In Vitro Bioactivities&nbsp;of Isoindolin-1-3-Phosophonate Compounds

doi:10.21203/rs.3.rs-284373/v1

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In Vitro Bioactivities of Isoindolin-1-3-Phosophonate Compounds

https://doi.org/10.21203/rs.3.rs-284373/v1

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In this work an efficient synthesis of isoindolin-1-one-3-phosphonates under catalyst- and solvent-free conditions was reported to afford the desired compounds in excellent yields with potent pharmacological properties. The synthetic method involves the preparation of isoindolin-1-one-3-phosphonates by a ‘one-pot’ three-component reaction of 2-formylbenzoic acid with primary amines and dimethyl phosphite under solvent and catalyst free-conditions. All new compounds were characterized by by ¹H NMR, ¹³C NMR, FT-IR and elemental analysis techniques. The synthesized compounds were screened for their antimicrobial activities against gram-positive bacterial strains (Micrococcus luteus, Listeria monocytogenes, Staphylococcus aureus and Bacillus cereus), a gram-negative bacterial strain (Salmonella typhimurium) and a fungus (Candida albicans). Compound 4a was found to be the most active against antimicrobial against L. M. luteus, L. monocytogenes and C. albicans with an inhibition zone of 35, 22 and 38 mm respectively. They were additionally also investigated for their anti-parasitical activities against Leishmania major promastigotes and amastigotes and Toxoplasma gondii in vitro. The compounds 4a,b are the most active against L. major amastigotes and promastigotes with EC50 < 1 µM. Cytotoxicity investigations of the isoindolin-1-one-3-phosphonates were conducted in two human cancer cell lines, MDA-MB-231 and MCF-7 all the compounds gave anticancer activity < 1.5 µM. We can conclude that 4a is a good drug candidate for all the biological assays, further studies for SAR detection and in vivo evaluation are highly recommended.

Biological Chemistry

Isoindolin-1-one phosphonates

Biological activity

Cytotoxicity

Synthesis.

Isoindolin-1-one moiety is an important scaffold that has attracted great attention in organic synthesis [1-4]. (Fig. 1). This motif is in reality found over regularly compounds, for example, magallanesine [1], lennoxamine [2], Also stachybotrin C [3-4]. (Fig. 1).

Compounds containing isoindolin-1-one moiety have differents biological activities such as antimicrobial [5], anti-viral [6], HIV-1 inhibitory [7-8]. Some isoindolin-1-one compounds also have been reported to be effective for treating diabetes [9-10], cancer [11-13], and CNS diseases [14-18]. Moreover, the derivatives isoindoline especially those come from isoindolin-1-one reduction suggested for the inhibition of dipeptidyl peptidase DPP8/9 [19-20].

In non-symmetrical preparation of some compounds from isoindolin-1-one they can introduced as building blocks for a Diels–Alder reaction [21-25]. Because of their multi biological properties of isoindoline derivatives, there are many chemical pathways have been reported for the preparation of these heterocycles [ 26-35].

Reduction of phthalimides to 3‑hydroxy-isoindolin-1-one followed by a reaction with trifluoroacetic anhydride and triethylphosphite afford the corresponding phosphonates in moderate yields [36-37]. The synthesis were carried out in toluene at reflux or under microwave irradiation [38-44].

As part of our interest to develop a practical and efficient synthesis method in an environmentally friendly manner [45-47], we herein report an alternative, simple route for the synthesis of isoindolin-1-one-3-phosphonates 4. Furthermore, these compounds were investigated for their antimicrobial activity against Micrococcus luteus, Listeria monocytogenes, Staphylococcus aureus, Bacillus cereus, Salmonella typhimurium and Candida albicans and for their anti-parasitical activity against Leishmania major and Toxoplasam gondii. Additionally, cytotoxicity were tested using MTT assay.

For the synthesis of target compounds 4, we initially decided to explore the use of 2-formylbenzoic acid as starting material, considering its recent application in the synthesis of N-substituted isoindolin-1-one compounds [48-58]. The process involves a ‘one-pot’ three-component reaction of 2-formylbenzoic acid, a primary amine and dimethyl phosphite under solvent-free for 1h at 80°C that yields compounds 4a-f. Scheme 1

Table 1: Structure of Isoindolin-1-one-3-phosphonantes 4a-f

Thus, the ‘one-pot’ three-component reaction of 2-formylbenzoic acid with a primary amine and diethylphosphite was stirred at 80 °C under solvent free‑conditions, which generated the corresponding isoindolin-1-one-3- phosphonate 4a-f in 70-88% yield after 1 h (Table 1). The scope and limitations of the reaction were studied by using various types of amines. Products starting from cyclohexylamine 2c and (4-methoxyphenyl) methanamine 2d were obtained in yields of 71 and 84%, respectively (Table 1, entries 3,4). The electron-donating substrates in the phenyl ring were found to promote the reaction. The different reactivities of butan-1-amine 2e and pentan-1-amine 2f can be explained similarly. Finally, the reaction was extended using phenylmethanamine 2b which generated the corresponding products in 72 % yield (Table 1, entries 2,3).

