Triclosan-caffeic acid hybrids: Synthesis, leishmanicidal, trypanocidal and cytotoxic activities.

The synthesis, cytotoxicity, anti-leishmanial and anti-trypanosomal activities of twelve triclosan-caffeic acid hybrids are described herein. The structure of the synthesized products was elucidated by a combination of spectrometric analyses. The synthesized compounds were evaluated against amastigotes forms of L. (V) panamensis, which is the most prevalent Leishmania species in Colombia, and against Trypanosoma cruzi, which is the pathogenic species to humans. Cytotoxicity was evaluated against human U-937 macrophages. Eight compounds were active against L. (V) panamensis (18-23, 26 and 30) and eight of them against T. cruzi (19-22, 24 and 28-30) with EC50 values lower than 40 µM. Compounds 19-22, 24 and 28-30 showed higher activities than benznidazole (BNZ). Esters 19 and 21 were the most active compounds for both L. (V) panamensis and T. cruzi with 3.82 and 11.65 µM and 8.25 and 8.69 µM, respectively. Compounds 19-22, 24 and 28-30 showed higher activities than benznidazole (BNZ). Most of the compounds showed antiprotozoal activity and with exception of 18, 26 and 28, the remaining compounds were toxic for mammalian cells, yet they have potential to be considered as candidates for anti-trypanosomal and anti-leishmanial drug development. The activity is dependent on the length of the alkyl linker with compound 19, bearing a four-carbon alkyl chain, the most performing hybrid. In general, hydroxyl groups increase both activity and cytotoxicity and the presence of the double bond in the side chain is not decisive for cytotoxicity and anti-protozoal activity.

Synthesis, leishmanicidal and cytotoxic activity of triclosan-chalcone, triclosan-chromone and triclosan-coumarin hybrids.

Twelve hybrids derived from triclosan were obtained via Williamson etherification of O-triclosan alkyl bromide plus chalcone and O-coumarin or O-chromone alkyl bromide plus triclosan, respectively. Structures of the products were elucidated by spectroscopic analysis. The synthesized compounds were evaluated for antileishmanial activity against L. (V) panamensis amastigotes. Cytotoxic activity was also evaluated against mammalian U-937 cells. Compounds 7-9 and 17, were active against Leishmania parasites (EC50=9.4; 10.2; 13.5 and 27.5 µg/mL, respectively) and showed no toxicity toward mammalian cells (>200 µg/mL). They are potential candidates for antileishmanial drug development. Compounds 25-27, were active and cytotoxic. Further studies using other cell types are needed in order to discriminate whether the toxicity shown by these compounds is against tumor or non-tumor cells. The results indicate that compounds containing small alkyl chains show better selectivity indices. Moreover, Michael acceptor moieties may modify both the leishmanicidal activity and cytotoxicity. Further studies are required to evaluate if the in vitro activity against Leishmania panamensis demonstrated here is also observed in vivo.

Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase.

Triclosan is a potent inhibitor of Toxoplasma gondii enoyl reductase (TgENR), which is an essential enzyme for parasite survival. In view of triclosan's poor druggability, which limits its therapeutic use, a new set of B-ring modified analogs were designed to optimize its physico-chemical properties. These derivatives were synthesized and evaluated by in vitro assay and TgENR enzyme assay. Some analogs display improved solubility, permeability and a comparable MIC50 value to that of triclosan. Modeling of these inhibitors revealed the same overall binding mode with the enzyme as triclosan, but the B-ring modifications have additional interactions with the strongly conserved Asn130.

Incorporation of low molecular weight biocides into polystyrene-divinyl benzene beads with controlled release characteristics.

Triclosan and phosphonium salt biocides have been separately incorporated into polystyrene-divinylbenzene (PS-DVB) beads by suspension polymerization. Ultraviolet (UV) absorption measurements have been used to monitor the release of these low molecular weight biocides out of the PS-DVB beads immersed in water-ethanol mixtures and in physiological saline. The release of the biocide agents is strongly dependent on either the DVB or/and the antimicrobial composition ratio in the beads. An increase of biocide incorporation in the PS/DVB beads was accompanied by a corresponding enhancement of its concentration in liquid mixtures. On the contrary, higher cross-linking densities hindered the biocide migration out of the beads by diminishing its release rate into either the aqueous ethanol solutions or the natural serum. Moreover, Fourier transform Raman (FT-Raman) spectra and Attenuated Total Reflectance Infrared (ATR-FTIR) measurements of the PS-DVB-Triclosan and PS-DVB-phosphonium salt beads, before and after their immersion in water-ethanol solutions, gave a similar qualitative evidence of the biocide release.