Synthesis of benzologues of Nitazoxanide and Tizoxanide: a comparative study of their in vitro broad-spectrum antiprotozoal activity.

We have synthesized two new benzologues of Nitazoxanide (NIT) and Tizoxanide (TIZ), using a short synthetic route. Both compounds were tested in vitro against six protozoa (Giardia intestinalis, Trichomonas vaginalis, Entamoeba histolytica, Plasmodium berghei, Leishmania mexicana and Trypanosoma cruzi). Compound 1 (benzologue of NIT) showed broad antiprotozoal effect against all parasites tested, showing IC(50)'s<5 µM. This compound was five-times more active than NIT, and 18-times more potent than metronidazole against G. intestinalis. It was 10-times more active than pentamidine against L. mexicana, and it was sevenfold more potent than benznidazole versus T. cruzi. This compound could be considered as a new broad spectrum antiprotozoal agent.

Design, synthesis and in vitro antiprotozoal activity of benzimidazole-pentamidine hybrids.

A series of ten novel hybrids from benzimidazole and pentamidine were prepared using a short synthetic route. Each compound was tested in vitro against the protozoa Trichomonas vaginalis, Giardia lamblia, Entamoeba histolytica, Leishmania mexicana, and Plasmodium berghei, in comparison with pentamidine and metronidazole. Some analogues showed high bioactivity in the low micromolar range (IC(50)<1 microM) against the first four protozoa, which make them significantly more potent than either standard. 1,5-bis[4-(5-methoxy-1H-benzimidazole-2-yl)phenoxy]pentane (2) was 3- and 9-fold more potent againstG. lamblia than metronidazole and pentamidine, respectively. This compound was 23-, 108-, and 13-fold more active than pentamidine against T. vaginalis, E. histolytica and L. mexicana, respectively. Studying further structure-activity relationships through the use of bioisosteric substitution in these hybrids should provide new leads against protozoal diseases.

Antimalarial 4-phenylcoumarins from the stem bark of Hintonia latiflora.

The EtOAc extract of the stem bark of Hintonia latiflora showed the suppression of total parasitemia and the chemosuppression of schizont numbers, when tested in vivo against Plasmodium berghei infection in mice. Bioassay-directed fractionation of the EtOAc extract, using the in vitro 16 h and the in vivo 4-day suppression tests on P. berghei schizont numbers, led to the isolation of the new compound 5-O-beta-D-glucopyranosyl-7,4'-dimethoxy-3'-hydroxy-4-phenylcoumarin (1), along with the known 5-O-beta-D-glucopyranosyl-7-methoxy-3',4'-dihydroxy-4-phenylcoumarin (2). The structure of compound 1 was established on the basis of spectroscopic data interpretation. Compounds 1 and 2 suppressed the development of P. berghei schizonts in vitro with IC50 values of 24.7 and 25.9 microM, respectively. Compound 2 suppressed the development of schizonts at the dose of 40 mg/kg by 70.8% in the in vivo assay.