Treatment of isoindolin-1-one-3-phosphonate 4b,c with concentrated HCl in dioxane at 80 °C for 72 h led to production of isoindoline-1-one-3-yl phosphonic acid 5b,c (Table 2).

Table 2: Isoindolin-1-one-3-yl-phosphonic acids 5b-c prepared

The structures of the synthesized products were deduced by IR, ¹H, ¹³C, and ³¹P NMR spectroscopy and elemental analyses. The IR spectrum of compound 4b exhibited strong absorption bands at 1681 (C=O), 1588 (C=C, acyclic), 1248 (P=O), and 1046 (P-O-C). In the ¹H‐NMR spectrum of 4b, the disappearance of one OH peak of 1 and the presence of a signal for the PCHN proton that appears as a doublet at δ 5.3 ppm with a strong coupling constant with the close phosphorous atom indicated that the synthesis of compound 4b was accomplished. The signals of aromatic protons were observed between δ 7.08-7.68 ppm. In the ¹³C NMR spectrum of compound 4b, the new peaks at 44.4 ppm and 54.8 ppm belonging to the NCH₂ (C₁₀) and PCHN (C₇) carbons, respectively, also confirmed that the cyclisation had occurred. The presence of the phosphonate group is clearly evidenced by the ³¹P NMR spectrum that exhibits a singlet at 18 ppm. ¹H, ¹³C and ³¹P NMR spectra of derivatives 4a-f show very similar patterns of signals for the PCHN group which are very characteristic of the isoindolin-1-one-3-phosphonate structure.

a-Antimicrobial activity of isoindolin-1-one-3-phosphonates 4a-f

The in vitro antimicrobial activities of the isoindolin-1-one-3-phosphonate compounds 4a–f were evaluated for in vitro antimicrobial activity by the well diffusion method [59]. All products were screened for activity against gram-positive bacteria (M. luteus, L. monocytogenes, S. aureus and B. cereus) and gram-negative bacteria (S. typhimurium). As shown in Table 3, all compounds exhibit considerable activity against the tested microorganisms except 4c. These results differ according to the compound structure and type of bacteria tested.

Table 3. Antibacterial inhibition zones of isoindolin-1-one-3- phosphonate compounds 4a-f in mm

Microorganisms Compounds	*M. luteus* LB 141107	*L. monocytogenes* ATCC 1911		*S. aureus* ATCC 6538	*S. Typhimurium* ATCC 14028	*B. cereus*
4a	35±3.13	22±2.14		-	-	-
4b	24±2.6	18±1.32		-	-	18±1.11
4c	-	-		-	-	-
4d	18±1.22	18±1.11		-	15±1.17	-
4e	-	-		-	15±1.15	18±2.12
4f	-	-		18±2.12	20±2.53	18±2.15
Tetracycline	22±3.1		23±3.3	20±1.6	18±3.5	18±2.9

This table indicates the antibacterial activities of tested compounds in inhibition zones by mm. The values are means ± S.D. Tetracycline was used as control positive drug.

A simple inspection of Table 3 indicates that the highest antibacterial activity against M. luteus LB 141107 was reported by 4a and 4b with inhibition zone (IZ) 35 mm and 24 mm respectively followed by 4d with IZ 18 mm. Also, 4f is the most active against S. Typhimurium ATCC 14028 with IZ 20 mm. Additionally, 4a was found to be the most active against L. monocytogenes with an inhibition zone of 22 mm. The other antibacterial results showed inhibition zones of less than 20 mm. As shown in Table 4, only 3 compounds possess antifungal activity against C. albicans—4a, 4b and 4d with inhibition zones of 38, 25 and 22 mm, respectively. The results obtained show that the different molecules have antimicrobial activity. 4a and 4b can be considered as good antimicrobial drug candidates. Isoindoline derivatives were found to have good and potent antimicrobial activity for a long time [60]. This supports our findings. Further studies for structure activity relation (SAR) is recommended to indicate the reason for these varying biological activity.

