Molecular Design for Transition-State Analogue Enzyme Inhibitors

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Molecular designs for enzyme inhibitors were tried in order to find lead compounds of growth regulators for plants and insects by considering particularly transition-state analogues. Analogues of active intermediates, multi-substrates, and ground-state substrates were also considered.Inhibitors of the synthetase of tryptophan, an essential amino acid, must be effective as plant-growth regulators without deleterious mammalian effects. 3-(Substituted)-dihydroindoles potently inhibited the enzyme as putative transition-state analogues and retarded the growth of plants. Some thiols derived from substituted benzimidazoles, oxadiazoles, and triazoles also showed high activity to inhibit both tryptophan synthetase and plant-growth. Protection of the thiol group by acylation gave the good in vivo effect.Trifluoromethylketones and trifluoroacetate derivatives were designed for insect esterase inhibitors. Metamorphosis of silkworm larvae was suppressed by N-(p-phenoxyphenoxy-ethyl) trifluoroacetamide which was designed as a candidate inhibitor for insect juvenile hormone esterase. On the other hand, p-(N,N-diisopropylaminomethyl)trifluoroacetophenone inhibited acetylcholinesterase. 1,5-Disubstituted imidazoles were designed to inhibit cytochrome P450s which participate in the synteses of juvenile hormone in insects and of gibberellin in plants. Some imidazole derivatives induced precocious metamorphosis in silkworm larvae and some others retarded growth of plants.As multi-substrate analogue of glutathione-dependent enzymes S-substituted glutathiones were synthesized. S-(1-naphthylmethyl) glutathione inhibited glyoxalase I as well as glutathione S-transferase. Bicyclic phosphates with anti-GABA activity and octopamine related compounds were also studied.