International Journal of Medicinal ChemistryVolume 2011 (2011), Article ID 678101, 11 pagesdoi:10.1155/2011/678101

Research Article

Design, Synthesis, and Antifungal Activity of New α-Aminophosphonates

Zahra Rezaei,¹ Soghra Khabnadideh,¹ Kamiar Zomorodian,² Keyvan Pakshir,²  Setareh Nadali,¹ Nadia Mohtashami,¹ and Ehsan Faghih Mirzaei1,3

¹Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz 71345, Iran²Department of Parasitology, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran³Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran

Received 18 May 2011; Revised 29 June 2011; Accepted 13 July 2011

Academic Editor: Stewart Schneller

Copyright © 2011 Zahra Rezaei et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

α-Aminophosphonates are bioisosteres of amino acids and have several pharmacological activities. These compounds have been synthesized by various routes from reaction between amine, aldehyde, and phosphite compounds. In order to synthesize α-aminophosphonates, catalytic effect of CuCl₂ was compared with FeCl₃. Also all designed structures as well as griseofulvin were docked into the active site of microtubule (1JFF), using Autodock program. The results showed that the reactions were carried out in the presence of CuCl₂ in lower yields, and also the time of reaction was longer in comparison with FeCl₃. The chemical structures of the new compounds were confirmed by spectral analyses. The compounds were investigated for antifungal activity against several fungi in comparison with griseofulvin. An indole-derived bis(α-aminophosphonates) with the best negative ΔG in docking study showed maximum antifungal activity against Microsporum canis, and other investigated compounds did not have a good antifungal activity.

1. Introduction

The α-aminophosphonates are amino acid analogues, which have found a wide range of applications in the areas of industrial, agricultural, and medicinal chemistry owing to their biological and physical properties as well as their utility as synthetic intermediates [1–5]. As a kind of natural amino acid analogues, α-aminophosphonates constitute an important class of compounds with diverse biological activities. The activity of α-aminophosphonates as pharmacogenic agents [6] is reported in the literature. Also it has been reported that some alkyl-substituted phosphonate compounds have antifungal activity [7, 8], antibacterial activity [9, 10], antitumor effects [11–13], and antiviral activity [14].

Three-component synthesis starting from aldehydes, amines and diethyl phosphite or triethyl phosphite have been reported by using Lewis and Bronsted acid catalysts such as LiClO4 [15], InCl₃ [16], AlCl₃ [17], lanthanide triflates/magnesium sulfate [18], SbCl₃/Al₂O₃ [19], TaCl₅-SiO₂ [20], CF₃CO₂H [21], scandium (tris-dodecyl sulfate) [22], BF₃·Et₂O [23], M(OTf)n    [24], and M(ClO₄)n [25], though, many of these methods suffer from some drawbacks such as long reaction times, low yields of the products, requiring stoichiometric amounts of catalysts, costly and moisture sensitive catalysts, and use of highly toxic or toxic catalysts. More recently, ZrOCl₂·8H₂O [26] or ZrO(ClO₄)₂·6H₂O [27] and TiO₂ [28] are reported to be effective catalysts for the formation of α-aminophosphonates using a three- component system composing of aldehydes/ketones, amines, and diethylphosphite under neat conditions. Recently, we have reported one-pot three-component synthesis starting from aldehydes, amines and diethylphosphite using FeCl₃ as a catalyst to formation of α-aminophosphonates [29]. As FeCl₃ suffers from being hygroscopic and is also a corrosive material, in this study the catalyst effect of CuCl₂ was compared with FeCl₃ for α-aminophosphonates preparation.

As it has been reported that α-aminophosphonates have antifungal and cytotoxic activity [7, 8, 29], in this study a series of α-aminophosphonates was designed having aromatic aldehydes and amines with Cl and methoxy moiety similar to griseofulvin structure. Griseofulvin inhibits the growth of fungal cells by inducing abnormal mitosis. It has been reported that griseofulvin blocked the cells at G2/M phase of cell cycle and caused a significant depolymerisation of the spindle microtubules [30]. Because the griseofulvin binding site partially overlaps with the paclitaxel site in tubulin [30], therefore, microtubul complexed with paclitaxel (1JFF) was obtained from Protein Data Bank for docking studies. Autodock program used and all designed structures as well as griseofulvin were docked into the active site of 1JFF. In addition, we synthesized and investigated antifungal activity of some new α-aminophosphonates in comparison with griseofulvin.

2. Results and Discussion

2.1. Chemistry

In order to synthesize α-aminophosphonates, the three components, aldehyde (benzaldehyde, 5.0 mmol), aromatic amine (aniline, 5.0 mmol), and diethyl phosphate (5.5 mmol), were reacted in the presence of catalytic amount (0.1 mmol) of FeCl₃ or CuCl₂ (Scheme 1). The reaction completely proceeded after 90 min with 73% yield in the presence of FeCl₃, but the reaction did not completely proceed even after 24 h using CuCl₂. The reactions were repeated with several aldehydes, amines, and diethyl phosphates with similar molar ratios as above in the presence of catalytic amount of FeCl₃ or CuCl₂. The reactions proceeded between 30–120 min in excellent isolated yields (73–84%) in the presence of FeCl₃, but CuCl₂ was not an effective catalyst like FeCl₃. The results of this study are summarized in Table 1.

Table 1: Comparison of the effect of catalysts in preparation of α-aminophosphonate by the reaction of an aldehyde, aniline and diethylphosphite.

Entry
Catalyst (0.1 mmol)
Solvent
Time (min)
Yield (%)

1
FeCl₃
THF
30–120
73–84

2
CuCl₂
THF
24
<5%

Compound 1: R₁  = OMe, R₂  = OH, R₃  = H; Compound 8: R₁  = Ome, R₂  = Ome, R₃  = H; Compound 11: R₁  = OMe, R₂  = OMe, R₃  = OMe; Compound 12: R₁ = H, R₂  = OMe, R₃ = H; Compound 14: R₁ = H, R₂  = H, R₃ = H; Compound 20: R₁ = H, R₂  = NO₂, R₃ = H.

Scheme 1: Three-component reaction of aromatic aldehydes with amine and diethylphosphite.

In this study 21 compounds were synthesized. The synthesis of compounds 1, 8, 11, 12, 14, and 20 was carried out in the presence of catalytic amount of FeCl₃ or CuCl₂ (Table 1). The reactions proceed between 30–120 min in excellent isolated yields (73–84%) using FeCl₃, but the reaction takes 24 h using CuCl₂. However, it has been reported that metal chloride or metal halide are efficient catalyst for preparation of aminophosphonate by three-component reaction [31] but it seems that CuCl₂ is not very efficient catalyst for formation of α-aminophosphonates in this condition. As our aim was comparison of the catalytic effect of CuCl₂ with FeCl₃ under same conditions, hence, other conditions were ignored. All compounds were synthesized by one-pot three-component synthesis using FeCl3 as a catalyst. The reactions completely proceeded after 30–180 min in excellent isolated yields (68–90%) in the presence of FeCl₃ (Table 2).