Table 4. Antifungal inhibition zones of isoindolin-1-one-3- phosphonate

compound 4a,b,d in mm

Microorganisms Compounds	*C. albicans*
4a	38±3.5
4b	25±3.6
4c	-
4d	22±2.7
4e	-
4f	-
Fluconazole	24±3.7

This table indicates the antifungal activities of tested compounds in inhibition zones by mm. The values are means ± S.D. Fluconazole was used as control positive drug.

b-Anti-leishmanial activities of isoindolin-1-one-3- phosphonate compounds 4a-f

Table 5 shows that all compounds except 4e had anti-leishmanial activity against L. major promastigotes in vitro with half maximal effective concentration (EC₅₀) less than 2.5 μM; two of them (4b and 4a) had EC₅₀ less than 1 μM, and their EC₅₀values were 0.4 and 0.8 μM with Selectivity index (SI) of 12.9 and 11.9, respectively. Additionally, 4a and 4b were the most active against L. major amastigotes with EC₅₀ values of 0.7 and 0.8 μM and SI of 13.5 and 6.4, respectively. All compounds had a very good SI in the range of 3.5 to 41.2 with the exception of 4c against L. major amastigote. According to its SI value 4a can be considered a good antileishmanial drug candidate. The variation observed in these results may be due to the structure biology relation. Further studies for structure activity relation (SAR) is recommended to indicate the reason for these varying biological activity. However, in general, synthesized isoindoline derivatives exhibited potent biological activities [61]. Additionally, phosphonium compounds were found to have potent anti-leishmanial activity [62]. These results can agree with these suggestions.

Table 5. Anti-leishmanial activity of isoindolin-1-one-3-phosphonate compounds 4a-f against L. major promastigotes and amastigotes

Isoindolin-1-one-3- phosphonates 4	IC₅₀ of Vero cells , (μM)	Amastigote EC₅₀(μM)	promastigotes EC₅₀(μM)	Amastigote SI	promastigote SI
4a	9.5 ± 3.1	0.7 ± 0.23	0.8 ± 0.26	13.5	11.9
4b	5.2 ± 1.8	0.8 ± 0.19	0.4 ± 0.08	6.4	12.9
4c	44.9 ± 8.6	> 50	2.3 ± 0.84	-	19.5
4d	48.7 ± 9.2	3.9 ± 0.82	1.8 ± 0.41	12.49	27.1
4e	50 ± 9.5	2.9 ± 0.75	14.2 ± 3.8	17.2	3.5
4f	45.3 ± 7.7	3.4 ± 1.1	1.1 ± 0.27	13.3	41.2
AmB	7.4 ± 2.64	0.46 ± 0.07	0.78 ± 0.09	16.09	9.49

This table indicates the antileishmanial activities of tested compounds in EC₅₀ of µM. The values are means ± S.D. Amphoteracin B (AmB) was used as control positive drug. SI values was calculated by CC₅₀ (from Vero cell) over EC₅₀.

c-Anti-toxoplasmal activities of isoindolin-1-one-3- phosphonate compounds 4a-f

Table 6 indicates that all compounds possess different levels of anti-toxoplasmal activity in vitro. Only 4b and 4a had EC₅₀ values of less than 4 μM (3.2 and 3.8 μM, respectively). The others had less potent anti-toxoplasmal activity with EC₅₀ values in the range of 11.9 to 33.9 μM and SI in the range of 1.4 to 3.8. The following results indicate that isoindolin-1-one-3-phosphonates are suitable candidates for anti-toxoplasmal drug discovery.

Table 6. Anti-toxoplasmal activity of isoindolin-1-one-3-phpshonates compounds 4a-f against T. gondii

Isoindolin-1-one-3- phosphonates 4	IC₅₀ of Vero cells , EC₅₀(μM)	Antitoxoplasma EC₅₀(μM)	SI
4a	9.5 ± 3.1	3.8 ± 0.88	2.5
4b	5.2 ± 1.8	3.2 ± 0.67	1.6
4c	44.9 ± 8.6	13.4 ± 3.4	3.3
4d	48.7 ± 9.2	33.9 ± 6.1	1.4
4e	50 ± 9.5	20.7 ± 4.8	2.4
4f	45.3 ± 7.7	11.9 ± 2.6	3.8
ATO	9.3 ± 2.08	0.09 ± 0.02	103.33

This table indicates the antitoxoplasmal activities of tested compounds in EC₅₀ of µM. The values are means ± S.D. Atovaqoune (ATO) was used as control positive drug. SI values was calculated by CC₅₀ (from Vero cell) over EC₅₀.

