983). The cancer cells were seeded in 100 µL of appropriate medium at a density of 2 × 10⁵ cells and grown for 24 h in 96 well plate. This was followed by the addition of different concentrations of test compounds to the cells. After 48 hr incubation, each well was washed with PBS (200 µL) and then incubated with 10 % MTT solution for 2 h at 37 °C. Finally, a multimode reader was employed to determine the optical density of the solubilized formazan crystals at 570 nm (Tecan Infinite 200 PRO).

2.13 Molecular docking

The insilico analysis of the hybrids 5b and 5h, were executed using AutoDockTools 4.2 at the active site of human tankyrase-1 (Morris et al., 2009). The three-dimensional crystal structure of human tankyrase-1 was collected from RCSB (PDB ID: 7KKO) and used as the target protein. The protein molecule was processed by the removal of co-crystallized hetero molecules and water. The ChemDraw ultra 19.0 software was used to generate three-dimensional structures of active ligands 5b and 5h. Further, the energies were minimized using MOPAC (semiempirical quantum mechanics) with AM1 MOZYME geometry acceleration. Around ten conformations were generated for each ligand and the best pose was selected with relatively lower binding free energy. The co-crystal ligand 09L (olaparib) was redocked with the target protein to validate the docking results. The 3D and 2D visualizations of the docked complexes were analyzed using PyMol and LIGPLOT, respectively (Wallace et al., 1995).

2.14 ADME and drug likeliness analysis

Computational analysis of ADME and drug-likeness properties of the synthesized hybrids (5a-j) were determined using SwissADME program provided by the Swiss Institute of Bioinformatics, Lausanne, Switzerland (Daina et al., 2017).

3.1 Chemistry

To access the desired novel phthalazinone based indole-pyran hybrids 5a-j, a new synthetic methodology was developed employing a one-pot four-component reaction promoted by an ionic liquid. We selected dimethyl phthalate 1 (1 mmol), 2-cyanoacetohydrazide 2 (1 mmol), 1H-indole-3-carbaldehydes 3a (1 mmol), and malononitrile 4a (1 mmol) as in the model multicomponent reaction. Initially, in this model reaction, different parameters such as the different ionic liquids, temperature, and amount of ionic liquid were screened to identify an optimized condition. The ionic liquids used in this study were based on 1-butyl-3-methyl imidazolium cation with diverse anions such as chloride [BMIM]Cl, fluoride [BMIM]F, hydroxide [BMIM]OH, and tetrafluoroborate [BMIM]BF₄. The screening of the different ionic liquids was carried around 75 °C, and the model MCR proceeded with good yields (76–78%) with halogen-based ionic liquids [BMIM]Cl and [BMIM]Br (Table 1). However, the reaction times were higher, i.e., 240 min (entries 1 and 2). With [BMIM]OH ionic liquid, the yields were slightly better with a significant reduction in the reaction time (90 min, entry 3). The best result was shown by [BMIM]BF₄ and the reaction proceeded with an 85 % yield with 60 min of reaction time (entry 4). As the temperature plays a critical role in reaction kinetics, we investigated the model reaction with [BMIM]BF₄ at both elevated and lowered temperatures. It was observed that on lowering the temperature, the reaction time increased substantially (entry 5). In contrast, the elevation of reaction temperature resulted in a decrease in reaction yield with a slight reduction in reaction time (entry 6). In addition to this, representative protic (ethanol) and aprotic (dimethylformamide) organic solvents were also investigated along with water. However, studied solvents showed lower yield and higher reaction time than ionic liquids (entry 7–9).

Table 1 Optimization of the four-component reaction with model substrates.^a

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Entry	Ionic liquid	Temp (°C)	Time (min)	Yield % (5a)
1	[BMIM]Cl	75–80	240	78
2	[BMIM]Br	75–80	240	76
3	[BMIM]OH	75–80	90	80
4	[BMIM]BF4	75–80	60	85
5	[BMIM]BF4	65–70	360	82
6	[BMIM]BF4	85–90	55	78
7	Ethanol	reflux	120	73
8	DMF	85–90	120	70
9	Water	85–90	180	68

a Reaction was carried out with 1 mmol of substrates 1,2,3a,4a, and 8 mmol of ionic liquid.

To further optimize the reaction conditions, the amount of ionic liquid was also investigated with different amounts of [BMIM]BF₄ at 75–80 °C (Table-2). It was observed that the multicomponent reaction achieved superior results with the use of 8 mmol [BMIM]BF₄ (Table 2).