Table 2: FeCl₃·THF solution catalyzed synthesis of bis(α-aminophosphonates) by using a three-component system.

Entry
Aldehyde
Amine
α-Aminophosphonate
Time (minutes)
Yield (%)

1

120
84

2

150
72

3

180
78

4

120
90

5

180
80

6

120
76

7

120
77

8

120
82

9

180
70

10

120
81

11

30
81

12

60
76

13

90
75

14

90
73

15

45
75

16

90
71

17

90
70

18

120
70

19

120
76

20

120
73

21

180
68

The recommended mechanism for preparation of α-aminophosphonates using FeCl₃ as a catalyst is shown in Figure 1. As shown in Figure 1, the reaction starts with activation of diethylphosphite a tautomer form in which the P (V) turns to P (III) with a free par of electron. Then the nitrogen of Schiff base that is formed in the first step of α-aminophosphonates formation donates a pair of electron to make a coordinante bond with FeCl₃. This makes nitrogen positively charged which induces partial positive charge on sp² carbon. The free pair of electrons of phosphorus attacks to the partially positively charged carbon and a cyclic current of electron displacement protonates nitrogen and detaches the FeCl₃ to enter the new cycle. It seems that CuCl₂ is not efficient as FeCl₃ for attending to this mechanism for formation of α-aminophosphonates.

Figure 1: Proposed mechanism for catalytic effect of FeCl₃.

2.2. Modeling

All the compounds (Table 2) as well as griseofulvin were docked into the active site of microtubule, which was obtained from Protein Data Bank (1JFF) using Autodock 4.2. All synthesized compounds were characterized by a docking mode in the active site of the microtubule. Compound 21 showed cytotoxic activity in our previous study [29]. However, this compound has indole moiety like vinca alkaloids but binds to the paclitaxel site in 1JFF like griseofulvin (Figure 2). Therefore, antifungal activity of this compound was investigated in comparison with griseofulvin. According to obtained ΔG, compound 21 had the maximum negative ΔG and compound 15 had the lowest negative ΔG (Table 3); other compounds had ΔG close to griseofulvin. Although compound 21 with maximum negative ΔG had the best MIC but there was no correlation between antifungal activity and ΔG for other compounds.

Table 3: Docking results of synthesized compounds into the active site of microtubule (1JFF).

Entry
ΔG (kcal/mol)
Entry
ΔG (kcal/mol)

1
−6.09
12
−5.55

2
−6.18
13
−5.88

3
−6.16
14
−5.79

4
−6.23
15
−5.49

5
−6.36
16
−6.22

6
−6.27
17
−6.34

7
−6.71
18
−6.10

8
−6.06
19
−6.61

9
−5.78
20
−6.74

10
−6.27
21
−7.4

11
−6.23
Griseofulvin
−6.76

Figure 2: Accommodation of Griseofulvin (red) and compound 21 (blue) in the active site of 1JFF.

2.3. Biological Assay

The synthesized compounds 1–21 were evaluated for antifungal activity against Candida albicans, Candida tropicalis, Aspergillus flavus, Microsporum canis, Microsporum gypseum, Trichophyton mentagrophyte, and Epidermophyton floccosum. Agar dilution assay and microdilution method were used to establish the Minimum Inhibitory Concentration (MIC). The results are presented in Table 4. As shown in Table 4 compounds 1, 7, and 9 showed very low antifungal activity against Trichophyton mentagrophytes. Compound 1 also showed very low antifungal activity against Microsporum gypseum. Compound 21 was the most active compound against Microsporum canis. This compound was previously evaluated in vitro for cytotoxicity effect and showed moderate cytotoxicity activity [29]; here this compound was evaluated for antifungal activity the MIC value found 5 μg/mL, and the MIC for compound 21 was better than MIC for griseofulvin. Compound 21 is a bis-phosphonate, and it has an indole ring system, perhaps this moiety causes its antifungal activity. Also this compound had the better ΔG in docking study. Nevertheless, it has been reported that aminophosphonates have antifungal activity against phytopathogenic fungi [8, 14]; our synthesized compounds did not show antifungal activity against tested human pathogenic fungi. Song and coworkers reported that antifungal activity of aminophosphonates is related to stereochemistry of them [8]; therefore, may be the antifungal activity of our compound is related to stereochemistry of them. Therefore, we suggest that antifungal evaluation should be done for each enantiomer separately.

Table 4: Antifungal activity of synthesized α-aminophosphonates.

Compound
Candida albicans
Aspergillus flavus
Aspergillus fumigatus
Trichophyton mentagrophytes
Microsporum gypsum
Microsporum canis
Epidermophyton floccosum

MIC g/mL

1
G
G
G
2048
2048
G
G

7
G
G
G
2048
G
G
G

9
G
G
G
1024
G
G
G

21
G
G
G
G
G
0.5
G

Fluconazole
2
4
4
NT
NT
NT
NT

Griseofulvin
NT
NT
NT
0.5
8
0.6
1

G: Growth, NT: Not Tested.

3. Experimental

All solvents and reagents were purchased from Sigma or Merck Chemical Companies. The products were purified by column chromatography techniques. NMR spectra were recorded on a Brucker Avance DPX 500 MHZ instrument. Mass spectra were recorded on a Hewlett-Packard GC-MS.

3.1. General Procedures for the Synthesis of Compounds

To a mixture of aldehyde (2 mmol), amine (1 mmol), and diethylphosphite (2.2 mmol) was added FeCl3 in THF (0.1 mmol) and stirred at 60°C for the appropriate reaction time. After completion of the reaction, EtOAc (10 mL) was added to the mixture. The mixture was washed with H₂O (10 mL). The organic phase was separated and dried over anhydrous Na₂SO₄. The solvent was evaporated in vacuo, and the resulting crude material was purified by chromatography on a short column of silica gel (EtOAc/petroleum ether, 1/3) and then recrystallized from petroleum benzine/dichloromethane (4/1) to afford the pure α-aminophosphonates.

