Sulfones antimalarial

The first are competitors of PABA (p-aminobenzoic acid) and thus intermpt host de novo formation of the tetrahydrofoUc acid required for nucleic acid synthesis. Examples of dmgs that fall into this group are the sulfones and sulfonamides. The most weU-known of the sulfones is dapsone (70, 4,4 -diaminodiphenyl sulfone, DDS), whose toxicity has discouraged its use. Production of foHc acid, which consists of PABA, a pteridine unit, and glutamate, is disturbed by the substitution of a sulfonamide (stmcturally similar to PABA). The antimalarial sulfonamides include sulfadoxine (71, Fanasd [2447-57-6]) sulfadiazine (25), and sulfalene (72, sulfamethoxypyrazine [152-47-6] Kelfizina). Compounds of this group are rapidly absorbed but are cleared slowly. 

As hydroxyl or hydroxyl-like radicals are produced by the superoxide-driven Fenton reaction, superoxide overproduction must also occur in thalassemic cells. First, it has been shown by Grinberg et al. [382], who demonstrated that thalassemic erythrocytes produced the enhanced amount of superoxide in comparison with normal cells in the presence of prooxidant antimalarial drug primaquine. Later on, it has been found that the production of superoxide and free radical-mediated damage (measured through the MetHb/Hb ratio) was much higher in thalassemic erythrocytes even in the absence of prooxidants, although quinones (menadione, l,4-naphthoquinone-2-methyl-3-sulfonate) and primaquine further increased oxidative stress [383]. Overproduction of superoxide was also observed in thalassemic leukocytes [384]. 

As in the case of the 1,2-dioxins, the 1,2-dithiins exist in various states of saturation, oxidation, and benzoannelation (cf. Scheme 1, 17-27) and they have been studied in detail both theoretically and experimentally. Not only were the conformations of the ring and attached substituents investigated, but the valence isomerism of 1,2-dithiin by both NMR and high-level ab initio molecular orbital (MO) calculations and the dithiol/disulfide equilibrium by MP2 calculations were also examined. The latter equilibrium has been applied successfully as a luminescent molecular switch (cf. Section 8.10.2.1). Finally, as a very interesting 1,2-dithiin derivative, the synthesis, structure, and reactivity of the (-l-)-camphor-derived analog 25 and its sulfoxide 26 and sulfone 27 have been reported. Both the synthesis and the antimalarial activity of the 2,3-dioxabicyclo[3.3.1]nonane pharmacophore 28, which contains the 1,2-dioxane moiety, have been reviewed recently <2006BML2991>. 

Just prior to 1950. great strides were made in anti-infective therapy. The sulfonamides and. sulfones (this chapter), more effective phenolic compounds such as hcxachlorophcnc. synthetic antimalarial compounds (Chapter 9). and a number of antibiotics (Chapter 10) wen introduced to the therapeutic armamentarium. 

Trost left the key operation at the end of his route to (+)-solamin, a natural product with a range of activities such as cytotoxicity, antimalarial and immunosuppressant activities. Applying the Myers modification, sulfone 110 was converted to butenolide diol 111 in good yield after desillylation.60... 

MECHANISMS OF ANTIMALARIAL ACTION AND RESISTANCE The 2,4-diaminopyrimidines inhibit dihydrofolate reductase of plasmodia at concentrations far lower than those required to inhibit the mammalian enzymes. The dihydrofolate reductase in malaria resides on the same polypeptide chain as thymidylate synthase and is not upregulated in the face of inhibition, which contributes to the selective toxicity of the antifolates. Synergism between pyrimethamine and the sulfonamides or sulfones has been attributed to inhibition of two steps in an essential metabolic pathway. 

Sulfonyldianiline (diaphenylsulfone, dapsone, DDS) (XXI) has occupied a pre-eminent position in the treatment of human leprosy since 1941 [110]. For several decades it has also been known that sulfones and sulfonamides exhibit noteworthy antimalarial properties, although until recently these sub-... 

Repository antimalarial effects were abohshed or drastically reduced when DADDS (XXXII) was modified by (1) replacement of the acetamide groups with a formamide function (MFDDS, /, Table 3) (2) replacement of both acetamide groups with amide functions containing more than two carbon atoms 11, 14, 15, 17 and 18, Table 4) (3) alkylation of one acetamide function (4, Table 3, and 22, Table 5) (4) introduction of a chlorine atom at positions 2 or 3 [19 and 20, Table 5) or (5) replacement of the sulfone moiety by a thio, sulfinyl, oxalyl, or 2,2,2-trichloroethylidene linakge (XXVI a-d) [38, 61, 117]. 

Table 7 Comparative antimalarial, antileprotic, and metabolic data on other sulfone Schiff bases and biopolymers [42, 125, 132-135]... 

The results of the repository antimalarial studies with CI-679 indicate that the drug is worthy of consideration for use as a repository antimalarial agent in drug-resistant malaria either alone or in combination with a long-acting sulfone such as DADDS or PSBA (vide supra). 

Potentiation of antimalarial effects are obtained by conhinatlons of driigs with varied mechanisms of action. The antimalarial effects of certain sulfones and svilfonamides apparently involve blockage of incorporation of jg-aminobenzoic acid (PABA) in the formation of folic acid in the parasite. Pyrimethamine acts at a different point in the same metabolic pathway. 30 dds may be competitive with PABA in the Zwitterion form.3I-... 

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