A series of both novel and reported combretastatin analogues, including diarylpyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles, were synthesized via improved protocols to evaluate their antimitotic antitubulin activity using in vivo sea urchin embryo assay and a panel of human cancer cells. A systematic comparative structure–activity relationship studies of these compounds were conducted. Pyrazoles 1i and 1p, isoxazole 3a, and triazole 7b were found to be the most potent antimitotics across all tested compounds causing cleavage alteration of the sea urchin embryo at 1, 0.25, 1, and 0.5 nM, respectively. These agents exhibited comparable cytotoxicity against human cancer cells. Structure–activity relationship studies revealed that compounds substituted with 3,4,5-trimethoxyphenyl ring A and 4-methoxyphenyl ring B displayed the highest activity. 3-Hydroxy group in the ring B was essential for the antiproliferative activity in the diarylisoxazole series, whereas it was not required for potency of diarylpyrazoles. Isoxazoles 3 with 3,4,5-trimethoxy-substituted ring A and 3-hydroxy-4-methoxy-substituted ring B were more active than the respective pyrazoles 1. Of the azoles substituted with the same set of other aryl pharmacophores, diarylpyrazoles 1, 4,5-diarylisoxazoles 3, and 4,5-diaryl-1,2,3-triazoles 7 displayed similar strongest antimitotic antitubulin effect followed by 3,4-diarylisoxazoles 5, 1,5-diaryl-1,2,3-triazoles 8, and pyrroles 10 that showed the lowest activity. Introduction of the amino group into the heterocyclic core decreased the antimitotic antitubulin effect of pyrazoles, triazoles, and to a lesser degree of 4,5-diarylisoxazoles, whereas potency of the respective 3,4-diarylisoxazoles was increased.

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A simple scalable procedure for the synthesis of 3,4‐diaryl‐isoxazole‐5‐carboxamides 6 under mild conditions from readily available material was developed. The targeted compounds 6, structural analogues of heat shock protein inhibitors, were obtained by the rearrangement of intermediate 3,4‐diaryl‐5‐carboxamido‐isoxazoline N‐oxides 5. In contrast to carboxamido‐isoxazoline oxides 5, base‐catalyzed recyclization of 3,4‐diaryl‐5‐(ethoxycarbonyl)isoxazoline N‐oxides 9c unexpectedly yielded 5‐hydroxy‐1,2‐oxazin‐6‐ones 17c instead of ethyl 3,4‐diaryl‐isoxazole‐5‐carboxylates 10. Crystal and molecular structure of 4‐(2,5‐dimethoxy‐3,4‐methylenedioxyphenyl)‐5‐hydroxy‐3‐phenyl‐6H‐1,2‐oxazin‐6‐one 17c was established by single‐crystal X‐ray diffraction study. In a phenotypic sea urchin embryo assay, carboxamide 6f showed moderate antimitotic antitubulin activity compared to 5‐unsubstituted 3,4‐diarylisoxazoles 15, which featured strong microtubule destabilizing effect.

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(095) 135 5085 4-Methox'y-l,l,l-trifluoropent-3-en-2-one reacts with cyanothioacetamide to give 3-cyano-4-methyl-6-trifluoromethylpyridine-2(1B)-thione, which was transformed into 3-amino-4-methyl-6-trifluoromethylthieno[2,3-b]pyridine-2-carboxanilide by the reaction with chloroacetaniiide. The crystal and molecular structure of the amide obtained was studied by X-ray analysis.

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The reaction of trifluoroacetylacetone with cyanothioacetamide proceeded regioselectively to form 3-cyano-6-methyl-4-tfifluoromethylpyridine-2(l/-/)-thione from which the corresponding 2-alkylthiopyridines and 3-aminothieno[2,3-b]pyridines were obtained. The crystal and molecular structure of 3-cyano-2-ethylthio-6-methyl-4-trifluoromethylpyridine was established by X-ray diffraction analysis.