Dan A. Ostlind

Isolation and structure of nodulisporic acid A1 and A2, novel insecticides from a Nodulisporium sp.

The isolation and structure elucidation of two novel indole terpene insecticides nodulisporic acid A1(2) and A2 (3) from a Nodulisporium sp. are reported.

Mechanism of action of MK-401 against Fasciola hepatica: Inhibition of phosphoglycerate kinase

The effect of MK-401 (4-amino-6-trichloroethenyl 1,3-benzenedisulfonamide) on Fasciola hepatica phosphoglycerate kinase (EC 2.7.2.3) was investigated. MK-401 was a competitive inhibitor of both 3-phosphoglycerate and ATP and had a Ki of 0.29 mM. ATP, 1,3-diphosphoglycerate and MK-401 protected the Fasciola enzyme from inhibition by N-ethylmaleimide. Analogues of MK-401 with different substituents at the 6 position (R = Cl, CF3, C2 F3, C3 F7) were competitive inhibitors of both 3-phosphoglycerate and ATP and a good correlation between the Ki and in vivo activity of these analogues was observed.

Discovery of the Development Candidate N-tert-Butyl Nodulisporamide: A Safe and Efficacious Once Monthly Oral Agent for the Control of Fleas and Ticks on Companion Animals

Nodulisporic acid A (1) is a structurally complex fungal metabolite that exhibits systemic efficacy against fleas via modulation of an invertebrate specific glutamate-gated ion channel. In order to identify a nodulisporamide suitable for monthly oral dosing in dogs, a library of 335 nodulisporamides was examined in an artificial flea feeding system for intrinsic systemic potency as well as in a mouse/bedbug assay for systemic efficacy and safety. A cohort of 66 nodulisporamides were selected for evaluation in a dog/flea model; pharmacokinetic analysis correlated plasma levels with flea efficacy. These efforts resulted in the identification of the development candidate N-tert-butyl nodulisporamide (3) as a potent and efficacious once monthly oral agent for the control of fleas and ticks on dogs and cats which was directly compared to the topical agents fipronil and imidacloprid, with favorable results obtained. Multidose studies over 3 months confirmed the in vivo ectoparasiticidal efficacy and established that 3 lacked overt mammalian toxicity. Tissue distribution studies in mice using [(14)C]-labeled 3 indicate that adipose beds serve as ligand depots, contributing to the long terminal half-lives of these compounds.

New, potent anthelmintic and acaricidal agents: 4″-deoxy-4″-thio-substituted avermectin derivatives

Abstract Sulfonylation of the 4″-α(or β)-hydroxyl of 5-OTBDMS-avermectin B 1a with trifluoromethanesulfonic anhydride yield triflates which were displaced stereospecifically with diverse sulfur nucleophiles. This sulfonylation/substitution protocol also was performed on the 4′-α(or β)-hydroxyl of the corresponding avermectin monosaccharide. The sulfides, sulfoxides and sulfones thus obtained exhibited potent, broad spectrum anthelmintic and acaricidal activity.

Synthesis of avermectin B1-4″,4″a-oxide: a precursor of potent anthelmintic agents

Abstract Treatment of 4″-oxo-5-OTBDMS-Avermectin B1 (2) with trimethylsilyldiazomethane or diazomethane resulted in the stereoselective formation of the 4″,4″a-oxide (3) in addition to the ring-expanded oxepinyl epoxide (4). The resultant epoxides were opened regiospecifically with sulfur, amine and halogen nucleophiles. The new 4″-substituted avermectins thus formed exhibited potent, broad-spectrum anthelmintic activity.

SPORANDOL: A NOVEL ANTIPARASITIC BINAPHTHALENE FROM CHRYSOSPORIUM MERIDARIUM

Abstract Sporandol (7,7′-diacetyl-1, 1′,8,8′-tetrahydroxy-3, 3′-dimethoxy-6, 6′-dimethyl-2, 2′-binaphthalene, 1 ) a novel endo and ecto parasiticide has been isolated from Chrysosporium meridarium . This compound appears to have much less mammalian toxicity than other members of the binaphthalene class. Axial stereochemistry of sporandol was determined as S by CD measurements.