Diethyl [Anilino(4-hydroxy-3-methoxyphenyl)methyl]phosphonate (1)This compound was synthesized after 120 min (84%. °C). ¹H NMR (500 MHz, CDCl₃): 7.15 (t, 2H,  Hz, ArH), 7.04 (s, 1H, ArH), 6.98 (d, 1H,  Hz, ArH), 6.90 (d, 1H,  Hz, ArH), 6.74 (t, 1H,  Hz, ArH), 6.64 (d, 2H,  Hz, ArH), 4.72 (d, 1H,  Hz, CHP), 4.12–4.18 (m, 2H, OCH₂CH₃), 3.97–4.02 (m, s, 1H, OCH₂CH₃), 3.87 (s, 3H, OCH₃), 3.72–3.77 (m, 1H, OCH₂CH₃), 1.32 (t, 3H,  Hz, CH₃), 1.18 (t, 3H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 147.35 (Ar-C), 146.93 (Ar-C), 146.81 (Ar-C), 145.97 (Ar-C), 129.57 (Ar-C), 127.87 (Ar-C), 114.93 (Ar-C), 114.32 (Ar-C), 110.67 (Ar-C), 63.72 (d,  Hz, OCH₂CH₃), 56.38 (d,  Hz, CHP), 55.64 (OCH₃), 16.87 (d,  Hz, CH₃), 16.70 (d,  Hz, CH₃); MS: (m/z%), 363 (M⁺, 21.8), 228 (100), 137 (9.3).

Diethyl [(4-Nitrophenyl amino) (3,4,5-trimethoxy) methyl]phosphonate (2)This compound was synthesized after 150 min (72%. °C). ¹H NMR (500 MHz, CDCl₃): 8.07 (d, 2H,  Hz, ArH), 6.96 (s, 2H, ArH), 6.64 (s, 2H, ArH), 5.72 (t, 1H,  Hz, NH), 4.75 (d, 1H,  Hz, CHP), 4.12–4.21 (m, 1H, OCH₂CH₃), 3.98–4.03 (m, 1H, OCH₂CH₃), 3.85 (s, 9H, OCH₃), 3.70–3.75 (m, 1H, OCH₂CH₃), 1.34 (t, 3H,  Hz, CH₃), 1.18 (t, 3H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 154.06 (Ar-C), 152.21 (Ar-C), 136.66 (Ar-C), 130.45 (Ar-C), 126.53 (Ar-C), 112.88 (Ar-C), 105.12 (Ar-C), 64.03 (d,  Hz, OCH₂CH₃), 59.74 (d,  Hz, CH₃), MS: (m/z%), 545 (M⁺, 5.7), 317 (100), 271 (5), 181 (5.7).

Diethyl [(4-Hydroxy, 3-methoxy phenyl) (4-nitrophenyl amino) methyl]phosphonate (3)This compound was synthesized after 180 min (78%. °C). ¹H NMR (500 MHz, CDCl₃): 8.04 (d, 2H,  Hz, ArH), 7.00 (d, 1H,  Hz, ArH), 6.97 (d, 2H,  Hz, ArH), 6.95 (s, 1H, ArH), 6.64 (d, 2H,  Hz, ArH), 5.86 (t, 1H,  Hz, NH), 4.76 (d, 1H,  Hz, CHP), 4.13–4.2 (m, 2H, OCH₂CH₃), 3.95–4.00 (m, 1H, OCH₂CH₃), 3.88 (s, 3H, OCH₃), 3.67–3.76 (m, 1H, OCH₂CH₃), 1.32 (t, 3H,  Hz, CH₃), 1.17 (t, 3H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 152.34 (Ar-C), 147.52 (Ar-C), 146.38 (Ar-C), 139.45 (Ar-C), 126.49 (Ar-C), 126.44 (Ar-C), 121.35 (Ar-C), 115.18 (Ar-C), 112.86 (Ar-C), 110.47 (Ar-C), 64.04 (d,  Hz, OCH₂CH₃), 56.38 (d,  Hz, CH₃), 55.07 (OCH₃)MS: (m/z%), 410 (M⁺, 5.5), 273 (100), 227 (8.8), 137 (7.7).

Diethyl [(3,4-Dimethoxy phenyl amino) (3,4,5-trimethoxy phenyl) methyl]phosphonate (4)This compound was synthesized after 120 min (87%. °C). ¹H NMR (500 MHz, CDCl₃): 6.72 (s, 2H, ArH), 6.68 (d, 1H,  Hz, ArH), 6.31 (s, 1H, ArH), 6.11 (d, 1H,  Hz, ArH), 4.60 (d, 1H,  Hz, CHP), 4.11–4.19 (m, 2H, OCH₂CH₃), 3.98–4.03 (m, 1H, OCH₂CH₃), 3.84 (s, 9H, OCH₃), 3.81 (s, 6H, OCH₃), 3.75–3.79 (m, 1H, OCH₂CH₃), 1.32 (t, 3H,  Hz, CH₃), 1.18 (t, 3H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 153.77 (Ar-C), 150.23 (Ar-C), 142.66 (Ar-C), 141.55 (Ar-C), 138.04 (Ar-C), 132.17 (Ar-C), 113.25 (Ar-C), 105.21 (Ar-C), 100.5 (Ar-C), 63.65 (d,  Hz, OCH₂CH₃), 57.10 (d,  Hz CHP), 56.91 (OCH₃), 56.58 (OCH₃), 56.1 (OCH₃), 16.88 (d,  Hz, CH₃), 16.70 (d,  Hz, CH₃); MS: (m/z%), 469 (M⁺, 7.1), 331 (100), 300 (3.5), 195 (11.9).

Diethyl [(3,4-Dimethoxy phenyl) (4-nitrophenyl amino) methyl]phosphonate (5)This compound was synthesized after 180 min (80%. °C). ¹H NMR (500 MHz, CDCl₃): 8.04 (d, 2H,  Hz, ArH), 7.01 (d, 2H,  Hz, ArH), 6.86 (s, 2H, ArH), 6.62 (d, 2H,  Hz, ArH), 5.87 (t, 1H, NH), 4.74 (d, 1H,  Hz, CHP), 4.13–4.18 (m, 2H, OCH₂CH₃), 3.94–3.98 (m, 1H, OCH₂CH₃), 3.69–3.74 (m, 1H, OCH₂CH₃), 1.32 (t, 3H,  Hz, CH₃), 1.16 (t, 3H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 152.35 (Ar-C), 149.78 (Ar-C), 149.60 (Ar-C), 139.45 (Ar-C), 127.15 (Ar-C), 126.48 (Ar-C), 120.63 (Ar-C), 112.86 (Ar-C), 111.67 (Ar-C), 111.08 (Ar-C), 63.98 (d,  Hz, OCH₂CH₃), 56.32 (d,  Hz CHP), 55.03 (OCH₃), 56.58 (OCH₃), 16.85 (d,  Hz, CH₃), 16.70 (d,  Hz, CH₃); MS: (m/z%), 424 (M⁺, 5.5), 287 (100), 241 (7), 149 (2.9).

