Identification of an orally active carbazole aminoalcohol derivative with broad-spectrum anti-animal trypanosomiasis activity.

Animal trypanosomiasis, caused by the members of subgenus Trypanozoon (Trypanosoma brucei brucei, T. evansi and T. equiperdum), has reduced animal productivity leading to significant negative economic impacts in endemic regions. Due to limited drug discovery and the emergence of drug-resistance over many recent decades, novel and effective compounds against animal trypanosomiasis are urgently required. This study was conducted to evaluate the antitrypanosomal potential of a batch of carbazole aminoalcohol derivatives. Among them, we found that the most effective compound was H1402, which exhibited potent trypanocidal efficacy against the bloodstream-form of T. b. brucei (EC50 = 0.73 ± 0.05 µM) and presented low cytotoxicity against two mammalian cell lines with CC50 > 30 µM. Using a murine model of acute infection, oral administration with H1402 demonstrated a complete clearance of T. b. brucei and all the infected mice were cured when they were treated twice daily for 5 days at a dose of 100 mg/kg. Furthermore, parasites were not detected in mice infected with T. evansi and T. equiperdum (the causative agents of surra and dourine, respectively, in animals) within 30 days following the same regimen with H1402. In addition, H1402 caused severe morphological and ultrastructural destruction to trypanosomes, as well as causing phosphatidylserine externalization, which are suggested to be the most likely cause of cell death. Overall, the present data demonstrated that H1402 could be promising as a rapid, safe and orally active lead compound for the development of new chemotherapeutics for animal trypanosomiasis.

In vitro and in vivo efficacies of carbazole aminoalcohols in the treatment of alveolar echinococcosis.

Benzimidazoles, including albendazole and mebendazole, are the major drugs for clinical chemotherapy of echinococcosis. They mainly exert parasitostatic effects depending on high dosages for long-term. Previous studies have identified carbazole aminoalcohols as novel anti-CE (cystic echinococcosis) agents. However, it is still to be confirmed whether it is effective on alveolar echinococcosis (AE) or not. In the present study, efficacies of novel carbazole aminoalcohols, propylamine, R-propylamine and S-propylamine were evaluated under in vitro and in vivo conditions. Carbazole aminoalcohols were tested against Echinococcus multilocularis (E. multilocularis) protoscoleces (PSC) in vitro. The effects of propylamine and R-propylamine exhibited a time-dependent manner at different concentrations, while the effect of S-propylamine was very poor. At a concentration of 20 µM, the mortality of PSC achieved to 100% on the 11th day after exposure to R-propylamine. The treatment of carbazole aminoalcohols to infected mice resulted in statistically significant reductions in the cyst weights compared with those obtained from negative control mice (p < 0.05), and no significant differences were found between albendazole and carbazole aminoalcohols (p > 0.05). The cytotoxicity examination in rat hepatoma (RH) cells indicated that propylamine and R/S-propylamine were lower that of albendazole at a low concentration (5 µM). In addition, histopathological observation of organs (liver, spleen and kidney) for experimental mice showed mild inflammatory changes in the liver and spleen. This study reveals the potential of carbazole aminoalcohols as a class of novel anti-AE agents.

Novel carbazole aminoalcohols as inhibitors of ß-hematin formation: Antiplasmodial and antischistosomal activities.

Malaria and schistosomiasis are two of the most socioeconomically devastating parasitic diseases in tropical and subtropical countries. Since current chemotherapeutic options are limited and defective, there is an urgent need to develop novel antiplasmodials and antischistosomals. Hemozoin is a disposal product formed from the hemoglobin digestion by some blood-feeding parasites. Hemozoin formation is an essential process for the parasites to detoxify free heme, which is a reliable therapeutic target for identifying novel antiparasitic agents. A series of novel carbazole aminoalcohols were designed and synthesized as potential antiplasmodial and antischistosomal agents, and several compounds showed potent in vitro activities against Plasmodium falciparum 3D7 and Dd2 strains and adult and juvenile Schistosoma japonicum. Investigations on the dual antiparasitic mechanisms showed the correlation between inhibitory activity of ß-hematin formation and antiparasitic activity. Inhibiting hemozoin formation was identified as one of the mechanisms of action of carbazole aminoalcohols. Compound 7 displayed potent antiplasmodial (Pf3D7 IC50 = 0.248 µM, PfDd2 IC50 = 0.091 µM) and antischistosomal activities (100% mortality of adult and juvenile schistosomes at 5 and 10 µg/mL, respectively) and exhibited low cytotoxicity (CC50 = 7.931 µM), which could be considered as a promising lead for further investigation. Stoichiometry determination and molecular docking studies were also performed to explain the mode of action of compound 7.

Carbazole Aminoalcohols Induce Antiproliferation and Apoptosis of Human Tumor Cells by Inhibiting Topoisomerase†I.

Novel carbazole aminoalcohols were designed and synthesized as anticancer agents. Among them, alkylamine-chain-substituted compounds showed the most promising antiproliferative activity, with IC50 values in the single-digit micromolar range against two human tumor cell lines. Topoisomerase I (topo I) is likely to be one of the targets of these compounds. Results of comet assays and molecular docking indicate that the representative compounds may act as topo I poisons, causing single-strand DNA damage by stabilizing the topo I-DNA cleavage complex. In particular, the most potent compound, 1-(butylamino)-3-(3,6-dichloro-9H-carbazol-9-yl)propan-2-ol (6), was shown to be able to induce G2 -phase cell-cycle arrest and apoptosis in HeLa cells.