Synthesis, Properties, and Therapeutic Applications of Dithiazoles

Abstract

Dithiazoles encompass four distinct systems, with 1,2,3-dithiazole being one of them. These five-membered aromatic and planar heterocycles, comprising sulfur and nitrogen atoms, can exist in open- or closed-shell configurations, exhibiting both neutrality and cationic tendencies. Sulfur-rich S-heterocycles, such as 1,2,3-dithiazoles, hold a particular fascination within the realm of organic chemistry. This chapter offers an all-encompassing exploration of historical development, contemporary prospects, and captivating biological applications associated with 1,2,3-dithiazoles, an exceptional subset of S-heterocycles. 1,2,3-Dithiazoles, which are not found in nature, made their synthetic debut in 1957. The synthesis of “Appel’s salt” (4,5-dichloro-1,2,3-dithiazolium chloride) in 1985 played a pivotal role in advancing the field of 1,2,3-dithiazole chemistry. This compound can be readily prepared from chloroacetonitrile and disulfur dichloride. Recent innovations in dithiazole chemistry include the transformation of 1,2,3-dithiazoles into pyrazolo[3,4-d]thiazoles, pyridothiazoles, pyrido[2,3-d]pyrimidines, and the uncommon 1,2,4-dithiazine system (pyrazolo-[3,4-e][1,2,4]dithiazines and benzo[e][1,2,4]dithiazines). Despite being relatively underexplored in the realm of medicinal chemistry, 1,2,3-dithiazoles have exhibited notable potential as antifungals, herbicides, antibacterial agents, anticancer drugs, antivirals, antifibrotics, melanin inhibitors, and Arabidopsis gibberellin 2-oxidase inhibitors. In 2016, their antiviral activity was first reported, demonstrating promise against feline immunodeficiency virus (FIV) as an HIV model. Furthermore, these compounds showed efficacy against various cancer cell lines, notably breast, bladder, and prostate cancers, unveiling a path for further scaffold development. Despite remaining synthetic challenges, the 1,2,3-dithiazole scaffold presents a compelling avenue for diverse biomedical applications.