Diethyl [(5-Chloro-2-methylphenyl amino) (3,4,5-trimethoxy phenyl) methyl]phosphonate (6)This compound was synthesized after 120 min (76%. °C). ¹H NMR (500 MHz, CDCl₃):6.96 (s, 1H, ArH), 6.94 (d, 1H,  Hz, ArH), 6.7 (s, 2H, ArH), 6.45 (s, 1H, ArH), 4.67 (d, 1H,  Hz, CHP), 4.09–4.17 (m, 2H, OCH₂CH₃), 3.96–4.01 (m, 1H, OCH₂CH₃), 3.85 (s, 9H, OCH₃), 3.72–3.77 (m, 1H, OCH₂CH₃), 2.24 (s, 3H, CH₃), 1.29 (t, 3H,  Hz, CH₃), 1.16 (t, 3H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 153.86 (Ar-C), 145.98 (Ar-C), 138.28 (Ar-C), 132.85 (Ar-C), 131.41 (Ar-C), 121.55 (Ar-C), 118.32 (Ar-C), 111.78 (Ar-C), 105.14 (Ar-C), 63.76 (d,  Hz, OCH₂CH₃), 57.30 (d,  Hz CHP), 56.60 (OCH₃), 17.47 (CH3), 16.84 (d,  Hz, CH₃), 16.66 (d,  Hz, CH₃); MS: (m/z%), 457 (M⁺, 5.3), 320 (100), 181 (6.6).

Diethyl [(5-Chloro-2-methylphenyl amino) (4-methoxy phenyl) methyl]phosphonate (7)This compound was synthesized after 120 min (77%. °C). ¹H NMR (500 MHz, CDCl₃): 7.40 (d, 2H,  Hz, ArH), 6.97 (s, 1H, ArH), 6.92 (d, 2H,  Hz, ArH), 6.64 (d, 1H,  Hz, ArH), 6.43 (d, 1H,  Hz, ArH), 4.71 (d, 1H,  Hz, CHP), 4.11–4.19 (m, 2H, OCH₂CH₃), 3.95–4.00 (m, 1H, OCH₂CH₃), 3.82 (s, 3H, OCH₃), 3.71–3.76 (m, 1H, OCH₂CH₃), 2.25 (s, 3H, CH₃), 1.32 (t, 3H,  Hz, CH₃), 1.17 (t, 3H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 159.88 (Ar-C), 145.85 (Ar-C), 132.83 (Ar-C), 131.35 (Ar-C), 129.19 (Ar-C), 127.54 (Ar-C), 121.59 (Ar-C), 118.10 (Ar-C), 114.63 (Ar-C), 111.71 (Ar-C), 63.68 (d,  Hz, OCH₂CH₃), 56.28 (d,  Hz CHP), 55.66 (OCH₃), 17.48 (CH3), 16.86 (d,  Hz, CH₃), 16.68 (d,  Hz, CH₃); MS: (m/z%), 397 (M⁺, 7.0), 260 (100), 121 (17.8).

Diethyl [(3,4-Dimethoxyphenyl) (phenyl amino) methyl]phosphonate (8)This compound was synthesized after 120 min (82%. °C). ¹H NMR (500 MHz, CDCl₃): 7.13 (t, 2H,  Hz, ArH), 7.04 (d, 2H,  Hz, ArH), 6.85 (s, 1H, ArH), 6.72 (t, 1H,  Hz, ArH), 6.63 (d, 2H,  Hz, ArH), 4.72 (d, 1H,  Hz, CHP), 4.10–4.17 (m, 2H, OCH₂CH₃), 3.96–4.01 (m, 1H, OCH₂CH₃), 3.88 (s, 6H, OCH₃), 3.71–3.76 (m, 1H, OCH₂CH₃), 1.31 (t, 3H,  Hz, CH₃), 1.17 (t, 3H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 149.52 (Ar-C), 149.14 (Ar-C), 146.87 (Ar-C), 129.56 (Ar-C), 128.65 (Ar-C), 120.63 (Ar-C), 118.84 (Ar-C), 114.31 (Ar-C), 111.54 (Ar-C), 111.25 (Ar-C), 63.64 (d,  Hz, OCH₂CH₃), 56.83 (d,  Hz CHP), 56.30 (OCH₃), 16.88 (d,  Hz, CH₃), 16.72 (d,  Hz, CH₃); MS: (m/z%), 379 (M⁺, 5.0), 242 (100), 151 (17.8).

Diethyl [(4-Chloro-2-nitrophenyl amino) (4-hydroxy-3-methoxyphenyl) methyl]phosphonate (9)This compound was synthesized after 180 min (70%. °C). ¹H NMR (500 MHz, CDCl₃): 8.22 (s, 1H, ArH), 7.30 (d, 1H,  Hz, ArH), 6.99 (d, 1H,  Hz, ArH), 6.93 (d, 2H,  Hz, ArH), 6.71 (s, 1H, ArH), 4.82 (d, 1H,  Hz, CHP), 4.03–4.14 (m, 2H, OCH₂CH₃), 3.96–3.99 (m, 1H, OCH₂CH₃), 3.91 (s, 3H, OCH₃), 3.71–3.76 (m, 1H, OCH₂CH₃), 1.28 (t, 3H,  Hz, CH₃), 1.17 (t, 3H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 147.53 (Ar-C), 146.42 (Ar-C), 143.15 (Ar-C), 136.59 (Ar-C), 133.52 (Ar-C), 126.41 (Ar-C), 126.03 (Ar-C), 122.01 (Ar-C), 121.05 (Ar-C), 116.66 (Ar-C), 115.14 (Ar-C), 110.21 (Ar-C), 64.11 (d,  Hz, OCH₂CH₃), 56.46 (d, Hz CHP), 55.23 (OCH₃), 16.84 (d,  Hz, CH₃), 16.75 (d,  Hz, CH₃); MS: (m/z%), 444 (M⁺, 1.0), 307 (100), 290 (23.5), 273 (41.1), 151 (26.4).

