Studies on sulphone and allied compounds

Abstract

Introduction The present thesis consists of 5 parts excluding introduction. Introduction deals in brief with: (1) the discovery and the development of sulfone series of drugs, (2) the chemistry of the more important sulfones, (3) the probable mechanism of action of these drugs, and (4) the correlation of chemotherapeutic activity and chemical structure.

Part I. Preparation of Sulfones Seeing the importance of 4,4'-diaminodiphenyl sulfone in leprosy and tuberculosis, methods were developed for its synthesis. The details of the preparation of sulfones have been described in this part.

Part II. Synthesis of Thioureas The relatively high toxicity of 4,4'-diaminodiphenyl sulfone precludes its application clinically as a drug in chemotherapy even though it showed a marked chemotherapeutic efficiency (Smith et al., J. Pharm. and Expt. Therap., 1942, 74, 163) in experimental tuberculosis. Researches are being done to modify the sulfone molecule by suitably substituting the aromatic p-amino groups. Though our knowledge of the chemical changes necessary to adapt a given compound to these conditions is scant, however, an endeavour in this direction is made in this part of the work to find a drug similar in activity to the parent sulfone, having more suitable physical and physico-chemical properties, but less toxicity. Unfortunately, as yet there is no adequate explanation for the profound changes in the therapeutic effect resulting from the variations in the structure; the effects have been studied on empirical lines. With this point in view, thioureas of 4,4'-diaminodiphenyl sulfone, 4-nitro-4'-aminodiphenyl sulfone, 4-nitro-4'-aminodiphenyl sulfide, and 4,4'-diaminodiphenyl sulfide have been prepared and detailed in this part.

Part III. Azo-dyes of 4,4'-diaminodiphenyl sulfone Even though the antistreptococcal activity of 4,4'-diaminodiphenyl sulfone was found experimentally to be approximately hundred times that of sulfanilamide and is probably the most potent and active principle of the antibacterial chemotherapeuticals which have been studied up till now with the single exception of the wonder-drug of the world namely 'Penicillin', its toxic nature prevented its practical utility in chemotherapy. 4,4'-diaminodiphenyl sulfone has come to the limelight in the field of chemotherapy as a possible cure of tuberculosis, leprosy and gas gangrene. But, the coupling of the toxicity of this useful compound with its high degree of specificity makes the search for more effective and less toxic derivatives a promising field of investigation. With this end in view, 21 azo-dyes of 4,4'-diaminodiphenyl sulfones have been prepared and detailed in this part.

Part IV. Alkylation of Thioureas In order that the thioureas may be converted to salt-like compounds so that they might be more soluble in water, like biguanides etc., attempts were made to convert them into their respective S-methyl and S-ethyl compounds. For this purpose, in view, 2-bis-thioureas (iodo and bromo) of sulfones were used for methylation and ethylation. The reactions were carried on with the usual reagents.

Part V. An in vitro evaluation of the tuberculostatic properties of some sulfone derivatives.