RESUMEN
The addition of a variety of thiols to the alpha,beta-unsaturated lactone functionality present in brefeldin A has been carried out, and the resulting sulfides have been oxidized to the corresponding sulfoxides. These sulfoxides have the potential to undergo syn elimination to regenerate brefeldin A. The sulfoxides were more active than the sulfides as cytotoxic agents in a variety of human cancer cell cultures with the activities of the sulfoxides approaching that of brefeldin A itself. The cytotoxicities of the sulfoxides may be due to their conversion back to brefeldin A. The kinetics of sulfoxide elimination to form brefeldin A were studied in four cases, and the results indicate that substantial amounts of brefeldin A are likely to be generated during the cytotoxicity assays of the sulfoxide derivatives. Since the oxidation of sulfides to sulfoxides is a common metabolic reaction, the sulfides derived from brefeldin A can be considered as potential brefeldin A prodrugs. Several of the sulfide derivatives were determined to have enhanced aqueous solubilities relative to brefeldin A itself. A number of brefeldin A succinates, glutarates, oxidation products, and sulfone derivatives were also prepared and evaluated for cytotoxicity in cancer cell cultures. Some of the more active brefeldin A derivatives were tested in an in vivo animal model in which hollow fibers containing cancer cell cultures were implanted subcutaneously (SC) and intraperitoneally (IP), and the compounds were administered IP. Greater cytotoxic activity was observed at the SC site than at the IP site for the majority of these compounds, an observation which is consistent with the hypothesis that they are acting as brefeldin A prodrugs in vivo.
Asunto(s)
Antibacterianos/síntesis química , Antibióticos Antineoplásicos/síntesis química , Ciclopentanos/síntesis química , Diseño de Fármacos , Profármacos/síntesis química , Sulfuros/síntesis química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Brefeldino A , División Celular/efectos de los fármacos , Ciclopentanos/química , Ciclopentanos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Macrólidos , Ratones , Trasplante de Neoplasias , Profármacos/química , Profármacos/farmacología , Solubilidad , Relación Estructura-Actividad , Sulfuros/química , Sulfuros/farmacología , Sulfonas/síntesis química , Sulfonas/química , Sulfonas/farmacología , Sulfóxidos/síntesis química , Sulfóxidos/química , Sulfóxidos/farmacología , Células Tumorales CultivadasRESUMEN
Nucleocapsid p7 (NCp7) proteins of human immunodeficiency virus type 1 (HIV-1) contain two zinc binding domains of the sequence Cys-(X)2-Cys-(X)4-His-(X)4-Cys (CCHC). The spacing pattern and metal-chelating residues (3 Cys, 1 His) of these nucleocapside CCHC zinc fingers are highly conserved among retroviruses. These CCHC domains are required during both the early and late phases of retroviral replication, making them attractive targets for antiviral agents. toward that end, we have identified a number of antiviral chemotypes that electrophilically attack the sulfur atoms of the zinc-coordinating cysteine residues of the domains. Such nucleocapside inhibitors were directly virucidal by preventing the initiation of reverse transcription and blocked formation of infectious virus from cells through modification of CCHC domains within Gag precursors. Herein we report that azodicarbonamide (ADA) represents a new compound that inhibits HIV-1 and a broad range of retroviruses by targeting the the nucleocapsid CCHC domains. Vandevelde et al. also recently disclosed that ADA inhibits HIV-1 infection via an unidentified mechanism and that ADA was introduced into Phase I/II clinical trials in Europe for advanced AIDS. These studies distinguish ADA as the first known nucleocapsid inhibitor to progress to human trials and provide a lead compound for drug optimization.