Diethyl [(3,4-Dimethoxy phenyl amino) (4-hydroxy-3-methoxy phenyl) methyl]phosphonate (10)This compound was synthesized after 120 min (81%. °C). ¹H NMR (500 MHz, CDCl₃): 7.00 (s, 2H, ArH), 6.81 (d, 1H,  Hz, ArH), 6.64 (d, 1H,  Hz, ArH), 6.26 (d, 1H,  Hz, ArH), 6.09 (d, 1H,  Hz, ArH), 4.60 (d, 1H,  Hz, CHP), 4.07–4.16 (m, 2H, OCH₂CH₃), 3.93–3.98 (m, 1H, OCH₂CH₃), 3.85 (s, 6H, OCH₃), 3.75 (s, 3H, OCH₃), 3.69–3.73 (m, 1H, OCH₂CH₃), 1.29 (t, 3H,  Hz, CH₃), 1.14 (t, 3H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 150.20 (Ar-C), 149.50 (Ar-C), 142.53 (Ar-C), 141.61 (Ar-C), 141.48 (Ar-C), 128.82 (Ar-C), 120.61 (Ar-C), 113.27 (Ar-C), 111.50 (Ar-C), 111.26 (Ar-C), 105.19 (Ar-C), 100.52(Ar-C), 63.60 (d,  Hz, OCH₂CH₃), 56.90 (d, Hz CHP), 56.32 (OCH₃), 56.05 (OCH₃), 16.86 (d,  Hz, CH₃), 16.70 (d,  Hz, CH₃); MS: (m/z%), 425 (M⁺, 25), 288 (100), 272 (3.5), 1490 (8.3).

Diethyl [(Phenyl amino) (3,4,5-trimethoxy phenyl) methyl]phosphonate (11)This compound was synthesized after 30 min (81%. °C). ¹H NMR (500 MHz, CDCl₃): 7.16 (t, 2H,  Hz, ArH), 6.75 (t, 3H, ArH), 6.65 (d, 2H,  Hz, ArH), 4.80 (d, 1H,  Hz, CHP), 4.10–4.17 (m, 2H, OCH₂CH₃), 3.99–4.03 (m, 1H, OCH₂CH₃), 3.85 (s, 9H, OCH₃), 3.75–3.79 (m, 1H, OCH₂CH₃), 1.32 (t, 3H,  Hz, CH₃), 1.18 (t, 3H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 153.76 (Ar-C), 146.92 (Ar-C), 131.96 (Ar-C), 129.61 (Ar-C), 118.96 (Ar-C), 114.27 (Ar-C), 105.23 (Ar-C), 63.72 (d,  Hz, OCH₂CH₃), 56.81 (d,  Hz CHP), 56.57 (OCH₃), 56.21 (OCH₃), 16.87 (d,  Hz, CH₃), 16.70 (d,  Hz, CH₃); MS: (m/z%), 409 (M⁺, 7.4), 272 (100), 181 (5.4).

Diethyl [4-Methoxyphenyl)(phenyl amino)methyl]phosphonate (12)This compound was synthesized after 60 min (76%. °C). ¹H NMR (500 MHz, CDCl₃): 7.42 (d, 2H,  Hz, ArH), 7.13 (t, 2H,  Hz, ArH), 6.90 (d, 2H  Hz, ArH), 6.72 (d, 2H,  Hz, ArH), 6.72 (t, 1H,  Hz, ArH), 6.63 (d, 2H,  Hz, ArH), 4.78 (s, 1H, NH), 4.76 (d, 1H,  Hz, CHP), 4.11–4.17 (m, 2H, OCH₂CH₃), 3.96–4.0 (m, 1H, OCH₂CH₃), 3.80 (s, 3H, OCH₃), 3.71–3.76 (m, 1H, OCH₂CH₃), 1.32 (t, 3H,  Hz, CH₃), 1.17 (t, 3H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 159.74 (Ar-C), 146.79 (Ar-C), 129.57 (Ar-C), 129.38 (Ar-C), 128.11 (Ar-C), 118.76 (Ar-C), 114.47 (Ar-C), 114.31 (Ar-C), 63.62 (d,  Hz, OCH₂CH₃), 55.87 (d,  Hz, CHP), 55.64 (OCH₃), 16.85 (d,  Hz, CH₃), 16.68 (d,  Hz, CH₃); MS: (m/z%), 349 (M⁺, 3.9), 212 (100), 121 (3.9).

Diethyl [(4-Chloro-2-nitrophenyl amino) (3,4,5-trimethoxy phenyl) methyl]phosphonate (13)This compound was synthesized after 90 min (75%. °C). ¹H NMR (500 MHz, CDCl₃): 8.84 (d, 1H,  Hz, ArH), 8.19 (s, 1H, ArH), 6.67–677 (m, 3H, ArH), 4.79 (d, 1H,  Hz, CHP), 4.09–4.14 (m, 2H, OCH₂CH₃), 4.03–4.07 (m, 1H, OCH₂CH₃), 3.97-3.99 (m, 1H, OCH₂CH₃), 3.84 (s, 9H, OCH₃), 1.31-1.25 (m, 6H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 154.6 (Ar-C), 143.17 (Ar-C), 143.06 (Ar-C), 138.53 (Ar-C), 136.66 (Ar-C), 130.09 (Ar-C), 130.06 (Ar-C), 126.38 (Ar-C), 122.15 (Ar-C), 116.67 (Ar-C), 64.19 (d,  Hz, OCH₂CH₃), 64.02 (d,  Hz, OCH₂CH₃), 56.66 (OCH₃), 56.32 (d,  Hz CHP), 16.82 (d,  Hz, CH₃), 16.73 (d,  Hz, CH₃); MS: (m/z%), 488 (M⁺, 4.3), 351 (100), 195 (8.7).

Diethyl [(Phenyl amino)(phenyl)methyl]phosphonate (14)This compound was synthesized after 90 min (73%. °C). ¹H NMR (500 MHz, CDCl₃): 7.53 (s, 2H, ArH), 7.38 (t, 2H,  Hz, ArH), 7.29-7.32 (m, 1H, ArH), 7.15 (t, 2H,  Hz, ArH), 6.74 (t, 1H,  Hz, ArH), 6.65 (d, 2H,  Hz, ArH), 4.82 (d, 1H,  Hz, CHP), 4.11–4.21 (m, 2H, OCH₂CH₃), 3.96–4.01 (m, 1H, OCH₂CH₃), 3.70–3.75 (m, 1H, OCH₂CH₃), 1.33 (t, 3H,  Hz, CH₃), 1.16 (t, 3H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 146.80 (Ar-C), 136.35 (Ar-C), 129.60 (Ar-C), 129.02 (Ar-C), 128.34 (Ar-C), 128.30 (Ar-C), 118.82 (Ar-C), 114.29 (Ar-C), 63.72 (d,  Hz, OCH₂CH₃), 63.66 (d,  Hz, OCH₂CH₃), 56.50 (d,  Hz, CHP), 16.88 (d,  Hz, CH₃), 16.64 (d,  Hz, CH₃); MS: (m/z%), 319 (M⁺, 16), 182 (100).

