Michael F. Clothier

Anthelmintic β-hydroxyketoamides (BKAs)

We have prepared several anthelmintic coumarins based on the β-hydroxyketoamide (BKA) template and have shown that this template remains valid over a wide range of changes to the coumarin moiety allowing for the inclusion of carbocyclic, bicyclic, and heterocyclic rings.

Marcfortine and Paraherquamide Class of Anthelmintics: Discovery of PNU- 141962

Three distinct chemical classes for the control of gastrointestinal nematodes are available: benzimidazoles, imidazothiazoles, and macrocyclic lactones. The relentless development of drug resistance has severely limited the usefulness of such drugs and the search for a new class of compounds preferably with a different mode of action is an important endeavor. Marcfortine A (1), a metabolite of Penicillium roqueforti, is structurally related to paraherquamide A (2), originally isolated from Penicillium paraherquei. Chemically the two compounds differ only in one ring; in marcfortine A, ring G is six-membered and carries no substituents, while in paraherquamide A, ring G is five-membered with methyl and hydroxyl substituents at C14. Paraherquamide A (2) is superior to marcfortine A as a nematocide. 2-Desoxoparaherquamide A (PNU-141962, 53) has excellent nematocidal activity, a superior safely profile, and is the first semi-synthetic member of this totally new class of nematocides that is a legitimate candidate for development. This review describes the chemistry, efficacy and mode of action of PNU-141962.

Synthesis and biological activity of anthelmintic thiadiazoles using an AF-2 receptor binding assay

Following our discovery of the strong binding of thiadiazole 1 to the AF-2 neuropeptide receptor of gastrointestinal nematodes (e.g., Ascaris suum), we prepared two series of analogs. Only the series containing the thiadiazole ring had potencies comparable to that of compound 1. Analog 50 exhibited an apparent potency in the AF-2 binding assay 300 times that of compound 1.

SELECTIVE REDUCTION OF SECONDARY AMIDES TO AMINES IN THE PRESENCE OF TERTIARY AMIDES

Abstract Secondary amides activated with a Cbz group can be reduced to their corresponding hemiaminals using lithium borohydride. Hydrogenation then removes the Cbz and hydroxyl groups to produce the related amine. Tertiary amides are not affected.

A Novel Reaction of Cyanogen Iodide with Cyclic Tertiary Amines

It has been shown that cyanogen iodide reacts with the tertiary amine ring of marcfortine A (1) to give cyano (4) and iodocyano (3) substituted products. We have now extended this reaction to various cyclic tertiary amines.

An improved synthesis of 14α-hydroxy-15,16-dehydro-17-oxomarcfortine A; A key intermediate in the synthesis of 14α-hydroxymarcfortine A

Abstract An improved synthesis of 14α-hydroxymarcfortine A from marcfortine A was achieved by means of a redesigned synthesis of the key intermediate [4α-hydroxy-15,16-dehydro-17-oxomarcfortine A ( 8 ).

C24 and C25 substituted marcfortine A derivatives

The dioxepinoindole ring found in marcfortine A (1) is unique among natural products. In order to determine the importance of the substitution pattern of the C24-C25 olefin, we synthesized a variety of analogs at these positions. With the exception of compound 5, none of these compounds exhibited any anthelmintic activity.

Functionalization of marcfortine A at C12 and C17 by treatment with metallic oxidizing agents

Abstract Treatment of Marcfortine A with various metallic oxidizing agents has led to functionalization at C12, C16, and C17. The new functional groups provide opportunities for further elaboration of this important new class of anthelmintics.

C26 DIALKYL AND SPIROALKYL ANALOGS OF MARCFORTINE A

Abstract The C26 dimethyl dioxepinoindole ring found in marcfortine A is unique among natural products. In order to ascertain the importance of the dimethyl moiety to anthelmintic activity, we prepared a variety of C26-dialkyl and spiroalkyl analogs. They include cyclobutyl, cyclohexyl, diethyl, and ethyl-methyl derivatives. This communication describes the synthesis of these compounds.