Asunto(s)
Fármacos Anti-VIH/farmacología , Compuestos Azo/farmacología , Proteínas de la Cápside , Cápside/efectos de los fármacos , Productos del Gen gag/efectos de los fármacos , Infecciones por VIH/virología , VIH-1/fisiología , Proteínas Virales , Replicación Viral/efectos de los fármacos , Sitios de Unión , Línea Celular , VIH-1/efectos de los fármacos , Humanos , Productos del Gen gag del Virus de la Inmunodeficiencia HumanaRESUMEN
Platinum (II) and platinum (IV) coordination complexes derived from beta-silyl-substituted amines were prepared. The solubility of selected complexes in water and physiological saline was measured, and the effect of the beta-silicon on the reactivity of the complex in aqueous solution was determined by HPLC. The stabilities of selected silyl complexes were compared to the carbon analogues. The cyclic complexes 2a ("silaplatin") and its Pt(IV) analogue, 2b, were very active against L1210 leukemia in vivo. Both the platinum (II) complex 2a and the platinum (IV) complex 2b produced a significant number of cures over the dose range 10-40 mg/kg. The platinum (II) complex 2a, silaplatin, was very active in vivo against an L1210 leukemia subline that was resistant to cisplatin; 2a was also active, when given ip, against ic implanted L1210. The cyclobutanedicarboxylic acid complex 3c was synthesized; this complex was active against both cisplatin sensitive and resistant L1210 leukemia but was less potent than the analogous dichloro compound 2a. The acyclic platinum (II) and platinum (IV) complexes 1a,b were synthesized and unexpectedly found to be inactive in vivo against L1210 leukemia. More lipophilic silaplatin analogues were prepared--Pt(II) complex 2c and Pt(IV) complex 2d have one additional methylene carbon compared to 2a,b, whereas Pt(II) complex 2e and Pt(IV) complex 2f have two additional methylene carbons. Cyclization of the alkyl groups attached to the silicon gave the spiro bicyclic Pt(II) complexes 10a and 11a and the Pt(IV) complexes 10b and 11b.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Cisplatino/análogos & derivados , Compuestos de Organosilicio/síntesis química , Compuestos de Organosilicio/farmacología , Compuestos de Platino/síntesis química , Compuestos de Platino/farmacología , Animales , Antineoplásicos/química , Cisplatino/síntesis química , Cisplatino/química , Cisplatino/farmacología , Resistencia a Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Leucemia L1210 , Ratones , Estructura Molecular , Trasplante de Neoplasias , Compuestos de Organosilicio/química , Compuestos de Organosilicio/toxicidad , Compuestos de Platino/química , Compuestos de Platino/toxicidad , Solubilidad , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
The potential therapeutic application of the naturally occurring, cytotoxic pseudoguaianolide sesquiterpene lactone ambrosin is limited by its aqueous insolubility. A number of water-soluble ambrosin derivatives have therefore been prepared for potential use as prodrugs. Michael addition of several secondary amines to both the alpha,beta-unsaturated ketone and alpha-methylene lactone moieties of ambrosin afforded tertiary amine diadducts that were converted to water-soluble hydrochloride salts. The salt of the bis-piperidine adduct proved to be the most potent, producing cytotoxic activity only slightly less potent than that of ambrosin itself in a variety of human cancer cell cultures. The sodium salt of the bis-sulfonic acid derivative of ambrosin was inactive, while the sodium salt of the bis-sulfinic acid analog had low activity. Biological evaluation of several ambrosin analogs with reduced and/or isomerized alpha,beta-unsaturated ketone and alpha-methylene lactone moieties demonstrated the importance of both of these functional groups for biological activity.
Asunto(s)
Antineoplásicos/síntesis química , Profármacos/síntesis química , Sesquiterpenos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Espectroscopía de Resonancia Magnética , Profármacos/química , Profármacos/farmacología , Sesquiterpenos/química , Sesquiterpenos/farmacología , Sesquiterpenos de Guayano , Células Tumorales CultivadasRESUMEN
A procedure is presented for the rapid calculation of the similarity between a pair of molecules based on atomic electrostatic multipole comparison. The multipoles are derived from semiempirical SCF wave functions, and the results obtained compare favorably with ab initio results. The method is illustrated by correlating the similarity and anti-HIV-1 activity of a series of azo compounds. Some generalizations are presented on the structure-activity relationships which are based on the atomic multipole distribution in the azo compounds.