Diethyl [(3,4-Dimethoxy phenyl amino) (3,4-dimethoxy phenyl) methyl]phosphonate (15)This compound was synthesized after 45 min (75%. °C). ¹H NMR (500 MHz, CDCl₃): 6.99–7.01 (m, 2H, ArH), 6.82 (d, 1H,  Hz, ArH), 6.63 (d, 1H,  Hz, ArH), 6.29 (s, 1H, ArH), 6.08 (d, 1H,  Hz, ArH), 4.65 (s, 1H, NH), 4.59 (d, 1H,  Hz, CHP), 4.07–4.16 (m, 2H, OCH₂CH₃), 3.93–3.98 (m, 1H, OCH₂CH₃), 3.85 (s, 6H, OCH₃), 3.74 (s, 6H, OCH₃), 3.69–3.74 (m, 1H, OCH₂CH₃), 1.29 (t, 3H,  Hz, CH₃), 1.14 (t, 3H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 150.20 (Ar-C), 149.50 (Ar-C), 149.10 (Ar-C), 142.53 (Ar-C), 141.55 (Ar-C), 128.82 (Ar-C), 120.63 (Ar-C), 113.27 (Ar-C), 111.50 (Ar-C), 111.26 (Ar-C), 105.19 (Ar-C), 100.52 (Ar-C), 63.63 (d,  Hz, OCH₂CH₃), 63.58 (d,  Hz, OCH₂CH₃), 57.03 (d,  Hz CHP), 56.99 (OCH₃), 56.32 (OCH₃), 56.23 (OCH₃), 56.05 (OCH₃), 16.86 (d,  Hz, CH₃), 16.70 (d,  Hz, CH₃); MS: (m/z%), 439 (M⁺, 9.3), 302 (100), 151 (6.6).

Diethyl [(5-Chloro-2-methylphenyl amino) (4-hydroxy-3-methoxy phenyl) methyl]phosphonate (16)This compound was synthesized after 90 min (64%. °C). 1H NMR (500 MHz, CDCl3): 7.01 (s, 1H, ArH), 6.95–6.98 (m, 2H, ArH), 6.91 (s, 1H, ArH), 6.65 (d, 1H,  Hz, ArH), 6.46 (s, 1H, ArH), 4.71 (s, 1H, CHP), 4.66 (s, 1H, NH), 4.09–4.19 (m, 2H, OCH2CH3), 3.96–4.01 (m, 1H, OCH2CH3), 3.89 (s, 3H, OCH3), 3.71–3.76 (m, 1H, OCH2CH3), 2.24 (s, 3H, CH3), 1.31 (t, 3H,  Hz, CH3), 1.29 (t, 3H,  Hz, CH3); 13C NMR (125 MHz, CDCl3): 147.45 (Ar-C), 146.17 (Ar-C), 145.09 (Ar-C), 132.82 (Ar-C), 131.38 (Ar-C), 127.24 (Ar-C), 121.65 (Ar-C), 121.13 (Ar-C), 118.21 (Ar-C), 115.12 (Ar-C), 111.79 (Ar-C), 110.63 (Ar-H), 63.91 (d,  Hz, OCH2CH3), 63.73 (d,  Hz CHP), 56.41 (OCH3), 56.13 (d,  Hz, CHP), 17.47 (CH3), 16.85 (d,  Hz, CH3), 16.68 (d,  Hz, CH3); MS: (m/z%), 413 (M+, 5.2), 276 (100), 137 (10.6).

Diethyl [(5-Chloro-2-methylphenyl amino) (3,4-dimethoxy phenyl) methyl]phosphonate (17)This compound was synthesized after 90 min (70%. °C). ¹H NMR (500 MHz, CDCl₃): 7.02 (s, 1H, ArH), 6.97 (d, 2H,  Hz, ArH), 6.87 (d, 1H,  Hz, ArH), 6.64 (d, 1H,  Hz, ArH), 6.44 (s, 1H, ArH), 4.69 (d, 1H,  Hz, CHP), 4.68 (s, 1H, NH), 4.1–4.16 (m, 2H, OCH₂CH₃), 3.96–4.01 (m, 1H, OCH₂CH₃), 3.9 (s, 6H, OCH₃), 3.71–3.75 (m, 1H, OCH₂CH₃), 2.24 (s, 3H, CH₃), 1.32 (t, 3H,  Hz, CH₃), 1.17 (t, 3H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 149.61 (Ar-C), 149.32 (Ar-C), 145.95 (Ar-C), 132.84 (Ar-C), 131.37 (Ar-C), 128.03 (Ar-C), 121.56 (Ar-C), 12.43 (Ar-C), 118.20 (Ar-C), 111.79 (Ar-C), 111.66 (Ar-C), 111.12 (Ar-H), 63.81 (d,  Hz, OCH₂CH₃), 63.62 (d,  Hz, OCH₂CH₃), 56.38 (OCH₃), 56.27 (OCH₃), 56.11 (d,  Hz, CHP), 17.49 (CH3), 16.87 (CH₃), 16.72 (d,  Hz, CH₃), 16.68 (d,  Hz, CH₃); MS: (m/z%), 427 (M⁺, 6.6), 290 (100), 151 (9.6).

Diethyl [(4-Chloro-2-nitrophenyl amino) (3,4-dimethoxyphenyl) methyl]phosphonate (18)This compound was synthesized after 120 min (65%. °C). ¹H NMR (500 MHz, CDCl₃): 8.87 (d, 1H,  Hz, ArH), 8.18 (s, 1H, ArH), 6.99 (s, 2H, ArH), 6.87 (d, 1H,  Hz, ArH), 6.69 (d, 1H,  Hz, ArH), 4.8 (d, 1H,  Hz, CHP), 4.09–4.12 (m, 2H, OCH₂CH₃), 3.97–4.09 (m, 2H, OCH₂CH₃), 4.03–4.06 (m, 2H, OCH₂CH₃), 3.89 (s, 6H, OCH₃), 1.23–1.32 (m, 6H, CH₃); ¹³C NMR (125 MHz, CDCl₃): 149.81 (Ar-C), 149.65 (Ar-C), 143.15 (Ar-C), 136.56 (Ar-C), 133.52 (Ar-C), 126.39 (Ar-C), 121.98 (Ar-C), 12030 (Ar-C), 116.66 (Ar-C), 111.72 (Ar-C), 110.88 (Ar-C), 64.16 (d,  Hz, OCH₂CH₃), 63.97 (d,  Hz, OCH₂CH₃), 56.44 (OCH₃), 56.31 (OCH₃), 55.77 (d,  Hz CHP), 16.84 (d,  Hz, CH₃), 16.76 (d,  Hz, CH₃); MS: (m/z%), 458 (M⁺, 1.4), 321 (100), 165 (14).