There have not been previous investigations of isoindoline against T. gondii, but previous investigations found that some isoindoline derivatives have less potent activity against Plasmodium [63-64]. These published results agree with our finding. Further studies for structure activity relation (SAR) is recommended to indicate the reason for these varying biological activity.

D-Anti-cancer activity

As shown in Table 7, all tested compounds significantly affected the viability of malignant cell lines, showing a promising level of cytotoxicity with EC₅₀ of < 1.5 μM. However, the cytotoxicities of isoindolin-1-one-3- phosphonate compounds 4d, 4c and 4d were much stronger in MCF7 cells with EC₅₀ values 0.6, 0.7 and 0.7 μM, respectively.

Table 7. Anticancer profile of synthesized of isoindolin-1-one-3-phosphonate compounds 4a-f.

Compounds	Anticancer activity EC₅₀(μM)
Compounds	*MCF7*	*MDA-MB-231*
4a	0.9 ± 0.6	0.9± 1.3
4b	0.8± 0.7	1.5± 0.9
4c	0.7± 0.6	0.8± 1.2
4d	0.6 ± 1.1	0.9 ±0.3
4e	0.68± 1.2	1.1± 0.6
4f	1.3± 1.1	0.8± 0.6
Dox	0.7±0.2	1.6±0.4

This table indicates the anticancer activities of tested compounds in EC₅₀ of µM. The values are means ± S.D. Doxorubicin (Dox) was used as control positive drug.

The cytotoxicity of isoindolin-1-one-3-phosphonate compounds 4c and 4f against MDA-MB-231 cells was strongest with EC₅₀ of 0.8 μM, followed by 4a and 4d with EC₅₀ of 0.9 μM. These results agree with previous results that showed that isoindoline derivatives have activity against cancer cells [65]. Further studies for structure activity relation (SAR) is recommended to indicate the reason for these varying biological activity.

In conclusion, we have developed an efficient three-component synthesis of isoindolin-1-one-3-phosphonates. The reaction proceeds quickly and with no undesirable side reactions observed. This procedure may find wide application in the large-scale synthesis of cyclic a-aminophosphonates. Further investigations are currently in progress to demonstrate the potential of this methodology in the diastereoselective preparation of isoindolin-1-ones bearing phosphonate functionality of biological interest. The biological activities revealed that 4a and 4b are good drug candidates for antimicrobial (better than standard antibiotic) and anti-leishmanial agents and have potent anticancer activity against both MCF7 and MDA-MB-123. However, the activity of the above compounds against normal vero cells indicates their safety (half maximal inhibitory concentration (IC₅₀) in the range between 5 – 50 µg/ml) that can support and enhance our suggestion about the uses of these compounds in future as drug candidates. Further studies for structure activity relation (SAR) is recommended to indicate the reason for these varying biological activity as well as in vivo evaluation.

General information

Chemicals were purchased from Sigma Aldrich and used without further purification. All solvents were purified and dried with the MBraun SPS 800 solvent purification system. NMR spectra were recorded with a Varian System instrument (400 MHz for ¹ H, and 100 MHz for ¹³C) with CDCl₃ as the solvent and TMS as the internal standard signal. NMR multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, and m = multiplet signal. IR spectra were recorded on a 398 spectrophotometer (Perkin-Elmer). Elemental microanalysis was performed on an ElementarVario El III Carlo Erba 1108 elemental analyzer, and the values found were within ± 0.3% of the theoretical values. Melting points were determined with Kofler bench at Isste of Borj cedria (Hammam Lif, University of Carthage, Borj Cedria, Tunisia) [46].

General procedure for the synthesis of Diethyl 3-oxoisoindolin-1-yl phosphonate compounds (4a-f)

2-Formylbenzoic acid (2.5 g, 17 mmol), amine (18 mmol) and diethylphosphite (2.9 g, 21 mmol) were stirred at 80 °C for 1.0 h, and the progress of the reaction was monitored by TLC. The mixture was extracted with dichloromethane, dried with MgSO₄, filtered and evaporated. Finally, the crude product was purified by column chromatography. The crude product was analyzed by ¹H, ¹³C and ³¹P NMR spectroscopy [46].