Asunto(s)
Antivirales/química , VIH-1/efectos de los fármacos , Antivirales/farmacología , Electroquímica , VIH-1/fisiología , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Cosalane (3), a novel anti-HIV agent having a disalicylmethane unit linked to C-3 of cholestane by a three-carbon linker, was synthesized from commercially available starting materials by a convergent route. Cosalane proved to be a potent inhibitor of HIV with a broad range of activity against a variety of laboratory, drug-resistant, and clinical HIV-1 isolates, HIV-2, and Rauscher murine leukemia virus. The cytotoxicity of cosalane is relatively low as reflected by an in vitro therapeutic index of > 100. Although cosalane inhibits HIV-1 reverse transcriptase and protease, time of addition experiments indicate that it prevents the cytopathic effect of HIV by acting earlier than reverse transcription in the viral replication cycle. The available evidence indicates that the primary mechanism of action of cosalane involves inhibition of gp120-CD4 binding as well as inhibition of a postattachment event prior to reverse transcription.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Ácido Aurintricarboxílico/análogos & derivados , VIH-1/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Ácido Aurintricarboxílico/síntesis química , Ácido Aurintricarboxílico/farmacología , Linfocitos B/microbiología , Fusión Celular , Células Cultivadas , ADN Viral/biosíntesis , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , VIH-1/fisiología , Células HeLa , Humanos , Macrófagos/microbiología , Fenotipo , Linfocitos T/microbiología , Virión/efectos de los fármacos , Zidovudina/farmacologíaRESUMEN
9-Methoxy-2-methylellipticinium acetate (6), along with the 9-methyl and 9-chloro derivatives (7, and 8, respectively) have shown remarkable selectivities in vitro against the NCI human CNS cancer subpanel. In order to target these types of compounds to the CNS in vivo, a series of 1,2-dihydroellipticines was synthesized. 9-Methoxy-2-methyl-1,2-dihydroellipticine (9) retained the potency and selectivity of the parent compound 6 but was unstable toward oxidation to 6. In order to improve the stability of 9, it was converted to the vinylogous amide 33 by introduction of a formyl group in the 4-position. Compound 33 proved to be much more stable than 9, but it was also less potent than 9 by about 1 order of magnitude, and it was less selective for the CNS subpanel than 9. To overcome the limited water solubilities of the ellipticines and dihydroellipticines, several ellipticine analogues incorporating polar groups on the N-2 nitrogen were prepared. The 2-(methoxymethyl)ellipticinium salts 24 and 25, as well as the (methylthio)methyl congener 26, were relatively potent anticancer agents which displayed cytotoxicity selectivity profiles similar to compound 6. The cytotoxic dihydroellipticines 9 and 10 exhibited potencies approaching that of ellipticine itself in facilitating the formation of a "cleavable complex", while the least cytotoxic ellipticine derivatives exhibited no cleavage above background.
Asunto(s)
Neoplasias Encefálicas/patología , Elipticinas/síntesis química , Neoplasias Encefálicas/tratamiento farmacológico , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Elipticinas/farmacología , Humanos , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
A simple synthesis of the sulfonated azo dye Quinobene (3) and its derivatives, as well as the results of their evaluation in anti-HIV screening have been described. Thus, reacting the diazonium salt of 4,4'-diaminostilbene-2,2'-disulfonic acid with 8-hydroxyquinoline-5-sulfonic acid yielded the readily isolable title compound. The lithium and tetramethylammonium salts of Quinobene and its complexes with Cu(II), Zn(II), Mg(II) were also prepared. In vitro tests showed considerable activity of these compounds against HIV-1.
Asunto(s)
Antivirales , Compuestos Azo/farmacología , VIH/efectos de los fármacos , Estilbenos/farmacología , Antivirales/química , Compuestos Azo/síntesis química , Células Cultivadas , Quelantes/farmacología , Humanos , Técnicas In Vitro , Estilbenos/síntesis química , Replicación Viral/efectos de los fármacosRESUMEN
An asymmetric synthesis of [beta-(4-pyridyl-1-oxide)-L-alanine4]-angiotensin I (1a), which is a potential suicide substrate (mechanism-based inhibitor) for protein-tyrosine kinases, has been performed. Deprotonation of 6 with n-butyllithium in THF gave the anion 7, which was alkylated with 4-(chloromethyl)pyridine-1-oxide to afford intermediate 9 as a crystalline solid. Hydrolysis of 9 afforded a mixture of 11 and 12 in a ratio of 96:4 as estimated by conversion to the diastereomeric dipeptides 13 and 14 followed by HPLC analysis. The 96:4 mixture of 11 and 12 was used in the solid phase synthesis of the target angiotensin analog 1a and its diastereomer 1b, which were separated and tested for inhibitory activity against two thymocyte protein-tyrosine kinases: p40 and p56lck. Neither peptide displayed significant inhibitory activity toward p40 and both served as weak competitive inhibitors of p56lck.
