Full Text
Chemistry
I. D. Neklesova, N. V. Egorova
Chemical Structure and Antimicrobial Properties of Organophosphorus Compounds
(Presented by Academician A. E. Arbuzov, 26 VI 1963)
It was shown earlier that esters of phosphorus acids possess fungicidal properties with respect to fungi—the causative agents of dermatomycoses in humans and warm-blooded animals. In a study of about 60 compounds, we were able to find that lengthening of the hydrocarbon radical located in the ester linkage at the phosphorus atom in esters of phosphoric, phosphinic, and pyrophosphoric acids leads to a decrease in toxicity
Table 1
Antimicrobial properties of imides of phosphorus acids
| Compounds | Fungal cultures | Concentrations of compounds, % | Concentrations of compounds, % | Concentrations of compounds, % | Strain of staphylococcus | Concentrations of compounds, % | Concentrations of compounds, % | Concentrations of compounds, % | Concentrations of compounds, % | Concentrations of compounds, % | Toxicity, white mice, \(LD_{50}\) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 0.1 | 0.25 | 1 | 0.01 | 0.05 | 0.1 | 0.25 | 0.5 | ||||
| \(\begin{array}{c} C_2H_5O \\ C_2H_5O \end{array}\!>\!P(=O)-N(C_4H_9)-P(=O)\!<\!\begin{array}{c} OC_2H_5 \\ OC_2H_5 \end{array}\) | a | + | + | + | 29799 | + | + | + | + | + | 11 |
| \(\begin{array}{c} C_2H_5O \\ C_2H_5O \end{array}\!>\!P(=O)-N(C_4H_9)-P(=O)\!<\!\begin{array}{c} OC_2H_5 \\ OC_2H_5 \end{array}\) | b | + | + | + | |||||||
| \(\begin{array}{c} C_2H_5O \\ C_2H_5O \end{array}\!>\!P(=O)-N(C_4H_9)-P(=O)\!<\!\begin{array}{c} OC_2H_5 \\ OC_2H_5 \end{array}\) | c | + | + | + | 30219 | + | + | + | + | + | |
| \(\begin{array}{c} C_4H_9O \\ C_4H_9O \end{array}\!>\!P(=O)-N(C_4H_9)-P(=O)\!<\!\begin{array}{c} OC_4H_9 \\ OC_4H_9 \end{array}\) | a | − | − | − | 29799 | + | + | + | − | − | 110 |
| \(\begin{array}{c} C_4H_9O \\ C_4H_9O \end{array}\!>\!P(=O)-N(C_4H_9)-P(=O)\!<\!\begin{array}{c} OC_4H_9 \\ OC_4H_9 \end{array}\) | b | − | − | − | |||||||
| \(\begin{array}{c} C_4H_9O \\ C_4H_9O \end{array}\!>\!P(=O)-N(C_4H_9)-P(=O)\!<\!\begin{array}{c} OC_4H_9 \\ OC_4H_9 \end{array}\) | c | − | − | − | 30219 | + | + | + | − | − | |
| \(\begin{array}{c} iso\text{-}C_4H_9O \\ iso\text{-}C_4H_9O \end{array}\!>\!P(=O)-N(C_2H_5)-P(=O)\!<\!\begin{array}{c} OC_4H_9 \\ OC_4H_9 \end{array}\) | a | 29799 | + | − | − | − | − | 870 | |||
| \(\begin{array}{c} iso\text{-}C_4H_9O \\ iso\text{-}C_4H_9O \end{array}\!>\!P(=O)-N(C_2H_5)-P(=O)\!<\!\begin{array}{c} OC_4H_9 \\ OC_4H_9 \end{array}\) | b | ||||||||||
| \(\begin{array}{c} iso\text{-}C_4H_9O \\ iso\text{-}C_4H_9O \end{array}\!>\!P(=O)-N(C_2H_5)-P(=O)\!<\!\begin{array}{c} OC_4H_9 \\ OC_4H_9 \end{array}\) | c | 30219 | + | − | − | − | − |
Note. \(+\) microbial growth; \(−\) absence of growth; \(+\!-\) inhibition of growth.
