Background: Herbal medicine has been a rich source of new drugs exemplified by quinine and artemisinin. In this study, a variety of Japanese traditional herbal medicine ('Kampo') were examined for their potential anti-malarial activities. Methods: A comprehensive screening methods were designed to identify novel anti-malarial drugs from a library of Kampo herbal extracts (n = 120) and related compounds (n = 96). The anti-malarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and-resistant (Dd2) strains of Plasmodium falciparum. The cytotoxicity was also evaluated using primary adult mouse brain cells. After being selected through the first in vitro assay, positive extracts and compounds were examined for possible in vivo anti-malarial activity. Results: Out of 120 herbal extracts, Coptis rhizome showed the highest anti-malarial activity (IC 50 1.9 µg/mL of 3D7 and 4.85 µg/mL of Dd2) with a high selectivity index (SI) > 263 (3D7) and > 103 (Dd2). Three major chlorinated compounds (coptisine, berberine, and palmatine) related to Coptis rhizome also showed anti-malarial activities with IC 50 1.1, 2.6, and 6.0 µM (against 3D7) and 3.1, 6.3, and 11.8 µM (against Dd2), respectively. Among them, coptisine chloride exhibited the highest anti-malarial activity (IC 50 1.1 µM against 3D7 and 3.1 µM against Dd2) with SI of 37.8 and 13.2, respectively. Finally, the herbal extract of Coptis rhizome and its major active compound coptisine chloride exhibited significant anti-malarial activity in mice infected with Plasmodium yoelii 17X strain with respect to its activity on parasite suppression consistently from day 3 to day 7 post-challenge. The effect ranged from 50.38 to 72.13% (P < 0.05) for Coptis rhizome and from 81 to 89% (P < 0.01) for coptisine chloride. Conclusion: Coptis rhizome and its major active compound coptisine chloride showed promising anti-malarial activity against chloroquine-sensitive (3D7) and-resistant (Dd2) strains in vitro as well as in vivo mouse malaria model. Thus, Kampo herbal medicine is a potential natural resource for novel anti-malarial agents.

緒 言 Despite significant advances in the prevention and treatment of malaria, it remains to be one of the calamitous global health and socioeconomic concern. Several drugs are currently available for malaria treatment, however parasites began to develop resistance against most of these drugs including the first line drug, Artemisinin. A newly approved vaccine, RTS, S, has raised hope for preventive therapy, yet suffered with limited efficacy (shorter and stage-specific immunity). As a result, look for new small molecule drug candidates with novel target/mechanism of action has become pivotal. There are various phenotypic screening methods to identify novel antimalarials, however, most of them are time-consuming, costly and laborious. In contrary, in silico approach found to be effective to screen millions of compounds comparatively at shorter time and less expensive way than conventional screening. Therefore, in this study, we developed new prediction models for in silico antimalarial compound screening based on the physicochemical properties of small chemical compounds (hemozoin inhibitors) identified from our previous study. 対象と方法In this study, 224 positive hemozoin inhibitors (obtained from our previous study), were tested for in vitro erythrocytic antimalarial activity against chloroquine -mefloquine sensitive Plasmodium falciparum strain, 3D7A and their antihemozoin activity. The physicochemical properties of the active compounds (antimalarials and hemozoin inhibitors) were extracted from ChemSpider and SciFinder databases. To develop the model, univariable logistic regression was performed to examine the association between physicochemical properties (variables) and antimalarial activity of the compounds (outcome). Subsequently, to find independent predictors, variables P<0.1 and/or significant variables in previous study, were subjected to multivariable analysis using Bayesian model averaging (BMA) based on the Bayesian information criterion (BIC), where the smaller BIC value indicates the better model. The data were randomly divided into two sets -training and testing, with a ratio of 70:30. The BMA models were developed using training set and validated by testing data set. The data were analysed by using RStudio 1.0.44