Asunto(s)
Angiotensina I/análogos & derivados , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Angiotensina I/síntesis química , Angiotensina I/metabolismoRESUMEN
Taxol has shown good in vivo antitumor activity in a number of test systems. The formulation of taxol for antitumor testing has been difficult. Esterification at either C-2' or C-7 resulted in loss of in vitro tubulin assembly activity but not cytotoxicity. These observations suggested that esters at C-2' and/or C-7, which would tend to promote water solubility, might serve as useful prodrugs of taxol. The reaction of taxol with either succinic anhydride or glutaric anhydride in pyridine solution at room temperature gave the crystalline mono 2'-adducts 1b and 1f, respectively. Salts of these acids (1b, 1f, 1i) were formed by the addition of 1 equiv of the corresponding base, followed by evaporation and/or freeze-drying of the solvent(s). The salts had improved antitumor activity as compared to the free acids. The triethanolamine and N-methylglucamine salts showed greatly improved aqueous solubility and were more active than the sodium salts. The glutarate series was preferred because of the higher activity and the higher yields obtained. 2'-Glutaryltaxol (1f) was coupled with 3-(dimethylamino)-1-propylamine, using CDI, to form in excellent yield the amino amide 1o. The hydrochloride salt (1p) showed good solubility and was extremely potent and active. At 10 mg/kg, in the B16 screen, 1p gave a T/C of 352 with 5 out of 10 cures. In the MX-1 breast xenograft assay, this prodrug gave values of -100 at doses of 40 and 20 mg/kg, with all live animals being tumor free.
Asunto(s)
Alcaloides/síntesis química , Neoplasias Experimentales/tratamiento farmacológico , Profármacos/síntesis química , Alcaloides/uso terapéutico , Animales , Antineoplásicos Fitogénicos , Fenómenos Químicos , Química , Evaluación Preclínica de Medicamentos , Espectroscopía de Resonancia Magnética , Ratones , Ratones Desnudos , Estructura Molecular , Paclitaxel , Profármacos/uso terapéutico , Solubilidad , Relación Estructura-Actividad , AguaRESUMEN
2',3'-Dideoxyadenosine, C10H13N5O2, Mr = 235.24, orthorhombic, P2(1)2(1)2(1), a = 7.7404(4), b = 9.9843(9), c = 14.0842(10) A, V = 1088.46 A3, Z = 4, Dx = 1.435 Mg m-3, lambda(CuK alpha) = 1.5418 A, mu = 0.8326 mm-1, F(000) = 496, T = 296 K, final R = 0.032 for 1088 observed reflections. 2',3'-Dideoxycytidine, C9H13N3O3, Mr = 211.21, tetragonal, P4(1)2(1)2, a = 8.6802(4), c = 26.1386(14) A, V = 1969.44 A3, Z = 8, Dx = 1.424 Mg m-3, lambda(CuKa) = 1.5418 A, mu = 0.8701 mm-1, F(000) = 896, T = 296 K, final R = 0.050 for 1116 observed reflections. In both compounds the sugar rings have conformations intermediate between envelope and half chair but somewhat different pseudorotations. The relative orientations of the sugar and base are different in the two molecules with dideoxyadenosine being at the boundary of syn and anti and deoxycytidine being anti.
