Elsevier

Tetrahedron

Volume 58, Issue 1, 1 January 2002, Pages 45-54
Tetrahedron

Spermicidal, anti-HIV, and micellar properties of di- and trihydroxylated cationic surfactants

https://doi.org/10.1016/S0040-4020(01)01114-0Get rights and content

Abstract

The syntheses of 2-hydroxy-N-(2-hydroxyethyl)-N,N-dimethyl-1-alkanaminium 1(p) and 2-hydroxy-N,N-bis(2-hydroxyethyl)-N-methyl-1-alkanaminium 2(p) bromides are described for the homologous series, tetradecanaminium (p=14) through octadecaminium (p=18). The critical micelle concentrations (cmc's), measured by conductivity at 25 and 37°C, of the even-numbered members of the series show the expected linear dependence on chain length. All compounds display spermicidal and virucidal activity. Plots of minimum effective concentration (MEC) versus chain length in the Sander–Cramer spermicidal assay of 1 and 2 show a cut-off effect and a parabolic relationship, respectively. The best compounds—1(17) and 1(18)—have MECs (∼0.12 mg mL−1) slightly lower than that of the commercial spermicide nonoxynol-9 (N-9). Compounds 1(16) and 2(17) show the best anti-HIV activity in in-vitro, cell-free and cell-associated virus inactivation assays. Both are highly effective at 0.1 mg mL−1 in the cell-free assay and 0.5 mg mL−1 in the cell-associated assay. Compound 1(16) shows the best combination of dual activity against sperm and HIV. In summary, hydroxylated cationic surfactants, 1 and 2, show promise as inexpensive topical, contraceptive microbicides.

Compounds 1(17) and 1(18) show excellent spermicidal activity; 1(16) and 2(17) show the best anti-HIV activity. Compound 1(16) shows the best combination of dual activity against sperm and HIV.

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Section snippets

Chemistry

Reaction of an alkene 3ae with N-bromosuccinimide32 in THF/H2O gave a mixture of two bromohydrins 4 and 5 in ratio of ca. 4:1. (Scheme 1.) The two isomers could be separated by careful flash column chromatography. Separation of 4 and 5 was unnecessary, however, because refluxing a mixture of either isomer with N,N-dimethylethanolamine (R1=CH3)28., 33. and N-methyldiethanolamine (R1=CH2CH2OH) in methanol gave quaternary ammonium salts, 1 and 2, respectively. Pure quaternary ammonium salts were

Spermicidal activity and micellar concentration

Fig. 1 presents the MECs for spermicidal activity and cmcs for 1 plotted as a function of chain length. The cmcs are expressed as mg mL−1 to facilitate comparison with the bioassays. The cmcs, which were measured in distilled water, represent an upper limit of the cmc under the conditions of the Sander–Cramer assay. That is, ∼1% bovine serum albumin (BSA), 0.9% saline, and Baker's (phosphate and glucose) solution might decrease the cmc. BSA absorbs cationic surfactants, e.g. benzalkonium;41 this

Conclusions

From these results, we draw three conclusions: (1) 1(17), 1(18), 1(16) and 2(17) display potent antispermatic activity and are just as spermicidal as, or in some cases even more than, N-9. (2) The structural differences among the compounds do not lead to large variations in anti-HIV activity; these compounds inhibit HIV by similar mechanisms. (3) Compound 1(16), which has excellent spermicidal and anti-HIV properties, merits further investigation. In summary, hydroxylated cationic surfactants, 1

General

Reagents were used as received. The solvents were HPLC grade and used as received. Flash chromatography was performed with silica gel, 60 X, 230–400 mesh. TLC was performed with PE SIL G/UV 250 μm plates. Apparent coupling constants, Japp, were the measured peak widths. Atlantic MicroLab Inc. performed the elemental analyses.

General method for synthesis of bromohydrins 4ae and 5ae

To a cooled solution of a 1-alkene (10–15 mmol) in THF/H2O (5:1) (ca. 40 mL g−1 of alkene), was added slowly N-bromosuccinimide (1.05 equiv.). The reaction mixture was stirred

Acknowledgements

This work was supported by contracts from the Contraceptive Research and Development (CONRAD) program, Eastern Virginia Medical School, under a Cooperative Agreement with the US Agency for International Development (USAID). The views expressed by the authors do not necessarily reflect those of CONRAD or USAID. We thank Personal Products Company, a division of Ortho-McNeil Pharmaceutical, Inc. (Raritan, NJ) for generously providing samples of N-9. We thank Professor Richey M. Davis, for the use

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    Present Address: Department of Computer Science, Wake Forest U., Winston-Salem, NC, USA.

    Present Address: Needle and Rosenberg, P.C., Atlanta, GA, USA.

    §

    Present Address: J-Star Research, Inc., South Plainfield, NJ, USA.

    Present Address: Department of Chemistry, Johns Hopkins U., Baltimore, MD, USA.

    Present Address: Rhodia ChiRex, Inc., Malvern, PA, USA.

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