The reactions of 2-, 3- and 4-aminopyridines with 4,5-dichloro-1,2,3-dithiazol-ium chloride (Appel salt) 4 to give N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-X-amines 1a (X = 2), 1g (X = 3) and 1k (X = 4) were optimized with respect to base, temperature and reaction time. Based on these conditions a total of thirteen [(dithiazol-ylidene)amino]azines 1a-m were prepared and fully characterized.
A chemical genomic screen of an in-house library of small molecule heterocycles was carried out using Xenopus laevis embryos. This led to the identification of N-IJ4-chloro-5H-1,2,3-dithiazol-5-ylidene)-4methoxyaniline (1c), which elicits loss of pigmentation in melanophores and the retinal pigment epithelium (RPE) of developing embryos, independent of the developmental stage of initial exposure. The phenotype was reversible, since pigmentation returned upon compound removal while analysis of neural crest cell markers (Pax7) and melanophore markers (Dct/Xtrp2) revealed that both neural crest precursors and fully differentiated melanophores were present in the dithiazole 1c treated embryos. A subsequent focused structure-activity relationship (SAR) study identified the more active dithiazole 4-benzyloxy-N-IJ4-chloro-5H-1,2,3-dithiazol-5-ylidene)-aniline (1l) and the need for a chlorine substituent at the dithiazole C-4 position. Both the initial chemical genomic screen and the focused SAR study highlighted the toxicity of (dithiazolylidene)aminoazines, and also of methoxyaniline (anisidine) analogues that hosted strong electron-withdrawing or electronegative substituents or acidic hydroxyl groups on the anisidine moiety.This study suggests that 1,2,3-dithiazoles can act as reversible melanin synthesis inhibitors, revealing a new biological activity for this class of compounds. The inhibition of melanin synthesis is medically relevant as a potential treatment for pigmentation disorders such as melasma.Med. Chem. Commun. This journal is
The thermolysis of several N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-n-amines (where n = 2, 3 and 4) gives a mixture of thiazolopyridine-2-carbonitriles in low to moderate yields. Introduction, by design, of a chlorine substituent at the C2 or C4 position of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-3-amine and other selected azines enables a BnEt(3)NI mediated ANRORC style ring transformation that provides fourteen heteroazine fused thiazole-2-carbonitriles in moderate to near quantitative yields. The synthesis described herein therefore provides a facile high yielding two-step route to heteroazine fused thiazole-2-carbonitriles starting from 4,5-dichloro-1,2,3-dithiazolium chloride (Appel salt) and ortho- or para-chloro substituted meta-aminoazines.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.