Asunto(s)
Didesoxiadenosina , Zalcitabina , Cristalografía , Enlace de Hidrógeno , Conformación Molecular , Estructura Molecular , Difracción de Rayos XRESUMEN
The synthesis, chemical stability and anti-tumor activity of pyrazine diazohydroxide, sodium salt, a compound that has been selected for development to clinical trials, are described. The compound shows a half-life of about 100 minutes at pH 7.4 and is active against a number of experimental tumors.
Asunto(s)
Antineoplásicos/síntesis química , Azidas/síntesis química , Pirazinas/síntesis química , Pirimetamina/análogos & derivados , Pirimidinas/síntesis química , Animales , Antineoplásicos/uso terapéutico , Azidas/farmacología , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Femenino , Semivida , Masculino , Ratones , Ratones Endogámicos , Neoplasias Experimentales/tratamiento farmacológico , Pirazinas/uso terapéutico , Pirimidinas/farmacologíaRESUMEN
Potential prodrugs of the highly insoluble, diimide antitumor agent mitindomide (1b) were synthesized by several different methods. The condensation reaction between mitindomide and formaldehyde cleanly gave the stable bis(hydroxymethyl) compound 7a, which was partially soluble in water (ca. 0.8%) and showed improved activity in the P-388 screen. When this compound was treated with secondary amines, good yields of Mannich bases could be isolated. The compound from N-methylpiperazine (7b) had excellent properties and is a candidate for clinical trials. Condensation with other aldehydes gave either no reaction or compounds with poor activity. A water-soluble ester was prepared from 7a and succinic anhydride, but had reduced potency and activity. Oxidation of the double bond of 1a with ozone gave an inactive diacid, whereas the dihydro compound was as active as the olefin. When other aromatics (anisole, p-xylene, mesitylene) were photolyzed with maleimide, the resulting photoproducts were found to be inactive. Diimides from other ring system were synthesized from the corresponding anhydrides and found to be inactive. However, the bis(hydroxymethyl) derivative of one of these (12a) was active in the P-388 screen.
Asunto(s)
Antineoplásicos/síntesis química , Indoles/síntesis química , Antineoplásicos/farmacología , Benceno , Indoles/farmacología , Isoindoles , Maleimidas , Fotoquímica , SolubilidadRESUMEN
The synthesis, physical properties, and antitumor activity of the cis-, d,l-trans-, d-trans-, and l-trans- stereoisomers of 1,2-diaminocyclohexane tetrachloroplatinum(IV) are described. The objective of the study was to produce a platinum complex with activity against cisplatin-resistant tumor cells and with suitable pharmaceutical properties for formulation development. The isomers had the following solubilities in saline: cis-, 2 mg/ml; d,l-trans-, 6.5 mg/ml; and d-trans- and l-trans-, 15-16 mg/ml. The four complexes showed slightly better activity than cisplatin against the ip implanted murine L1210 leukemia. In contrast to cisplatin, all complexes produced significant increases in life span against L1210/cisplatin, a subline of L1210 with acquired resistance to cisplatin. However, the cis- isomer was less active against L1210/cisplatin. The d,l-trans- isomer (tetraplatin) was selected for further studies based on greater ease for large-scale synthesis. It showed superior activity to cisplatin against P388/cisplatin and like cisplatin showed significant and reproducible activity against the ip implanted B16 melanoma, ip implanted M5076 sarcoma, ip implanted P388 leukemia, and MX-1 human breast xenograft implanted under the renal capsule. Purity and stability (greater than 24 hours in saline) were evaluated by high-performance liquid chromatography and found to be suitable for development of a parenteral dosage form. Preliminary studies in a rat model (to be reported elsewhere) showed it to be less nephrotoxic than cisplatin on a molar basis and worthy of further study.
