Respiratory syncytial virus (RSV) represents a threat to infants, the elderly, and the immunocompromised. RSV entry blockers are in clinical trials, but escape mutations challenge their potential. In search of RSV inhibitors, we have integrated a signature resistance mutation into are combinant RSV virus and applied the strain to high-throughput screening. Counter screening of candidates returned 14 confirmed hits with activity in the nano- to low-micromolar range. All blocked RSV polymerase activity in minigenome assays. Compound 1a (GRP-74915) was selected for development based on activity (EC50=0.21 µM, selectivity index (SI) 40), and scaffold. Resynthesis confirmed potency of the compound, which suppressed viral RNA synthesis in infected cells. However, metabolic testing revealed a short half-life in the presence of mouse hepatocyte fractions. Metabolite tracking and chemical elaboration combined with 3D-quantitative structure-activity relationship modeling yielded analogs (i.e. 8n: EC50=0.06 µM, SI 500) that establish a platform for the development of a therapeutic candidate.

A substrate-induced stereocontrol strategy was used to gain access to the tetracyclic core of (-)-lemonomycin. An advanced intermediate was prepared from a known substituted tyrosinol through a 16-step sequence, which involved a Pictet-Spengler reaction, a [3+2] dipolar cycloaddition and an enamide hydrogenation.

No abstract

Natural concentration of antimalaric components in Tropical arthropods (in vitro). Alcohol, hexane and dichlorometane extracts of 751 samples of Costa Rican arthropods were studied for the presence of antimalaric components. With Plasmodium berghei we set an in vitro model in which the effect of the extract was determined by staining of the parasites with cresil brilliant blue. Active extracts at concentration of 50 mg or less, were considered positive. Promissory extracts were found in the orders Lepidoptera (24.1%), Coleoptera (32.8%), Hemiptera (38.5%) and Polydesmida (81.3%). Since most of the Lepidoptera samples were in the immature stages, the relation with the host plant was analyzed. Cannaceae, Flacourtiaceae, Crisobalanaceae, Lauraceae, Fagaceae, Ulmaceae, Rosaceae, Asteraceae, Rubiaceae, Lauraceae and Caprifoliaceae were related with the Lepidoptera larvae, and an antimalaric effect has been reported in most of these families. In the orders Polydesmida, Opiliones and Blattodea, the extract from adults also had some important effect, probably because all of them fed on plants. Polydesmida and Opiliones have chemical substances that probably serve as defensive purposes; these chemicals could also have some antiparasitic effect. Therefore, the detection of antimalaric components in arthropod species led to the identification of plants with promissory antimalaric components. Rev. Biol. Trop. 56 (2): 473-485. Epub 2008 June 30.