a — Trichophyton gypseum, b — Microsporum lanosum, c — M. ferrugineum.
toward warm-blooded animals and to an enhancement of antifungal properties \((^{1,2})\). Consequently, by changing the chemical structure of compounds in this direction, it is possible to approach the preparation of a drug. It seemed of interest to test the data obtained on other species of microbes with different types of organophosphorus compounds, in order to reveal the possibility of carrying out a purposeful synthesis.
For this purpose, another 74 compounds were investigated, synthesized at the A. E. Arbuzov Chemical Institute of the Academy of Sciences of the USSR and at the A. M. Butlerov Chemical Institute of Kazan University. The results of the studies are summarized in Tables 1–4, which present the most interesting compounds, making it possible to reveal the relationship between biological action and chemical structure.
The tables give the results of studies on white mice (with determination of \(LD_{50}\) according to Behrens), pathogenic fungi (Trichophyton gypseum, Microsporum lanosum, Epidermophyton) and golden staphylococcus (Staphylococcus pyogenes aureus).
In studying the fungicidal action of the compounds, Sabouraud medium containing increasing doses of the compounds was inoculated with a fungal culture. The absence of fungal growth in the test tubes for 30 days, with luxuriant growth in the control, served as the criterion of the fungistatic action of the compounds. In studying the antibacterial action, a one-day culture of staphylococcus was incubated at 37° in physiological solution containing various concentrations of the compounds. Each 1 ml of sample contained 500 million microbial bodies. After 6 hours of incubation, inoculations were made
Table 2
Antimicrobial properties of mixed esters of phosphoric and phosphinic acids
| Compounds | Fungal cultures | Concentration of compounds, %: 0.005 | 0.01 | 0.05 | 0.1 | 0.25 | 1.0 | Staphylococcus strains | Concentration of compounds, %: 0.01 | 0.05 | 0.1 | 0.5 | 1.0 | Toxicity, mg/kg (white mice, $LD_{50}$) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| $\mathrm{(C_2H_5O)(C_2H_5)P(=O)-OCH=CCl_2}$ | a | + | + | + | − | − | − | 29799 | + | + | + | − | 0.9 | |
| $\mathrm{(C_2H_5O)(C_2H_5)P(=O)-OCH=CCl_2}$ | b | + | + | + | − | − | − | 0.9 | ||||||
| $\mathrm{(C_2H_5O)(C_2H_5)P(=O)-OCH=CCl_2}$ | c | + | + | + | − | − | − | 0.9 | ||||||
| $\mathrm{(C_2H_5O)(C_2H_5)P(=O)-OCH=CCl_2}$ | d | + | + | + | − | − | − | 30219 | + | + | + | − | 0.9 | |
| $\mathrm{(C_5H_{11}O)(C_2H_5)P(=O)-OCH=CCl_2}$ | a | + | − | − | − | − | − | 29799 | + | − | − | − | − | 1 |
| $\mathrm{(C_5H_{11}O)(C_2H_5)P(=O)-OCH=CCl_2}$ | b | + | − | − | − | − | − | 1 | ||||||