Diethyl [(4-Methoxy phenyl) (4-nitrophenyl amino) methyl]phosphonate (19)This compound was synthesized after 120 min (76%. °C). ¹H NMR (500 MHz, CDCl₃): 8.0 (d, 2H,  Hz, ArH), 7.42 (d, 2H,  Hz, ArH), 6.89 (d, 2H,  Hz, ArH), 6.64 (d, 2H,  Hz, ArH), 6.37 (t, 1H,  Hz, ArH), 4.81 (d, 1H, Hz, CHP), 4.13–4.2 (m, 2H, OCH₂CH₃), 3.99–3.94 (m, 1H, OCH₂CH₃), 3.79 (s, 3H, OCH₃), 3.67–3.72 (m, 1H, OCH₂CH₃), 1.30 (t, 3H,  Hz, CH₃), 1.16 (t, 3H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 160.08 (Ar-C), 152.68 (Ar-C), 139.13 (Ar-C), 129.43 (Ar-C), 126.83 (Ar-C), 126.42 (Ar-C), 114.70 (Ar-C), 112.79 (Ar-C), 64.20 (d,  Hz, OCH₂CH₃), 63.68 (d,  Hz, OCH₂CH₃), 55.67 (OCH₃), 55.29 (d,  Hz, CH₃); MS: (m/z%), 394 (M⁺, 4), 257 (100), 211 (18), 121 (3.8).

Diethyl [(4-Nitrophenyl)(phenyl amino)methyl]phosphonate (20)This compound was synthesized after 90 min (73%. °C). ¹H NMR (500 MHz, CDCl₃): 8.24 (d, 2H,  Hz, ArH), 7.70 (d, 2H,  Hz, ArH), 7.16 (t, 1H,  Hz, ArH), 6.78 (t, 1H,  Hz, ArH), 6.58 (d, 2H,  Hz, ArH), 4.89 (d, 1H,  Hz, CHP), 4.87 (s. 1H, NH), 4.17–4.23 (m, 2H, OCH₂CH₃), 4.06–4.16 (m, 1H, OCH₂CH₃), 3.90–3.95 (m, 1H, OCH₂CH₃), 1.34 (t, 3H,  Hz, CH₃), 1.23 (t, 3H,  Hz, CH₃); ¹³C NMR (125 MHz, CDCl₃): 148.07 (Ar-C), 146.06 (Ar-C), 144.49 (Ar-C), 129.79 (Ar-C), 129.06 (Ar-C), 124.19 (Ar-C), 119.55 (Ar-C), 114.24 (Ar-C), 64.16 (d,  Hz, OCH₂CH₃), 63.9 (d,  Hz, OCH₂CH₃), 56.48 (d,  Hz, CHP), 16.84 (d,  Hz, CH₃), 16.67 (d,  Hz, CH₃); MS: (m/z%), 364 (M⁺, 7.9), 227 (100), 181 (23.8), 104 (3.6).

Tetraethyl-1,4-phenylene bis((2-(1H-indolyl)ethylamino)methylene)diphosphonate (21)This compound was previously synthesized [29].

3.2. Modeling

The ligands were drawn in the Hyperchem 8. The geometry was optimized through the molecular dynamic method AMBER and semiempirical method PM3. The microtubule complexed with paclitaxol was obtained from Protein Data Bank (1JFF).

The Autodock software version 4.2 was used for the molecular docking process. The grids were constructed around the proteins. The Lamarckian Genetic Algorithm method was used for the global optimum binding position search. A number of 100 cycles of calculation were used in order to get a final binding position as accurate as possible. All the compounds as well as griseofulvin were docked into the active site of 1JFF. The complex of ligand-receptor was viewed by Accelry’s Discovery Studio Visualizer. The docking procedure was run, and the maximum negative ΔG was calculated (Table 3).

3.3. Antifungal Assay

Microorganisms were obtained from the Mycology and Parasitology Department of the Shiraz University of Medical Sciences. Sabouraud dextrose agar (SDA), potato dextrose agar (PDA), and RPMI 1640 were used for agar dilution and microdilution methods. The clinical isolates of fungi including M. canis, T. mentagrophytes, T. rubrum, E. floccosum, and C. albicans were purified and subcultured on SC, SCC, and PDA media before testing. The stock solution of compounds was prepared in DMSO at a concentration of 200 mg/mL. The compounds were diluted in solid and broth media to obtain final concentration from 0.0625 to 2048 μg/mL, using PDA and RPMI 1640 media. The inocula of the molds and yeast were prepared from 2–10 day mature colonies grown. Fluconazole and griseofulvin were used as positive and the solvents of the compounds as negative blanks.

4. Conclusion

α-Aminophosphonates are valuable compounds to be investigated as bioactive molecules and pharmacological agents. Recently, we have reported one-pot three-component synthesis starting from aldehydes, amines, and diethylphosphite using FeCl₃ as a catalyst to formation of α-aminophosphonates [29]. In this study, synthesis of α-aminophosphonates using FeCl₃ was compared with CuCl₂. The results showed that FeCl₃ is more efficient than CuCl₂ as a catalyst for synthesis of α-aminophosphonates.

The biological assays show that only an indole containing bis-α-aminophosphonates has antifungal activity against M. canis. The docking results show that these compounds are candidate for cytotoxic activity studies.

Acknowledgments

This work was supported by Shiraz University of Medical Sciences. The authors are also thankful to Dr. Mohammad Reza Jafari.

References

R. Engel, “Phosphonates as analogues of natural phosphates,” Chemical Reviews, vol. 77, no. 3, pp. 349–367, 1977.

J. Hiratake and J. Oda, “Aminophosphonic and aminoboronic acids as key elements of a transition state analogue inhibitor of enzymes,” Bioscience, Biotechnology and Biochemistry, vol. 61, no. 2, pp. 211–218, 1997.

K. Moonen, I. Laureyn, and C. V. Stevens, “Synthetic methods for azaheterocyclic phosphonates and their biological activity,” Chemical Reviews, vol. 104, no. 12, pp. 6177–6215, 2004.

F. Palacios, C. Alonso, and J. M. de los Santos, “β-phosphono- and phosphinopeptides derived from β-amino-phosphonic and phosphinic acids,” Current Organic Chemistry, vol. 8, no. 15, pp. 1481–1496, 2004.

K. A. Schug and W. Lindner, “Noncovalent binding between guanidinium and anionic groups: focus on biological- and synthetic-based arginine/guanidinium interactions with phosph[on]ate and sulf[on]ate residues,” Chemical Reviews, vol. 105, no. 1, pp. 67–113, 2005.

E. K. Baylis, C. D. Campbell, and J. G. Dingwall, “1-Aminoalkylphosphonous acids. Part 1. Isosteres of the protein amino acids,” Journal of the Chemical Society, Perkin Transactions 1, pp. 2845–2853, 1984.

