benzofurans and Malaria

We screened a collection of synthetic compounds consisting of natural-product-like substructural motifs to identify a spirocyclic chromane as a novel antiplasmodial pharmacophore using an unbiased cell-based assay. The most active spirocyclic compound UCF 201 exhibits a 50% effective concentration (EC50) of 350 nM against the chloroquine-resistant Dd2 strain and a selectivity over 50 using human liver HepG2 cells. Our analyses of physicochemical properties of UCF 201 showed that it is in compliance with Lipinski's parameters and has an acceptable physicochemical profile. We have performed a limited structure-activity-relationship study with commercially available chromanes preserving the spirocyclic motif. Our evaluation of stage specificities of UCF 201 indicated that the compound is early-acting in blocking parasite development at ring, trophozoite and schizont stages of development as well as merozoite invasion. SPC is an attractive lead candidate scaffold because of its ability to act on all stages of parasite's aexual life cycle unlike current antimalarials.

Topics: Animals; Antimalarials; Benzofurans; Drug Evaluation, Preclinical; Erythrocytes; Life Cycle Stages; Malaria; Merozoites; Mice, Inbred BALB C; Plasmodium berghei; Plasmodium falciparum; Schizonts; Spiro Compounds; Structure-Activity Relationship; Trophozoites

The evolution of drug resistance is a recurrent problem that has plagued efforts to treat and control malaria. Recent emergence of artemisinin resistance in Southeast Asia underscores the need to develop novel antimalarials and identify new targetable pathways in Plasmodium parasites. Transmission-blocking approaches, which typically target gametocytes in the host bloodstream or parasite stages in the mosquito gut, are recognized collectively as a strategy that when used in combination with antimalarials that target erythrocytic stages will not only cure malaria but will also prevent subsequent transmission. We tested four derivatives of (+)-usnic acid, a metabolite isolated from lichens, for transmission-blocking activity against Plasmodium falciparum using the standard membrane feeding assay. For two of the derivatives, BT37 and BT122, we observed a consistent dose-response relationship between concentration in the blood meal and oocyst intensity in the midgut. To explore their mechanism of action, we used the murine model Plasmodium berghei and found that both derivatives prevent ookinete maturation. Using fluorescence microscopy, we demonstrated that in the presence of each compound zygote vitality was severely affected, and those that did survive failed to elongate and mature into ookinetes. The observed phenotypes were similar to those described for mutants of specific kinases (NEK2/NEK4) and of inner membrane complex 1 (IMC1) proteins, which are all vital to the zygote-to-ookinete transition. We discuss the implications of our findings and our high-throughput screening approach to identifying next generation, transmission-blocking antimalarials based on the scaffolds of these (+)-usnic acid derivatives.

Topics: Animals; Anopheles; Antimalarials; Benzofurans; Cell Line; Drug Discovery; Female; Insect Vectors; Malaria; Mice; Plasmodium berghei; Plasmodium falciparum; Rats; Zygote

Chloroquine resistance is nowadays a great problem. Aurone derivatives are effective against chloroquine resistant parasite. Ligand based validated comparative chemometric modeling through 2D-QSAR and kNN-MFA 3DQSAR studies as well as common feature 3D pharmacophore mapping were done on thirtyfive aurone derivatives having antimalarial activity. Statistically significant 2D-QSAR models were generated on unsplitted as well as splitted dataset by MLR and PLS technique. The MLR model of the unsplitted method was validated by two-deep cross validation and 10 fold cross validation for determining the predictive ability. The PLS technique of the unsplitted method was done to compare the significance of these methods. In the splitted method, model was developed on the training set by Y-based ranking method by using the same descriptors and was validated on fifty pairs of the test and the training sets by k-MCA technique. These models generated by using the same descriptors were well validated irrespective of MLR as well as PLS analysis of unsplitted as well as splitted methods and are showing similar results. Therefore, these descriptors and model generated were reliable and robust. The kNN-MFA 3D-QSAR models were generated by three variable selection methods: genetic algorithm, simulated annealing and stepwise regression. The kNN-MFA 3D-QSAR results support the 2D QSAR data and in turn validate the earlier observed SAR results. Common feature 3D-pharmacophore generation was performed on these compounds to validate both 2D and 3D-QSAR studies as well as the earlier observed SAR data. The work highlights the required structural features for the higher antimalarial activity.

Topics: Algorithms; Antimalarials; Benzofurans; Computer-Aided Design; Drug Design; Humans; Ligands; Malaria; Models, Molecular; Plasmodium; Quantitative Structure-Activity Relationship

Acute exposure of adult mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a selective suppression of proliferating cells of the immune system, including hematopoietic stem cells and B cells. Suppression of B cell-mediated or humoral immunity, in turn, results in altered host resistance to the parasite Plasmodium yoelii, a malaria model. Data presented in this study demonstrate a direct effect of TCDD on cultured lymphoctes resulting in a selective inhibition of the differentiation of B cells into antibody-secreting cells. A structure-activity study suggested that this inhibition was mediated by the Ah receptor. As previously defined by receptor binding studies in hepatic cytosol, active congeners were inhibitory, whereas inactive congeners were without effect. Using lymphocytes from congenic mice which differ only at the Ah locus, it was determined that the Ahbb-derived cells were inhibited by TCDD in vitro, whereas the Ahdd-derived cells were not. B cell differentiation thus provides a valuable model for understanding TCDD toxicity as well as the role of the Ah receptor in growth and differentiation.

Topics: Animals; Antibody Formation; B-Lymphocytes; Benzofurans; Cell Differentiation; Dioxins; Female; Malaria; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Polychlorinated Dibenzodioxins; Structure-Activity Relationship; Thymectomy