Asunto(s)
Antineoplásicos , Compuestos Organoplatinos/uso terapéutico , Animales , Peso Corporal/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular , Cisplatino/uso terapéutico , Evaluación Preclínica de Medicamentos , Resistencia a Medicamentos , Humanos , Leucemia L1210/tratamiento farmacológico , Leucemia L1210/genética , Leucemia P388/tratamiento farmacológico , Leucemia P388/genética , Melanoma/tratamiento farmacológico , Ratones , Mutación , Compuestos Organoplatinos/análisis , Compuestos Organoplatinos/síntesis química , Ratas , Sarcoma Experimental/tratamiento farmacológico , EstereoisomerismoRESUMEN
The syntheses and anthelmintic activities of 31 3- and 5-(isothiocyanatophenyl)-1,2,4-oxadiazoles are reported. In the primary anthelmintic screen, 3-(4-isothiocyanatophenyl)-1,2,4-oxadiazole (39) showed 100% nematocidal activity and 3-(2-furanyl)-5-(4-isothiocyanatophenyl)-1,2,4-oxadiazole (63), 3-(2-furanyl)-5-(2-chloro-4-isothiocyanatophenyl)-1,2,4-oxadiazole (64), and 3-(2-furanyl)-5-(4-chloro-3-isothiocyanatophenyl)-1,2,4-oxadiazole (66) showed 100% taeniacidal activity when administered orally to mice. The two most active members of this series, 39 and 63, were active against the gastrointestinal nematodes of sheep at 100 mg/kg. In addition, 39 was also found to be active against hookworms in dogs at a single, oral dose of 200 mg/kg.
Asunto(s)
Helmintiasis/tratamiento farmacológico , Oxadiazoles/uso terapéutico , Tiocianatos/uso terapéutico , Anquilostomiasis/tratamiento farmacológico , Animales , Enfermedades de los Gatos/tratamiento farmacológico , Gatos , Fenómenos Químicos , Química , Enfermedades de los Perros/tratamiento farmacológico , Perros , Evaluación Preclínica de Medicamentos , Hemoncosis/tratamiento farmacológico , Helmintiasis Animal , Himenolepiasis/tratamiento farmacológico , Ratones , Infecciones por Nematodos/tratamiento farmacológico , Oxadiazoles/síntesis química , Ovinos , Enfermedades de las Ovejas/tratamiento farmacológico , Teniasis/tratamiento farmacológico , Tiocianatos/síntesis químicaRESUMEN
The synthesis and antiparasitic properties of 22 isothiocyanato-2-pyridinylbenzoxazoles and benzothiazoles are described; the preparation and anthelmintic activities of 14 isothiocyanato-2-thienyl-, -furyl-, and -pyrrolylbenzoxazoles are outlined. In mice experimentally infected with Nematospiroides dubius (nematode) and Hymenolepis nana (tapeworm), three derivatives, i.e., 5-isothiocyanato-2-(2-furyl)benzoxazole (34), 5-isothiocyanato-2-(5-methyl-2-furyl)benzoxazole (35), and 5-isothiocyanato-2-(1-methyl-1H-2-pyrroly)benzoxazole (37), show 100% nematocidal activity and two, i.e., 5- and 6-isothiocyanato-2-(3-pyridinyl)benzoxazole (5) and 5- and 6-isothiocyanato-2-(3-pyridinyl)benzthiazole (21), show 10% taeniacidal activity at 0.2% in the diet. Two derivatives (5 and 21) show good nematocidal activity in sheep. Maximum activity requires 3-pyridinyl derivatives for both the benzoxazole and benzothiazole series.
Asunto(s)
Antihelmínticos/síntesis química , Benzoxazoles/síntesis química , Tiazoles/síntesis química , Animales , Benzoxazoles/farmacología , Fenómenos Químicos , Química , Infecciones por Uncinaria/tratamiento farmacológico , Himenolepiasis/tratamiento farmacológico , Ratones , Nippostrongylus/efectos de los fármacos , Tiazoles/farmacologíaAsunto(s)
Antihelmínticos/administración & dosificación , Guanidinas/administración & dosificación , Acetanilidas/administración & dosificación , Animales , Perros , Inyecciones Subcutáneas , Infecciones por Nematodos/tratamiento farmacológico , Ovinos , Infecciones por Trematodos/tratamiento farmacológicoRESUMEN
The preparation and anthelmintic activities of a series of 2-pyridinyl-5-isothiocyanatobenzimidazoles are described. In the primary oral mouse screen, six derivatives showed 100% taeniacidal activity at 0.2% in diet. The most active member in this series, 1c, is potentially an effective gastrointestinal nematocide in sheep at 50 mg/kg po.