Diethyl 2-(2,2-dimethoxyethyl)-3-oxoisoindolin-1-yl phosphonate (4a)

Yield = 70%;oil; ¹H NMR (300 MHz, CDCl₃) δ(ppm): 1.02 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H), 3.27 (d, J = 9.6 Hz, 6H), 3.62-3.91 (m , 3H), 3.99-4.09 (m, 2H), 4.22 (dd, J = 4.0, 14.4 Hz, 1H), 4.50 (dd, J = 4.0, 6.5 Hz, 1H), 5.11 (d, J = 13.1 Hz, 1H), 7.39-7.52 (m, 2H), 7.70 (dd, J= 3.4, 7.6 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ (ppm): 16.0 (d, J = 5.5 Hz, CH₃), 16.2 (d, J = 5.7 Hz, CH₃), 42.4 (CH₂), 53.5 (CH₃), 54.4 (CH₃), 57.0 (CH₂), 59.0 (CH₂) 63.05(CH₂),102.31(CH);123.59(CH);124.32(CH);128.56(CH);131.50(CH);131.69( C);139.03(C );168.80(C ); ³¹P NMR (121 MHz, CDCl₃) δ (ppm):18.3. Anal. Calc. for

C₁₆H₂₄NO₆P (%): C, 53.78 %; H, 6.77 %; N, 3.92 %. Found (%): C, 53.7; H, 6.7; N, 4.1.

Diethyl 2-benzyl-3-oxoisoindolin-1-yl phosphonate (4b)

Yield = 72%;oil; ¹H NMR (300 MHz, CDCl₃) δ (ppm): 0.90 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.1 Hz, 3H), 3.56-3.91 (m, 4H), 4.43 (dd, J = 14.1, 18.9 Hz, 2H), 5.32 (d, J = 14.9 Hz, 1H), 6.94-7.09 (m, 5H), 7.22-7.32 (m, 2H), 7.47 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H);¹³C NMR (75 MHz, CDCl₃) δ (ppm): 15.7 (d, J = 5.4 Hz, CH₃), 15.9 (d, J = 5.4 Hz, CH₃), 44.4 (CH₂), 55.9 (d, J = 156 Hz, CH), 62.7 (d, J = 6.9 Hz , 2CH₂), 123.3 (CH), 124.0 (CH), 127.1 (CH), 127.7 (2CH), 128.2 (2CH), 128.3 (CH), 131.1 (CH), 131.4 (C), 136.3 (C), 138.2 (C), 168.2 (C);³¹P NMR (121 MHz, CDCl₃) δ (ppm) :18.0. Anal. Calc. for C₁₉H₂₂NO₄P (%): C, 63.50 %; H, 6.17 %; N, 3.90 % %. Found (%): C, 63.6; H, 6.2; N, 3.9.

Diethyl (2-cyclohexyl-2-oxoisoindolin-1-yl) phosphonate (4c)

Yield= 71%; oil;¹H NMR (300 MHz, CDCl₃) δ(ppm) : 1.11 (t, J = 7.1 Hz, 3H), 1.19-1.40 (m, 6H), 1.65-1.93 (m, 5H), 2.14-2.49 (m, 2H), 3.71-4.13 (m, 5H), 4.82 (d, J = 13.2 Hz, 1H), 7.43-7.54 (m, 2H), 7.71 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H).¹³C NMR (75 MHz, CDCl₃) δ(ppm): 16.35 (d, J = 4.0 Hz, CH₃), 16.42 (d, J = 4.5 Hz, CH₃), 25.4 (CH₂), 26.2 (CH₂), 26.5 (CH₂), 29.5 (CH₂), 29.8 (CH₂), 56.8 (CH), 58.7 (d, J = 156 Hz, CH), 63.3 (d, J = 7.4 Hz, CH₂), 63.5 (d, J = 7.1 Hz, CH₂), 123.5 (CH), 124.6 (CH), 128.8 (CH), 131.3 (CH), 133.7 (C ), 138.9 (C ), 169.1 (C ); ³¹P NMR (121 MHz, CDCl₃) δ (ppm) :18.6. Anal. Calc. for C18H26NO4P (%): C, 61.53 %; H, 7.46 %; N, 3.99 %. Found (%): C, 61.6; H, 7.5; N, 4.1.