| $\mathrm{(C_5H_{11}O)(C_2H_5)P(=O)-OCH=CCl_2}$ | c | + | − | − | − | − | − | 1 | ||||||
| $\mathrm{(C_5H_{11}O)(C_2H_5)P(=O)-OCH=CCl_2}$ | d | + | − | − | − | − | − | 30219 | + | − | − | − | − | 1 |
| $\mathrm{(CH_3)_2C(CN)-O-P(=O)(OC_2H_5)_2}$ | a | + | + | + | + | + | + | 29799 | + | + | + | + | + | 150 |
| $\mathrm{(CH_3)_2C(CN)-O-P(=O)(OC_2H_5)_2}$ | d | + | + | + | + | + | + | 30219 | + | + | + | + | + | 150 |
| $\mathrm{(CH_3)_2C(CN)-O-P(=O)(OC_5H_{11})_2}$ | a | + | + | + | − | − | − | 29799 | + | + | − | − | − | 300 |
| $\mathrm{(CH_3)_2C(CN)-O-P(=O)(OC_5H_{11})_2}$ | d | + | + | + | − | − | − | 30219 | + | + | − | − | − | 300 |
| $\mathrm{(CH_3O)_2P(=O)-CH(CCl_3)-O-C(=O)-CH_3}$ | a | + | + | + | + | − | − | 700 | ||||||
| $\mathrm{(CH_3O)_2P(=O)-CH(CCl_3)-O-C(=O)-CH_3}$ | b | + | + | + | + | − | − | 29799 | + | + | + | − | − | 700 |
| $\mathrm{(CH_3O)_2P(=O)-CH(CCl_3)-O-C(=O)-CH_3}$ | c | + | + | + | + | − | − | 700 | ||||||
| $\mathrm{(CH_3O)_2P(=O)-CH(CCl_3)-O-C(=O)-CH_3}$ | e | + | + | + | + | − | − | 30219 | + | + | + | − | − | 700 |
| $\mathrm{(C_4H_9O)_2P(=O)-CH(CCl_3)-O-C(=O)-CH_3}$ | a | + | + | + | − | − | − | 29799 | + | − | − | − | − | 2300 |
| $\mathrm{(C_4H_9O)_2P(=O)-CH(CCl_3)-O-C(=O)-CH_3}$ | d | + | + | + | − | − | − | 30219 | + | − | − | − | − | 2300 |
Note. a — Trichophyton gypseum, b — Microsporum lanosum, c — M. ferrugineum, d — Epidermophyton, e — Achorion Schönleini, f — Trichophyton faviforme.
Table 3
Antimicrobial properties of quaternary phosphonium salts and arsine sulfides
| Compounds | Fungal cultures | Concentration of compounds, %: 0.01 | 0.05 | 0.1 | 0.25 | 1 | Staphylococcus strains | Concentration of compounds, %: 0.01 | 0.05 | 0.1 | 0.5 | Toxicity, mg/kg (white mice, $LD_{50}$) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| $\left[\mathrm{CH_3(C_7H_7)(C_2H_5)(C_6H_5)P}\right]\mathrm{Br}$ | a | + | + | + | + | + | 29799 | + | + | + | + | 16.8 |
| $\left[\mathrm{CH_3(C_7H_7)(C_2H_5)(C_6H_5)P}\right]\mathrm{Br}$ | b | + | + | + | + | + | 30219 | + | + | + | + | 16.8 |
| $\left[\mathrm{CH_3(C_{18}H_{37})(C_2H_5)(C_6H_5)P}\right]\mathrm{Br}$ | a | + | − | − | − | − | 29799 | − | − | − | − | 9 |
| $\left[\mathrm{CH_3(C_{18}H_{37})(C_2H_5)(C_6H_5)P}\right]\mathrm{Br}$ | b | + | − | − | − | − | 30219 | − | − | − | − | 9 |
| $\mathrm{CH_3(C_2H_5)(C_6H_5)As=S}$ | a | + | + | +− | − | − | 90 | |||||
| $\mathrm{CH_3(C_2H_5)(C_6H_5)As=S}$ | b | + | + | + | − | − | 90 | |||||
| $\mathrm{C_9H_{19}(C_2H_5)(C_6H_5)As=S}$ | a | +− | − | − | − | − | 100 | |||||
| $\mathrm{C_9H_{19}(C_2H_5)(C_6H_5)As=S}$ | b | +− | − | − | − | − | 100 |
Note. a — Trichophyton gypseum, b — Epidermophyton.
onto Petri dishes with meat-peptone agar. The absence of growth served as the criterion of the antimicrobial action of the compounds.