Upon establishing the optimized reaction conditions, the methodology was extended by utilizing different indole derivatives (3a-c) and active methylene derivatives (4a, b) along with dimethyl phthalate 1 and 2-cyanoacetohydrazide 2 to access desired novel phthalazinone based indole-pyran hybrids 5a-j (Scheme 1). The multicomponent reaction with various substrates afforded the corresponding products in good yields. The active methylene derivatives exhibited a slight effect on the yield of the reaction as malononitrile (4a) gave marginally higher yields when compared to ethyl 2-cyanoacetate (4b).

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Scheme 1

Synthesis of novel phthalazinone based indole-pyran hybrids 5a-j.

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A plausible mechanism for the synthesis of hybrids 5a-j mediated by ionic liquid is proposed. The ionic liquids with weakly basic tetrafluoroborate anion exhibit a weak base catalysis phenomenon (MacFarlane et al., 2006). It helps in the formation of a carbanion of 2, which undertakes a nucleophilic attack on the carbonyl carbon of indole carboxaldehyde 3, affording the intermediate A. The intermediate A attacks dimethyl phthalate 1, resulting in nucleophilic substitution to afford intermediate B, which loses a methanol molecule and forms intermediate C. A carbanion of malononitrile attacks the intermediate C to give intermediate D, which undergoes cyclization, affording imine intermediate E that tautomerizes to give the final product 5 (Fig. 2).

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Fig. 2

Plausible mechanism for the formation of phthalazinone based indole-pyran hybrids 5a-j.

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3.2 Anticancer activity

To assess the anticancer potency of the synthesized novel phthalazinone based indole-pyran hybrids 5a-j, we conducted an MTT cytotoxicity assay against three cancer cell lines, namely, cervical (HeLa), lung (A549) and breast cancer (MCF-7) of human body. The synthesized hybrids exhibited good to moderate activity except for the hybrids, 5e and 5j (Table 3). Among the series, 5h and 5b were the most active hybrids with IC₅₀values of 5.8–9.6 µM against all the tested cells. Based on the screening results, hybrid 5h was the most potent that unveiled significant activity against HeLa (IC₅₀: 5.8 µM) and MCF-7 (IC₅₀: 6.6 µM) cancer cell lines. Further, compounds 5a, 5b, and 5g showed good activity towards all the tested cells with less than 15.0 µM of IC₅₀ value. Similarly, the other compounds showed moderate cytotoxicity with all the cell lines that were screened.

Table 3 Cytotoxic potency and structure–activity relationship of novel phthalazinone based indole-pyran hybrids 5a-j.

Test compound	IC50 value in µM (Mean±SD)a
	MCF-7	A549	HeLa
5a	14.2 ± 0.36	11.2 ± 0.14	7.8 ± 0.19
5b	7.6 ± 0.22	6.6 ± 0.27	9.6 ± 0.15
5c	12.2 ± 0.18	>100	11.4 ± 0.16
5d	24.7 ± 0.27	36.8 ± 0.25	19.3 ± 0.39
5e	>100	100	>100
5f	21.5 ± 0.32	16.6 ± 0.17	25.5 ± 0.38
5g	10.8 ± 0.14	12.2 ± 0.26	9.5 ± 0.23
5h	6.6 ± 0.12	9.3 ± 0.33	5.8 ± 0.16
5i	16.7 ± 0.26	14.5 ± 0.19	9.4 ± 0.44
5j	>100	>100	>100
Doxorubicin	0.9 ± 0.06	0.7 ± 0.08	0.8 ± 0.09

a Results expressed as mean with standard deviation as experiments were performed in triplicates. Doxorubicin was used as a positive control for all the cell lines.

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The experimental data revealed an interesting structure–activity relationship (SAR) of the phthalazinone based indole-pyran hybrids (Table 3). The substitutions on the indole ring were crucial in imparting activity to the hybrids. The hybrids with N-methyl or ethyl substitution on the indole ring exhibited better activity than the hybrids with no substitution. On the other hand, the substitution on the 5th position of indole moiety with chlorine and bromine substituents reduced the activity, and the bromo derivatives showed complete loss of activity. Finally, no pronounced effect was noticed when the cyano group was replaced with ethoxycarbonyl group on the 5th position of the pyran ring. In our previous research finding, we reported the anticancer activity of pyran-linked phthalazinone-pyrazole derivatives. On comparing the present finding, it was observed the replacement of the pyrazole ring with a fused indole ring resulted in enhancement in cytotoxic potency of the hybrids. The most active compound of the present series 5h was almost two folds more active than the active compound of phthalazinone-pyrazole series (Malik et al., 2021).

