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 My cobacterium leprae were prepared in other laboratories. We 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-I-butanol)di-isoniazid methane sul phonate was also inactive at this dosage. Three compounds related to dapsone, 4-nitro-N'-phenylsulphonamide, 4-amino-N'-phenylsulphonamide, and 4,4'-dia minobenzene 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 pyri dinal-2-thiosemicarbazone, were inactive in dosages of 0•0 I %; 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 trimetho prim but has a longer half-life, was inactive in a dosage of 0• 1 %; it had no synergistic effect with 0•0 I % 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. Experi ments 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.

Structure-activity relationships of tetramethylpiperidine-substituted phenazines against Mycobacterium leprae in vitro

“…Although a wide variety of structural analogs of B663 has been synthesized (11), only a limited number of compounds have been evaluated in the 6-to 12-month mouse footpad model (13), which until recently was the only available screening system for new antileprotics. An examination of six structural analogs of clofazimine in a Mycobacterium leprae-macrophage in vitro system failed to identify compounds with superior activity (10).…”

Pharmacochemical aspects of leprosy

“…The problems with the existing drugs can be summarized as follows: primary and secondary resistance to dapsone have been reported [2]; strains resistant against rifampicin have emerged [3]; clofazimine provokes a red colouration of the skin [4]; the thioamides are hepatotoxic [5].…”

The contribution of Charles C. Shepard to leprosy research: from the mouse footpad model to new DNA technology

“…It was Shep's policy to retain a few strains of M. leprae by serial passage in mice, particularly as «standard» strains for drug testing. Some of these had been serially passaged in mice for [16][17][18][19][20][21][22][23][24] years , without any detectable change in pathogenicity or growth patterns in mice . Fi nally the stability and survival of M. leprae outside the body was assessed using the foot-pad model, on bacilli recovered from dried nasal discharges.…”

“…Many of these were new drugs or new or modified series of known anti-leprosy drugs arising from the Drug Development Sub-Committee of the Thera py of Leprosy (THELEP) Scientific Working Group (18). This contribution is yet another example of the enthusiastic dedication of Shep for any studies which might advance the treat ment and control of leprosy.…”