1.2.4- Thiadiazoles properties

Several thiadiazolo-triazoles 43 have been synthesized that show antifungal and cytotoxic properties. hiadiazoles 45 were prepared from hydrazones 44 by treating them neat with thionyl chloride at room temperatures. The thiadiazoles were formed regio-selectively on the methyl group of the hydrazone. 

Heteroaromatic sulfur compounds do form sulfoxides and sulfones, but these derivatives have their own special reactivity. Francesca Clerici (Milan, Italy) has now provided an up-to-date survey of the preparation and properties of the S-oxides of thiazoles and thiadiazoles, collecting literature scattered in many publications. 

As 1,2,5-thiadiazole analogues, potent HlV-1 reverse transcriptase inhibitors, some simple 1,2,5-oxadiazoles, compounds 4-6 (Fig. 9), have been synthesized using the traditional Wieland procedure as key for the heterocycle formation [121]. Such as thiadiazole parent compounds, derivative with chlorine atoms on the phenyl ring, i.e., 5, showed the best anti-viral activity. Selectivity index (ratio of cytotoxic concentration to effective concentration) ranked in the order of 5 > 6 > 4. The activity of Fz derivative 6 proved the N-oxide lack of relevance in the studied bioactivity. These products have been claimed in an invention patent [122]. On the other hand, compound 7 (Fig. 9) was evaluated for its nitric oxide (NO)-releasing property (see below) as modulator of the catalytic activity of HlV-1 reverse transcriptase. It was found that NO inhibited dose-dependently the enzyme activity, which is hkely due to oxidation of Cys residues [123]. 

Chloro-l,2,3-thiadiazole-4-carboxamides 38 react with the sodium salt of diethyl malonate to give the corresponding malonic acid derivatives 39. The yield in these reactions falls as the electron-releasing properties of the 4-substituents in the aromatic ring increase (Equation 8) <1997JCM396>. 

Thiadiazoles have found applications as pharmaceuticals, fungicides, herbicides, bacteriocides, dyes, lubricant additives, and vulcanization accelerators. Cephalosporins incorporating a 1,2,4-thiadiazole ring into the side chain have good antibiotic and antimicrobial properties. 

Ethoxy-3-trichloromethyl-l,2,4-thiadiazole has excellent pesticidal and fungicidal properties. It is a commercial product, whose most common trade name is Terrazole. 

The 1,2,4-thiadiazole moiety has been incorporated in (3-lactam antibacterials to modulate pharmacokinetic properties and more recently into a cephalosporin. The cephalosporin 129 displays a good balance of serum stability and in vitro activity. The cephalosporin derivative 48 (see Section 5.08.7.4) also shows good pharmacokinetic properties <2001JAN364>. 

Thiadiazole 1 and its derivatives were used as model compounds for the calculation of molecular parameters related to physical properties for their use in quantitative structure-activity relationship (QSAR) and quantitative structure-property relationship (QSPR) studies <1999EJM41, 2003IJB2583, 2005JMT27>. 

Other 3,6-disubstituted-[l,2,4]triazolo[3,4- ][l,3,4]thiadiazoles 139 or [l,2,4]triazolo[3,4- ][l,3,4]oxadiazoles 145 were also evaluated for anticancer properties but showed little, if any, activity <2004PS1595, 2004JCCS1343>. 

Diamino-1,2,4-thiadiazoles of type (361) have been patented for use in the treatment of hypertension <82EUP44266), while 5-amino-1,2,4-thiadiazoles such as (362) are claimed to be useful for treating autoimmune diseases and in the prevention of graft rejection. Compounds of type (362) also have antirheumatic properties and are, in particular, useful in the treatment of rheumatoid arthritis and immune diseases such as systemic lupus <91EUP455356). 

The excellent pesticidal and fungicidal properties of 5-ethoxy-3-trichloromethyl-1,2,4-thiadiazole (363) are well known <82AHC(32)285). It is a commercial product and is marketed under a variety of names of which Terrazole is the most common. Since 1984, a variety of 1,2,4-thiadiazole derivatives have been found to possess fungicidal activity. Thus, compounds such as (364), (365), and (366) and... 

The fusion of the 1,2,5-thiadiazole system to a heterocyclic nucleus greatly enhances the elec-trophilicity of the substituted ring. These properties are manifested in increased rates of hydrolysis and more facile displacement, Diels-Alder, and cycloaddition reactions. The synthetically useful nucleophilic cleavage of the pyrimidine ring of l,2,5-thiadiazolo[3,4- /]pyrimidines was studied in detail by Shealy and co-workers and previously discussed <68ahc(9)107>. 

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