3.3 In silico binding studies

Tankyrases are members of poly ADP ribosyl polymerases (PARPs) enzymes that play a critical role in cell growth and survival by interfering with Wnt/β-catenin signaling pathway (Haikarainen et al., 2014). The function of tankyrases is overdone in cancer cells resulting in their emergence as a novel molecular target in cancer disease (Lakshmi et al., 2017). Olaparib is reported to inhibit human tankyrase-1 protein, and the structural similarity of our novel phthalazinone based indole-pyran hybrids to olaparib encouraged us to perform in silico studies to recognize their binding affinity towards the mentioned protein. Based on the preliminary cytotoxicity results, the active hydrids 5b and 5h were studied for binding interactions with tankyrase-1 protein, and olaparib (09L) was the control. The studies revealed that both the docked ligands (5b and 5h) displayed pronounced binding affinities towards the target receptor active site (Figs. 3 and 4). The hydrogen bond formation and hydrophobic interactions assisted in the binding of the ligands with the target protein. A set of ten different poses for each docked ligand was generated, and the best conformations were fully analyzed as shown in Fig. 3. The outcome of docking analysis revealed that 5b and 5h binded at the same site of the co-crystalized olaparib (09L) (Fig. 4A). The binding energy value provides a good indication of the affinity of a ligand towards the target receptor. The binding energy value of the active ligands 5b was −10.2 Kcal/mole, whereas the binding energy value of ligand 5h was −11.2 Kcal/mol (Fig. 4B). The findings revealed that compound 5h was the best-docked ligand as compared 5b. The ligands 5b and 5h interacted via two hydrogen bond formation with the receptor protein compared to one hydrogen bond formation by the control (09L). However, the co-crystal ligand 09L exhibited more hydrophobic interaction and a higher binding energy score (−14.1 Kcal/mol). The different amino acid residues of the receptor protein responsible for various interactions with ligands 5b, 5h and 09L are provided (Table 4).

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Fig. 3

(A) 3D binding conformations of the hybrids (5b and 5h) with human tankyrase-1 protein (PDB ID: 7KKO) along with co-crystalized ligand (09L). (B) Surface representation of target protein with docked molecules at the binding site. (C) 2D binding interactions of the hydrids and olaparib with the target.

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Fig. 4

(A) The overlayed structures of 5b and 5h along with co-crystalized ligand 09L at the binding site. (B) Binding energies (kcal/mol) shown was docked ligands at active site of human tankyrase-1 protein.

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3.4 ADME, drug likeness analyses

In drug design, computational pharmacodynamics and pharmacokinetics analysis help understand how the drug behaves in the physiological environment, thereby reducing drug attribution rate in advanced stages (Alqahtani 2017). The experimental results prompted us to carry out ADME and drug likeness calculations of our synthesized novel phthalazinone based indole-pyran hybrids 5a-j. The cytochrome P450 (CYP) enzymes are responsible for the metabolism of foreign substances in the body, and the inhibition of the five CYPs (CYPs 1A2, 2C19, 2C9, 2D6, and 3A4) results in significant drug-drug interactions that may lead to unanticipated adverse reactions (Beck et al. 2021). All the hybrids 5a-j were shown to inhibit CYP2C9 isoenzyme with no inhibition of CYP1A2 isoform (Table 5). Interestingly, the most active hybrids 5h and 5b exhibited a similar cytochrome inhibition profile. In the absorption aspect, the hybrids 5a-j were predicted to exhibit low gastrointestinal absorption properties and were non-permeable to the blood–brain barrier. The hybrids' skin permeability coefficient (log Kp) was in the range of −7.44 to −7.01 cm/s. In addition to this, the bioactivity score of the hybrids was around 0.55, except few of them (5f, 5i, and 5j) that showed a value of 0.11.

Drug likeliness predictions of the hybrids (5a-j) revealed that the Lipinski rule is followed by almost all the hybrids with respect to critical descriptors like molecular weight, lipophilicity (log P) number of hydrogen bond donors, and acceptors. In the case of hybrids 5e and 5i, the molecular weight was almost around the threshold of 500 amu, whereas a single Lipinski rule violation was shown by hybrid 5j (Fig. 5). Some other additional descriptors related to Ghose and Veber’s rules were also predicted. According to Ghose’s rule, the molecular refractivity of a chemical compound in the range of 40–130 shows more drug likeliness properties. The hybrids 5a-5f followed the rule with molecular refractivity value in the range of 116–127, whereas the other hybrids showed marginally higher molecular refractivity value (131–135). The number of rotational bonds (<10) and topological surface area (<140) are critical molecular descriptors according to Veber’s rule. The computational analysis showed that the hybrids showed two to six rotational bonds. However, the TPSA values were slightly higher in the range of 142–156.

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Fig. 5

Drug likeliness properties of hybrids 5a-j where log P (lipophilicity), HBA (hydrogen bond acceptor), HBD (hydrogen bond donor), MW (molecular weight) denotes Lipinski filter. The descriptors RB (rotational bonds), MR (molecular refractivity), and PSA (polar surface area) denote additional drug likeliness filters.

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