Two phenylpropanoid conjugated iridoids, deglucosyl gaertneroside (1) and morindoidin (2), were isolated from the leaves of Morinda morindoides (Rubiaceae) by activity-guided fractionation using an anti-malarial activity assay. The known related iridoids molucidin (3) and prismatomerin (4), two lignans, abscisic acid, two megastigmanes, and two avonol glycosides were also identi ed. The structures of isolated compounds were elucidated using spectroscopic analysis. The isolated compounds were evaluated for anti-malarial activity against the chloroquine/me oquine-sensitive strains of Plasmodium falciparum together with cytotoxicity against adult mouse brain cells. Potent anti-malarial activity of and 4 (IC 50 of 0.96 and 0.80 µM, respectively) was shown, while new iridoids 1 and 2 and pinoresinol (5) displayed moderate activity (IC 50 of 40.9, 20.6, and 24.2 µM, respectively). These results indicate that 1-5 may be promising lead compounds for anti-malarial drugs and that extracts of M. morindoides leaves could be effective remedies for malaria infection.

Three phenylpropanoid-conjugated iridoid glucosides, acetylgaertneric acid (1), acetyldehydrogaertneroside (2), and dehydrogaertneric acid (10), together with nine known related iridoid glucosides (3-9, 11, and 12), two coumaroyl alkaloids, one benzenoid, and three flavonoid glucosides were isolated from leaves of Morinda morindoides (Rubiaceae). Structures of these isolated compounds were determined using spectroscopic analysis. Compounds 1-18 and previously isolated compounds (19-29) were evaluated for anti-trypanosomal activity against Trypanosoma cruzi Tulahuen strain (trypomastigote and amastigote) together with cytotoxicity against host cells, new-born mouse heart cells. Among them, molucidin (21) and prismatomerin ( 22) exhibited good anti-trypanosomal activity (IC 50 of 4.67 and 5.70 µM, respectively), together with cytotoxicity (CC 50 of 2.76 and 3.22 μM, respectively). Compounds 1-18 did not show anti-malarial activity against a chloroquine/mefloquine-sensitive strain of Plasmodium falciparum.

Background: The herbal medicine has been a rich source of new drugs exemplified by quinine and artemisinin. In this study, examined a variety of Japanese traditional herbal medicine (Kampo) for their potential antimalarial activities. Methods: We designed a comprehensive screening to identify novel antimalarial drugs from a library of Kampo herbal extracts (n = 120) and related compounds (n=96). The antimalarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and -resistant (Dd2) strains of Plasmodium falciparum . The cytotoxicity was also evaluated using primary Adult Mouse Brain cells. After being selected through the first in vitro assay, positive extracts and compounds were examined for possible in vivo antimalarial activity. Results: Out of 120 herbal extracts, Coptis Rhizome showed the highest antimalarial activity (IC 50 1.9 µg/mL of 3D7 and 4.85 µg/mL of Dd2) with a high selectivity index (SI) > 263 (3D7) and > 103 (Dd2). Three major chlorinated compounds (coptisine, berberine, and palmatine) related to Coptis Rhizome also showed antimalarial activities with IC 50 1.1, 2.6, and 6.0 µM (against 3D7) and 3.1, 6.3, and 11.8 µM (against Dd2), respectively. Among them, coptisine chloride exhibited the highest antimalarial activity (IC 50 1.1 µM against 3D7 and 3.1 µM against Dd2) with SI of 37.8 and 13.2, respectively. . Finally, the herbal extract of Coptis Rhizome and its major active compound coptisine chloride exhibited significant antimalarial activity in mice infected with P. yoelii 17X strain with respect to its activity on parasite suppression consistently from day 3 to day 7 post-challenge. The effect ranged from 50.38 to 72.13% (P <.05) for Coptis Rhizome and from 81 to 89% (P <.01) for coptisine chloride. Conclusion: Coptis Rhizome and its major active compound coptisine chloride showed promising antimalarial activity against chloroquine-sensitive (3D7) and -resistant (Dd2) strains in vitro as well as in vivo mouse malaria model. Thus Kampo herbal medicine is a potential natural resource for novel antipathogenic agents.