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

Tuomo Laitinen,Antti Poso,Christopher R M Asquith,Oleg A Rakitin,Lidia S Konstantinova,Ilia V Baranovsky

doi:10.3390/antibiotics9070369

Abstract

We report our investigations into the underlying differences between 1,2,3-dithiazole and their ultra-rare counterpart, 1,2,3-thiaselenazole. This rare 1,2,3-thiaselenazole chemotype was afforded by sulfur extrusion and selenium insertion into the preconstructed 1,2,3-dithiazoles. We built a library of matched paired compounds to compare and contrast the two ring systems. This led to the development of both narrow and broad-spectrum antimicrobial compounds with sub-micro molar potency, limited to no toxicity and a further understanding of the transition state electronics through molecular simulations. We also identified the potent 4,5,6-trichlorocyclopenta[d][1,2,3]thiaselenazole 11a, for use against Candida albicans, Cryptococcus neoformans var. grubii, Staphylococcus aureus and Acinetobacter baumannii, all of which have limited clinical treatment options. The 1,2,3-thiaselenazole represents a new class of potential compounds for the treatment of a host of multi-resistant hospital derived infections.

Highlights

Despite the advances in antibiotics and antifungals in recent years, there is an ever-increasing resistance emerging, with a real need for innovative solutions to reduce the infection burden [1].Antimicrobial drugs can be divided into groups based on the mechanism of action
There are three major classes of antifungals currently used clinically for the treatment of invasive fungal infections [6]. This is compared to a plethora of options for bacterial infections [7]
These three classes include polyenes that sequester ergosterol which destabilizes the fungal cell membrane [8], and azoles that directly inhibit the biosynthesis of ergosterol, the major

Summary

Introduction

Antimicrobial drugs can be divided into groups based on the mechanism of action. These inhibitors include agents targeting protein synthesis, nucleic acid synthesis, cell wall synthesis, metabolic pathways and drugs that cause depolarization of the cell membrane [2,3]. There are three major classes of antifungals currently used clinically for the treatment of invasive fungal infections [6]. This is compared to a plethora of options for bacterial infections [7]. These three classes include polyenes that sequester ergosterol which destabilizes the fungal cell membrane [8], and azoles that directly inhibit the biosynthesis of ergosterol, the major

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Conclusion