As is evident from Tables 1, 2, and 4, lengthening of the hydrocarbon radical located at the phosphorus atom in esters of phosphoric and phosphinic acids,
Table 4
Antimicrobial properties of esters of organophosphorus acids of the general structure
\[ \mathrm{R_2-P(=O)(OR)(OR)}, \quad \text{where } R=\mathrm{Alk};\ R_2=\text{residue of a heterocyclic compound} \]
| Compounds | Fungal cultures | Concentrations of compounds, % 0.05 | 0.1 | 0.25 | 1.0 | Staphylococcus strains | Concentrations of compounds, % 0.05 | 0.1 | 0.25 | 0.5 | Toxicity, mg/kg; white mice, \(LD_{50}\) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Morpholine–\(P(=O)(OC_2H_5)_2\) | a | + | + | + | + | 29799 | + | + | + | + | 450 |
| Morpholine–\(P(=O)(OC_2H_5)_2\) | b | + | + | + | + | 30219 | + | + | + | + | 450 |
| Morpholine–\(P(=O)(OC_4H_9)_2\)-iso | a | + | + | − | − | 29799 | 450 | ||||
| Morpholine–\(P(=O)(OC_4H_9)_2\)-iso | b | + | + | − | − | 30219 | 450 | ||||
| Benzimidazole–\(P(=O)(OC_2H_5)_2\) | a | + | + | − | − | 29799 | + | − | − | − | 750 |
| Benzimidazole–\(P(=O)(OC_2H_5)_2\) | b | + | + | − | − | 30219 | + | − | − | − | 750 |
| Benzimidazole–\(P(=O)(OC_4H_9)_2\)-iso | a | + | ± | − | − | 29799 | − | − | − | − | 900 |
| Benzimidazole–\(P(=O)(OC_4H_9)_2\)-iso | b | + | ± | − | − | 30219 | − | − | − | − | 900 |
| Quinoxaline derivative, \(C{-}CH_2{-}P(=O)(OC_2H_5)_2\), \(C{-}CH_3\) | a | + | + | + | + | 29799 | + | + | + | + | 800 |
| Quinoxaline derivative, \(C{-}CH_2{-}P(=O)(OC_2H_5)_2\), \(C{-}CH_3\) | b | + | + | + | + | 30219 | + | + | + | + | 800 |
| Quinoxaline derivative, \(C{-}CH_2{-}P(=O)(OC_3H_7)_2\)-iso, \(C{-}CH_3\) | a | + | − | − | − | 29799 | 1000 | ||||
| Quinoxaline derivative, \(C{-}CH_2{-}P(=O)(OC_3H_7)_2\)-iso, \(C{-}CH_3\) | b | + | + | − | − | 30219 | 1000 |
Note. a — Trichophyton gypseum, b — Epidermophyton.
in the imides of phosphorus acids leads to a change in physiological properties in the direction we need: the antimicrobial properties improve and, as a rule, toxicity toward warm-blooded animals decreases. From examination of Table 1 it is evident that the asymmetry of the compound decreases toxicity toward warm-blooded animals, while at the same time improving antimicrobial properties (Table 1). The antimicrobial properties of quaternary phosphonium salts and arsine sulfides are also enhanced when the hydrocarbon radical located at the phosphorus and arsenic atom is lengthened (Table 3).
Thus, by changing the structure of organophosphorus compounds in this direction, it is possible to obtain a compound with selective action against microorganisms.
Chemical Institute named after A. E. Arbuzov
Academy of Sciences of the USSR
Kazan
Received
22 VI 1963
CITED LITERATURE
- I. D. Neklesova, Z. Sh. Minyusheva, Proceedings of the Second Conference, 1959, Publishing House of the Academy of Sciences of the USSR, 1962, p. 524.
- I. D. Neklesova, Z. Sh. Minyusheva, M. A. Kudrina, Pathological Physiology and Experimental Therapy, No. 5, 75 (1961).