Recent studies of antileprosy drugs

Abstract

As a part of the programme of the Therapy of Leprosy (THELEP) Scientific Working Group, a number of compounds with potential activity against Mycobacterium leprae were prepared in other laboratories. The authors report here the results of studies of their activity against M. leprae with the use of the kinetic method in mice. A modified protocol is described that facilitates comparison of drugs in the same experiment. Two analogues of cycloserine, glycylhydroxamic acid and beta-analylhydroxamic acid were inactive in a dosage of 0.1% in the diet. Isoetam, (D-2,2'-(ethylendiimino)-di-l-butanol)di-isoniazid methane sulphonate was also inactive at this dosage. Three compounds related to dapsone, 4-nitro-N'-phenylsulphonamide, 4-amino-N'-phenylsulphonamide, and 4,4'-diaminobenzene sulphonic acid phenyl ester, had little or no activity at dosages of 0.01% in the diet in experiments with strains shown to have normal susceptibility to dapsone. Two thiosemicarbazones, pyridinal-4-thiosemicarbazone and pyridinal-2-thiosemicarbazone, were inactive in dosages of 0.01%; the latter was inactive at 0.01% in an experiment where thiacetazone was shown to have bactericidal-type activity at a dosage of 0.1% and marginal activity at 0.01%. Brodimoprim, a dihydrofolate reductase inhibitor, which is related to trimethoprim but has a longer half-life, was inactive in a dosage of 0.1%; it had no synergistic effect with 0.01% dapsone against a dapsone-susceptible strain. It was also inactive against a dapsone-resistant strain, alone or in combination with dapsone. The cyanimino analogs of ethionamide and prothionamide were inactive in a dosage of 0.1% against an ethionamide-susceptible strain. Experiments with a series of compounds related to chaulmoogric acid were unsuccessful because the compounds were too toxic. Experiments with a series of compounds related to clofazimine were unsuccessful because their pharmacokinetics were unfavourable for study at dosages where clofazimine itself was active. The limitations imposed by the mouse-foot-pad system are discussed and related to those in other experimental systems.