1,2,3-Dithiazoles – new reversible melanin synthesis inhibitors: a chemical genomics study

Abstract

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

Synthesis and Applications of 5‐Membered Chalcogen‐Nitrogen π‐Heterocycles with Three Heteroatoms

“…Substituted 5‐imino‐1,2,3‐dithiazoles were identified in a chemical genomic screen as compounds affecting the pigmentation of melanophores of the dorsal pigment stripe and the retinal pigment epithelium in developing Xenopus embryos. Unlike other compounds known to affect levels of melanophore pigmentation in vivo, some derivatives elicit a phenotype of severe pigment loss at extremely low doses (<10 μM), with higher doses being increasingly toxic …”

Evaluation of Substituted 1,2,3‐Dithiazoles as Inhibitors of the Feline Immunodeficiency Virus (FIV) Nucleocapsid Protein via a Proposed Zinc Ejection Mechanism

“…To develop novel therapeutic agents against the NCp of FIV, we used an in silico homology model derived from HIV‐1 and EIAV nucleocapsid proteins to explore heteroatom‐rich disulfide‐containing compounds, by building on our previous knowledge relating to bis[1,2]dithiolo[1,4]thiazines and bis[1,2]dithiolopyrrole derivatives and tetrathiocine derivatives . The 1,2,3‐diathiazole core caught our interest, as it has been shown to have a broad biological activity profile, including antibacterial, anticancer, antifungal/herbicidal, and anti‐melanin activities …”

“…[32] The 1,2,3-diathiazole core caught our interest, as it has been shown to have ab road biological activity profile, including antibacterial, [33][34][35] anticancer, [37][38] antifungal/herbicidal, [39][40][41][42][43] and anti-melanin activities. [44] The 1,2,3-dithiazole scaffold is stable and has the potential to be substituted at the C4 and C5 positions,w hile containing an electrophilicd isulfide bond. Substitutionsw ere made to explore the propensity of the disulfide to react with the cysteine thiolates of the NCp model.I nvestigationo ft he alignment and electronic distribution of the 1,2,3-dithiazole core led to as malls election of structurally diverse compounds, which were computationally modeled using density functional theory (DFT), and as malls election of compounds were then synthesized and tested ( Figure 2).…”

Antimicrobial and Antifungal Activity of Rare Substituted 1,2,3-Thiaselenazoles and Corresponding Matched Pair 1,2,3-Dithiazoles

“…The 1,2,3-dithiazole core has provided a number of interesting medicinal chemistry applications (Figure 1). In fact, 1,2,3-dithiazole scaffold has a broad biological activity profile which includes inhibition of cancer (1−3), [13][14][15] bacteria (4,5), [13,[16][17][18][19] fungus (6,7) [19][20][21][22][23][24], virus [25,26] and melanin [27]. Although not definitively proven in most cases it is thought that most of these activities have centered around a cysteine-activated nucleophilic attack.…”