Diethyl (2-(4-methoxybenzyl)-3-oxoisoindolin-1-yl) phosphonate (4d)

Yield = 84%;oil; ¹H NMR (300 MHz, CDCl₃) δ(ppm) :1.03 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H), 3.62 (s, 3H), 3.70-4.05 (m, 4H), 4.43 (d, J = 14.7 Hz, 1H), 4.57 (d, J = 13.4 Hz, 1H), 5.39 (d, J = 14.7 Hz, 1H), 6.70 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 7.36-7.45 (m, 2H), 7.58 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ (ppm): 16.0 (d, J = 5.5 Hz, CH₃), 16.2 (d, J = 5.5 Hz, CH₃), 44.1(CH₂), 54.9(CH₃), 55.9 (d, J = 157 Hz, CH), 63.1 (d, J = 6.9, 2CH₂), 113.8 (2CH), 123.6 (CH), 124.2 (CH), 128.55 (CH), 128.60 (C), 129.5 (2CH), 131.4 (CH), 131.8 (C), 138.6 (C), 158.7 (C), 168.5 (C);³¹P NMR (121 MHz, CDCl₃) δ (ppm) :18.1. Anal. Calc. for C₂₀H₂₄NO₅P (%): C, 61.69 %; H, 6.21 %; N, 3.60 % .Found (%): C, 61.7; H, 6.3; N, 3.7.

Diethyl (2-butyl-3-oxoisoindolin-1-yl) phosphonate (4e)

Yield = 88%;oil; ¹H NMR (300 MHz, CDCl₃) δ(ppm) : 0.66-1.40 (m, 13H), 3.30-3.87 (m, 6H), 4.66-4.74 (m, 1H), 7.27-7.55 (m, 4H). ¹³C NMR (75 MHz, CDCl₃) δ(ppm): 13.3 (CH₃), 15.8 (2CH₃), 19.5 (CH₂), 29.5 (CH₂), 41.0 (CH₂), 56.6 (d, J = 155 Hz, CH), 62.8 (d, J = 14.8 Hz, 2CH₂), 123.1 (CH), 124.0 (CH), 128.3 (CH), 130.9 (CH), 131.9 (C), 138.1 (C), 168.1 (C); ³¹P NMR (121 MHz, CDCl₃) δ(ppm) : 17.9. Anal. Calc. for C₁₆H₂₄NO₄P (%): C, 59.07 %; H, 7.44 %; N, 4.31 %. Found (%): C, 59.1; H, 7.5; N, 4.4.

Diethyl (3-oxo-2-pentylisoindolin-1-yl) phosphonate (4f)

Yield=78%; oil; ¹H NMR (300 MHz, CDCl₃) δ(ppm): 0.76 (t, J = 7.0 Hz, 3H), 1.00 (t, J = 7.1 Hz, 3H), 1.12-1.25 (m, 7H), 1.46-1.65 (m, 2H), 3.40-3.49 (m, 1H), 3.66-4.06 (m , 5H), 4.79 (d, J = 13.6 Hz, 1H), 7.36-7.48 (m, 2H), 7.70 (dd, J = 2.3, 7.5 Hz, 2H). ¹³C NMR (75MHz, CDCl₃) δ(ppm): 13.8 (CH₃), 16.1 (d, J = 5.5 Hz, CH₃), 16.2 (d, J = 5.7 Hz, CH₃), 22.2 (CH₂), 27.4 (CH₂), 28.8 (CH₂), 41.6 (CH₂), 57.0 (d, J = 155 Hz, CH), 63.0 (d, J = 7.2 Hz, CH₂), 63.3 (d, J = 7.1 Hz,CH₂), 123.5 (CH), 124.3 (CH), 128.6 (CH), 131.3 (CH ), 132.3 (C), 138.4 (C), 168.5 (C); ³¹P NMR (121 MHz, CDCl₃) δ(ppm) : 17.9. Anal. Calc. for C17H26NO4P (%): C, 60.17 %; H, 7.72%; N, 4.13 %. Found (%): C, 60.2; H, 7.8; N, 4.2.

Synthesis of isoindolin-1-one-3-yl phosphonic acids (5a-b)

A solution of isoindolin-1-one-3-yl phosphonate 4a-b (3.01 mmol) in a mixture of concentrated HCl and dioxane (1:1) (100 ml) was heated at 80 °C for 72 h, cooled and the solvent was evaporated. The crystalline residue was treated with ethanol (10 ml), filtered off, washed and dried to give compounds 5a-b as solids.