D. Ouimette and M. Coffey, “Comparative antifungal activity of four phosphonate compounds against isolates of nine Phytophthora species,” Phytopathology, vol. 79, no. 7, pp. 761–767, 1989.

S. Yang, X. W. Gao, C. L. Diao et al., “Synthesis and antifungal activity of novel chiral α-aminophosphonates containing fluorine moiety,” Chinese Journal of Chemistry, vol. 24, no. 11, pp. 1581–1588, 2006.

B. S. Kumar, A. U. R. Sankar, C. Suresh Reddy, S. K. Nayak, and C. Naga Raju, “Synthesis, and antimicrobial activity of 2,10-dichloro-6- substituted aminobenzyl-12H-dibenzo [d, g][1,3,2]dioxaphosphocin- 6-oxides,” Arkivoc, vol. 2007, no. 13, pp. 155–166, 2007.

S. S. Sonar, S. A. Sadaphal, V. B. Labade, B. B. Shingate, and M. S. Shingare, “An efficient synthesis and antibacterial screening of novel oxazepine α-aminophosphonates by ultrasound approach,” Phosphorus, Sulfur and Silicon and the Related Elements, vol. 185, no. 1, pp. 65–73, 2010.

M. J. Bloemink, J. J. H. Diederen, J. P. Dorenbos, R. J. Heetebrij, B. K. Keppler, and J. Reedijk, “Calcium ions do accelerate the DNA binding of new antitumor-active platinum aminophosphonate complexes,” European Journal of Inorganic Chemistry, no. 10, pp. 1655–1657, 1999.

L. Jin, B. Song, G. Zhang et al., “Synthesis, X-ray crystallographic analysis, and antitumor activity of N-(benzothiazole-2-yl)-1-(fluorophenyl)-O,O-dialkyl-α-aminophosphonates,” Bioorganic and Medicinal Chemistry Letters, vol. 16, no. 6, pp. 1537–1543, 2006.

X. Rao, Z. Song, and L. He, “Synthesis and antitumor activity of novel α-aminophosphonates from diterpenic dehydroabietylaminer,” Heteroatom Chemistry, vol. 19, no. 5, pp. 512–516, 2008.

Y. Xu, K. Yan, B. Song et al., “Synthesis and antiviral bioactivities of α-aminophosphonates containing alkoxyethyl moieties,” Molecules, vol. 11, no. 9, pp. 666–676, 2006.

M. R. Saidi and N. Azizi, “A new protocol for a one-pot synthesis of α-amino phosphonates by reaction of imines prepared in situ with trialkylphosphites,” Synlett, no. 8, pp. 1347–1349, 2002.

B. C. Ranu, A. Hajra, and U. Jana, “General procedure for the synthesis of α-amino phosphonates from aldehydes and ketones using indium(III) chloride as a catalyst,” Organic Letters, vol. 1, no. 8, pp. 1141–1143, 1999.

A. Manjula, B. V. Rao, and P. Neelakantan, “One-pot synthesis of α-aminophosphonates: an inexpensive approach,” Synthetic Communications, vol. 33, no. 17, pp. 2963–2969, 2003.

C. Qian and T. Huang, “One-pot synthesis of α-amino phosphonates from aldehydes using lanthanide triflate as a catalyst,” Journal of Organic Chemistry, vol. 63, no. 12, pp. 4125–4128, 1998.

S. Kumar, S. C. Taneja, M. S. Hundal, and K. K. Kapoor, “One-pot synthesis of α-aminophosphonates catalyzed by antimony trichloride adsorbed on alumina,” Tetrahedron Letters, vol. 49, no. 14, pp. 2208–2212, 2008.

S. Chandrasekhar, S. J. Prakash, V. Jagadeshwar, and C. Narsihmulu, “Three component coupling catalyzed by TaCl₅-SiO₂: synthesis of α-amino phosphonates,” Tetrahedron Letters, vol. 42, no. 32, pp. 5561–5563, 2001.

T. Akiyama, M. Sanada, and K. Fuchibe, “Bronsted acid-mediated synthesis of α-amino phosphonates under solvent-free conditions,” Synlett, no. 10, pp. 1463–1464, 2003.

K. Manabe and S. Kobayashi, “Facile synthesis of α-amino phosphonates in water using a Lewis acid- surfactant-combined catalyst,” Chemical Communications, no. 8, pp. 669–670, 2000.

H. J. Ha and G. S. Nam, “An efficient synthesis of anilinobenzylphosphonates,” Synthetic Communications, vol. 22, no. 8, pp. 1143–1148, 1992.

H. Firouzabadi, N. Iranpoor, and S. Sobhani, “Metal triflate-catalyzed one-pot synthesis of α-aminophosphonates from carbonyl compounds in the absence of solvent,” Synthesis, no. 16, pp. 2692–2696, 2004.

S. Bhagat and A. K. Chakraborti, “An extremely efficient three-component reaction of aldehydes/ketones, amines, and phosphites (Kabachnik-Fields reaction) for the synthesis of α-aminophosphonates catalyzed by magnesium perchlorate,” Journal of Organic Chemistry, vol. 72, no. 4, pp. 1263–1270, 2007.

H. Firouzabadi and M. Jafarpour, “Some applications of zirconium(IV) tetrachloride (ZrCl4) and zirconium(IV) oxydichloride octahydrate (ZrOCl₂·8H₂O) as catalysts or reagents in organic synthesis,” Journal of the Iranian Chemical Society, vol. 5, no. 2, pp. 159–183, 2008.

S. Bhagat and A. K. Chakraborti, “Zirconium(IV) compounds as efficient catalysts for synthesis of α-aminophosphonates,” Journal of Organic Chemistry, vol. 73, no. 15, pp. 6029–6032, 2008.

M. Hosseini-Sarvari, “TiO₂ as a new and reusable catalyst for one-pot three-component syntheses of α-aminophosphonates in solvent-free conditions,” Tetrahedron, vol. 64, no. 23, pp. 5459–5466, 2008.

Z. Rezaei, H. Firouzabadi, N. Iranpoor et al., “Design and one-pot synthesis of α-aminophosphonates and bis(α-aminophosphonates) by iron(III) chloride and cytotoxic activity,” European Journal of Medicinal Chemistry, vol. 44, no. 11, pp. 4266–4275, 2009.

K. Rathinasamy, B. Jindal, J. Asthana, P. Singh, P. V. Balaji, and D. Panda, “Griseofulvin stabilizes microtubule dynamics, activates p53 and inhibits the proliferation of MCF-7 cells synergistically with vinblastine,” BMC Cancer, vol. 10, pp. 213–226, 2010.

M. Syamala, “Recent progress in three-component reactions. An update,” Organic Preparations and Procedures International, vol. 41, no. 1, pp. 1–68, 2009.