“…Despite the presence of the 5-amino-3-substituted-1,2,4-thiadiazole and the isomeric 3-amino-5-substituted-1,2,4-thiadiazole in potential pharmaceuticals and cytotoxic natural products (Figure ), there is a dearth of methods available for the rapid synthesis of analogs . The most efficient of these methods requires the use of amidine and isothiocyanate intermediates (eq ). , For our purposes, access to the unfunctionalized 3-aryl-5-amino-1,2,4-thiadiazoles was required (R = H, eq ).…”
A novel approach to the synthesis of substituted 5-amino- and 3-amino-1,2,4-thiadiazoles beginning from a common precursor has been achieved. Derivatization by palladium-catalyzed Suzuki-Miyaura coupling enables the rapid preparation of analogs around this pharmaceutically relevant core. FMO calculations rationalize the observed chemoselectivity for coupling at chlorine.
“…Despite the presence of the 5-amino-3-substituted-1,2,4-thiadiazole and the isomeric 3-amino-5-substituted-1,2,4-thiadiazole in potential pharmaceuticals and cytotoxic natural products (Figure ), there is a dearth of methods available for the rapid synthesis of analogs . The most efficient of these methods requires the use of amidine and isothiocyanate intermediates (eq ). , For our purposes, access to the unfunctionalized 3-aryl-5-amino-1,2,4-thiadiazoles was required (R = H, eq ).…”
A novel approach to the synthesis of substituted 5-amino- and 3-amino-1,2,4-thiadiazoles beginning from a common precursor has been achieved. Derivatization by palladium-catalyzed Suzuki-Miyaura coupling enables the rapid preparation of analogs around this pharmaceutically relevant core. FMO calculations rationalize the observed chemoselectivity for coupling at chlorine.
“…Similarly, the 1,2,4-thiadiazoline derivative (8) reacted with the sulfide nucleophile (9) to afford the disulfide compound (11) and the ring-opened product (12), via the disulfide intermediate (10) (Scheme 2) [16].…”
Section: Mechanism Of Action Of Selected Cysteine Dependent Enzymesmentioning
confidence: 99%
“…The majority of the claims relate to the use of such compounds as insecticides, herbicides and fungicides [11][12][13]. For example, the THD derivative 18 shown in Fig.…”
1,2,4-Thiadiazole is a distinctive class of small heterocyclic thiol trapping agents that serve as an interesting pharmacophore in the design of inhibitors targeting the cysteine residues of proteins. X-Ray crystal structures of enzyme-inhibitor complex indicate that the cysteine thiol reacts with the N-S bond of the thiadiazole moiety to form a disulfide bond resulting in the inactivation of the enzymes. This review addresses the medicinal chemistry and various properties of 1,2,4-thiadiazoles in their potential as new electrophilic "warheads" for targeting the cysteine residues of biomolecules (e.g, H+/K+ ATPase), and cysteine-dependent enzymes (e.g., cathepsin B and transglutaminase).
“…Monocyclic [1,2,4]thiadiazoles ([1,2,4]THDs) have been widely claimed to be useful insecticidal, herbicidal and fungicidal agents . For example, 5-ethoxy-3-(trichloromethyl)-[1,2,4]thiadiazole ( 1 ) is a soil fungicide marketed as etridiazole or terrazole (Figure )…”
Section: Introductionmentioning
confidence: 99%
“…Early on, in our discovery program on the design of novel inhibitors targeting cysteine residues of biomolecules, , we recognized the advantage of employing the [1,2,4]THD heterocycle as the thiol trapping electrophile via S−S bond formation with concomitant N−S ring opening (Scheme ). Contrary to the commonly reported electrophilic “warheads” (e.g., epoxides, chloromethyl ketones, vinyl sulfones, and aldehydes), the [1,2,4]THD heterocycle displayed lack of reactivity (N−S bond cleavage) toward nucleophiles such as amines and alcohols, but reacted with thiols. , 1 Examples of commercial monocyclic [1,2,4]THD derivatives. 1 Mechanism of Inhibition of Cysteine Residues of Biomolecules by [1,2,4]THDs…”
A versatile synthetic route to potentially useful fused-ring [1,2,4]thiadiazole scaffolds (e.g., 7a and 10b) via exchange reactions of the precursor [1,2,4]thiadiazol-3-(2H)one derivatives (e.g., 6 and 9) with appropriately substituted nitriles (e.g., cyanogen bromide or p-toluenesulfonyl cyanide) under mild conditions is described. For example, the tricyclic 3-bromo [1,2,4]THD derivative (7a) underwent S(N)Ar substitution with a variety of nucleophiles, which included amines, malonate esters and alcohols. Likewise, the bicyclic 3-p-tosyl [1,2,4]THD (10b) was employed as a template in reaction with diamines, and the resulting substituted diamines (e.g., 12a or 12e) were further selectively derivatized at the N1 and/or N2 positions in a linear fashion. The X-ray crystal structure of the 3-methyl bicyclic [1,2,4]THD (21) was obtained, and selective methylation at the N1 position via a protection-alkylation-deprotection protocol, as illustrated in Scheme 6, was confirmed. Alternatively, a short convergent synthesis of N1-functionalized derivatives from the reaction of 10b with appropriately substituted secondary amines was also developed. Hence, these synthetic strategies were advantageously exploited to provide access to a variety of diversely derivatized 3-substituted fused-ring [1,2,4]thiadiazole derivatives.
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