(2-Benzyl-3-oxoisoindolin-1-yl) phosphonic acid (5a)

Yield=60%; mp: 119-120 °C; NMR ¹H (300 MHz, DMSO) δ(ppm) 4.50 (d, J = 16.3 Hz, 1H), 4.78 (d, J = 15.0 Hz, 1H), 5.25 (d, J = 15.0 Hz, 1H), 7.21(s, 5H), 7.45-7.57 (m, 2H), 7.71 (d, J = 7.3 Hz, 1H), 7.82 (d, J = 6.7 Hz, 1H); NMR ¹³C (75 MHz, DMSO) δ(ppm): 44.1 (CH₂), 57.9 (d, J = 149 Hz, CH), 122.8 (2CH), 125.1 (CH), 127.3 (CH), 127.9 (2CH), 128.6 (2CH), 131.1 (CH), 131.7 (C), 137.8 (C), 141.5 (C), 168.1 (C); NMR ³¹P (121 MHz, DMSO) δ(ppm) : 11.5. Anal. Calc. for C₁₅H₁₄NO₄P (%): C, 59.41; H, 4.65; N, 4.62. Found (%): C, 59.5; H, 4.7; N, 4.5.

(2-Cyclohexyl-3-oxoisoindolin-1-yl) phosphonic acid (5b)

Yield=68%; mp: 259-260 °C; NMR ¹H (300 MHz, DMSO) δ(ppm) : 1.15-1.25 (m, 3H), 1.59-2.26 (m, 7H), 3.74 (t, J = 11.9 Hz, 1H), 4.78-4.92 (d, J = 15.3 Hz, 1H), 7.43-7.67 (m, 4H); NMR ¹³C (75 MHz, DMSO) δ(ppm): 25.2 (CH₂), 25.8 (CH₂), 26.0 (CH₂), 28.7 (CH₂), 29.1 (CH₂), 55.4 (CH), 59.7 (d, J = 148 Hz, CH), 122.2 (CH), 124.5 (CH), 127.8 (CH), 130.8 (CH), 133.3 (C), 141.0 (C), 167.8 (C). NMR ³¹P (121 MHz, DMSO) δ(ppm): 14.0. Anal. Calc. for C₁₈H₂₆NO₄P (%): C, 61.53 %; H, 7.46 %; N, 3.99 %. Found (%): C, 61.6; H, 7.5; N, 4.1.

Bioassays

Antimicrobial activity by the disk diffusion method

M.luteus (LB 141107), L. monocytogenes (ATCC 1911), S. aureus (ATCC 6538), B. cereus, S. typhimurium (ATCC 14028) and B. cereuswere grown on nutrient agar plates (HiMedia, India), and C. albicans (ATCC 90028) was grown on potato dextrose agar (HiMedia, India) for 24 h at 35 °C. All cultures were obtained from the American Type Culture Collection (ATCC). The disc diffusion method was used to assess the antimicrobial activities [11,59] (Breytenbach et al. 2000). Microbes were suspended in sterile saline solution (0.9%), and the turbidity was adjusted to 0.5 OD values using a spectrophotometer (Labomed Inc., USA). The inoculum was swabbed on the surface of agar plates used using a sterilized cotton swab. Sterile blank disks (6-mm) were loaded with 10 µl of compound stock solution (10 mg/mL), giving a concentration of 50 µg/disc. Commercial tetracycline discs (30 µg per disc) were used as positive controls, and methanol as a negative control for comparison. The petri-plates were incubated at 35 °C for 24 h. The diameters of the zones of inhibition produced by the compounds on the test isolates were measured in mm [46,64].

L. major cell isolation, culture conditions, and assays

Promastigotes of L. major were isolated from a Saudi male patient in February 2016 and maintained at 26 °C in Schneider’s Drosophila medium supplemented with 10% heat-inactivated fetal bovine serum (FBS) and antibiotics in a tissue culture flask with weekly transfers. Promastigotes were cryopreserved in liquid nitrogen at concentrations of 3 × 10⁶ parasites/mL. The virulence of L. major parasites was maintained by passing in female BALB/c mice by injecting hind footpads with 1x10⁶. Fifty-six days later, the amastigotes of L. major were collected from the infected animals. Then transformed to promastigote stages via culturing at room temperature using complete Schneider's medium containing FBS 10% with antimicrobial. For infection, in vitro subculturing was used for maintaining different pathogen stages [65,66].

For the evaluation of the compounds for their activity against L. major promastigotes, complete RPMI 1640 medium containing 10% FBS without phenol red-free was used for culturing the parasite in 96-wells plates to yield 10⁶ organisms mL^-1 (200 µl/well), the counting was conducted by hemocytometer. Then the compounds were added in concentrations of (50, 25, 12.5, 6.25, 3.13, 1.65, and 0.75 µg/ml). DMSO with (1%) was used as negative control, while Amphotericin (AmB) was used as positive control with the same compounds concentrations ( 50, 25, 12.5, 6.25, 3.13, 1.65, and 0.75 µg/ml). After that they were allowed to stay at room temperature for 3 days. Tetrazolium salt colorimetric assay (MTT) was used for assessing the viable organisms. The samples were analyzed with an spectrophotometer at 570 nm. EC₅₀ values were derived from three independent experiments [66].

