Drugs For Treating Leprosy

Lesions of the skin, loss of sensitivity to pain, and superficial nerves are the three main signs of leprosy, a disease caused by the mycobacteria Mycobacterium leprae. This disease is extremely infectious. Children and men are more susceptible to it than women. The incubation period can last several years, which makes early detection of leprosy difficult. Up until 1982, chemotherapy of leprosy consisted of taking dapsone, which gave good clinical results. However, because of the primary and secondary resistance that originated from prolonged use, it is now necessary to use a certain combination of drugs. Currently, dapsone is used along with rifampin and clofazimine. Ethionamide is also prescribed.

Dapsone: Dapsone, 4,4'-diaminodiphenylsulfone (34.2.3), is synthesized from either 4-chloronitrobenzene or from the sodium salt of 4-acetamidobenzenesulfonic acid. Reacting 4-chloronitrobenzene with sodium sulfide gives 4,4'-dinitrodiphenylthioester (34.2.1), and oxidation of the sulfur atom in this compound using potassium dichromate in sulfuric acid gives 4,4'-dinitrodiphenylsulfone (34.2.2). Reduction of the nitro group in the resulting compound using tin dichloride in hydrochloric acid makes the desired dapsone.

It has also been suggested to reduce the nitro group to an amino group, protect it with an acetyl protection, oxidize the sulfur atom to a sulfone using potassium dichromate, and then remove the protective acetyl group by hydrolysis [48-50].


Another way of the synthesis of dapsone begins with 4-acetamidobenzenesulfonic acid, which is reacted with 4-chloronitrobenzene at high temperatures to give 4-acetamido-4'-nitrodiphenylsulfone (34.2.4). Reducing the nitro group in this compound with tin dichloride in hydrochloric acid along with the simultaneous hydrolysis of the acetyl group under the reaction conditions gives the desired dapsone [51-53].

Dapsone, which was first proposed in 1941, possesses both bactericidal as well as bacteriostatic activity with respect to Mycobacterium leprae and Mycobacterium tuberculosis. It is used to treat patients with herpetiform dermatitis. It is believed that the mechanism of its action consists of competitive inhibition of the enzyme dihydroprotease synthetase, which blocks synthesis of folic acid in microorganisms, allowing it to also be viewed as an analog of p-aminobenzoic acid. Synonyms of this drug are avosulfon, croysulfon and others.

Clofazimine: Clofazimine, 2-(p-chloroanilino)-5-(p-chlorophenyl)-3,5-dihydro-3-(iso-propylimino)-phenazine (34.2.6), is synthesized by oxidizing 2-(p-chloroanilino)aniline using a solution of iron (III) chloride in water, which leads to the formation of 2-(p-chloroanilino)-5-(p-chlorophenyl)-3,5-dihydro-3-iminophenazine (34.2.5). Upon reacting this with a primary amine, in particular isopropylamine, the hydrogen atom in the imine region of the molecule is formally replaced with an alkyl group of the introduced amino group (in this case with an isopropyl group), forming the desired drug—clofazimine [54-56].

Clofazimine is a substituted iminophenazine that was first proposed for treating leprosy in 1962; however, it entered into medical practice toward the end of the 1980s. The mechanisms of its action is not definitively known, although there is the assumption that it can inhibit the formation of matrixes with DNA, which leads to a delay in the growth of mycobacteria. Clofazimine exhibits a bactericidal effect between that of dapsone and rifampicin. Synonym of this drug is lamprene.

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