For the assessing the compounds activities against intramacrophages amastigotes, a group of 6 mice of 56 days age were used for macrophages collection from peritoneum cavity by aspiration. Ninety-six well ELISA plates were used for culturing the cells at concentration 5 x 10⁴ cells/well supplied by complete RPMI 1640 medium with 10% FBS for 4 h at 37 °C and 5% CO₂ for enhancing the adhesion of the cell. Followed by the discarding of the medium and washing with phosphate buffered saline (PBS). Promastigotes in a complete RPMI 1640 medium with 10% FBS solution of 200 µl containing promastigotes to ration of 10 promastigotes: 1 macrophage for each well. Then followed by overnight incubation at 37 °C in a humidified 5% CO₂ atmosphere for enhancing differentiation and amastigote infection. PBS was used for washing the infected macrophages and removal of free promastigotes. For compound assessing against amastigotes, the final concentrations of (50, 25, 12.5, 6.25, 3.13, 1.65, and 0.75 µg/ml) in complete RPMI 1640 medium were added and cells were added to each well and then incubated at 37 °C in with 5% CO₂ atmosphere for 3 days. DMSO with (1%) was used as negative control, while AmB was used as positive control with the same compounds concentrations ( 50, 25, 12.5, 6.25, 3.13, 1.65, and 0.75 µg/ml).. The evaluation of macrophages percentage infection was carried out microscopically after removing medium, washing, fixation, and Giemsa staining. EC₅₀ values were obtained from three independent experiments [66,67].

T. gondii cell line, culture conditions, and assay

Vero cells (ATCC® CCL81™, USA) were cultured in complete RPMI 1640 medium (5 X 10³ cell/ well in 200 µl), then incubated at 37 °C in with 5% CO₂ atmosphere for 24 hours. After washing cells using PBS, cells were infected by T. gondii (Rh strain). Then compounds were applied at concentrations (50, 25, 12.5, 6.25, 3.13, 1.65, and 0.75 µg/ml). DMSO with (1%) was used as negative control, while atovaquone (ATO) was used as positive control with the same compounds concentrations. After that, toluidine blue of 1% was used for staining and then PBS used for washing and the fixation took place by 10% formalin. Inverted photomicroscope was used for the examination of cells and the determination of the infection index (number of infected cells out of 200 examined cells) of T. gondii. For the calculation inhibition% the following equation was applied.

Inhibition (%) = (I Control - I Experimental)/(I Control) × 100

where “I Control” refers to the infection index of untreated cells, and “I Experimental” refers to the infection index of cells treated with test compounds.

Then, the effects of test compounds on parasite growth were expressed as EC₅₀ (effective concentration at 50%) values. EC₅₀ values were obtained from three independent experiments [68,69].

In vitro cytotoxicity assay

For the assessing the compound cytotoxicity MTT colorimetric assay was carried out according to the method described previously [67]. Ninety six well plates were used for culturing vero cells and two human cancer cell lines—MCF7 and MDA-MB-231—at concentration of (5 × 10³ cells/well/200 µl) for one day in complete RPMI 1640 medium containing 10% FBS and then kept in 5% CO₂ with temperature of 37 °C. followed by washing with PBS and then incubated with the compounds for 3 days at varying concentrations (100, 33, 11, 3.7, 1.2, 0.4, 0.14 and 0.04 µg/ml). Medium in 2% FBS was used as a negative control. Thereafter, the supernatant was removed, 50 µl of RPMI 1640 medium containing 14 µl of MTT (5 mg/ml) was added, and the cells were incubated for 4 h. After that, the supernatant was removed, and 200 µl of DMSO was added to dissolve the formazan. A FLUOstar OPTIMA spectrophotometer was applied for colorimetric analysis (λ = 540 nm). Cytotoxic effects were expressed as IC₅₀ values (concentration that caused a 50% reduction in viable cells). IC₅₀ values were obtained from three independent experiments [70-72].

Funding

This paper did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Conflict of interest The authors declare that they have no conflict of interest.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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[12] Buchert M, Meinke S, Prenzel A, Deppermann N, Maison W. Azabicycloalkenes as Synthetic Intermediates − Synthesis of Azabicyclo[X.3.0]alkane Scaffolds. Organic Letters. 2006; 24: 5553-5556.

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