Synthetic Derivatives against Wild-Type and Non-Wild-Type Sporothrix brasiliensis: In Vitro and In Silico Analyses.

Vítor Francisco Ferreira,André Luis Souza Dos Santos,Lucas Martins Alcântara,Nathália Faria Reis,Helena Carla Castro,Débora Sena De Oliveira,Pãmella Antunes De Macêdo-Sales,Reinaldo Barros Geraldo,Daniel Tadeu Gomes Gonzaga,Fernando De Carvalho Da Silva,Lais Cavalcanti Dos Santos Velasco De Souza,Andréa Regina De Souza Baptista,Ricardo Luiz Dantas Machado

doi:10.3390/ph15010055

Abstract

Recently, the well-known geographically wide distribution of sporotrichosis in Brazil, combined with the difficulties of effective domestic feline treatment, has emphasized the pressing need for new therapeutic alternatives. This work considers a range of synthetic derivatives as potential antifungals against Sporothrix brasiliensis isolated from cats from the hyperendemic Brazilian region. Six S. brasiliensis isolates from the sporotrichotic lesions of itraconazole responsive or non-responsive domestic cats were studied. The minimum inhibitory concentrations (MICs) of three novel hydrazone derivatives and eleven novel quinone derivatives were determined using the broth microdilution method (M38-A2). In silico tests were also used to predict the pharmacological profile and toxicity parameters of these synthetic derivatives. MICs and MFCs ranged from 1 to >128 µg/mL. The ADMET computational analysis failed to detect toxicity while a good pharmacological predictive profile, with parameters similar to itraconazole, was obtained. Three hydrazone derivatives were particularly promising candidates as antifungal agents against itraconazole-resistant S. brasiliensis from the Brazilian hyperendemic region. Since sporotrichosis is a neglected zoonosis currently spreading in Latin America, particularly in Brazil, the present data can contribute to its future control by alternative antifungal drug design against S. brasiliensis, the most virulent and prevalent species of the hyperendemic context.

Highlights

Sporotrichosis is a post-traumatic implantation subcutaneous mycosis of worldwide occurrence and increasing incidence, especially in tropical and subtropical regions such asAsia and Latin America
The present work investigated S. brasiliensis isolates obtained from the lesions of domestic cats with sporotrichosis, clinically classified as responsive or non-responsive to treatment with itraconazole
Six clinical S. brasiliensis isolates were obtained from the lesions of cats with laboratoryconfirmed sporotrichosis

Summary

Introduction

Sporotrichosis is a post-traumatic implantation subcutaneous mycosis of worldwide occurrence and increasing incidence, especially in tropical and subtropical regions such asAsia and Latin America. Sporothrix brasiliensis is the most prevalent species in Brazil, directly related to the cat-transmitted zoonotic route [2,3]. The recent detection of feline and human patients with S. brasiliensiscaused sporotrichosis in Argentina [4,5,6] in addition to reports of zoonotic cases in other countries such as Paraguay and Panamá [7,8]. Suspected or possible cases were detected in Bolivia and Colombia, revealing its potential dissemination across South America [9]. One of the main challenges to be addressed is the occurrence of severe non-responsive forms of this mycosis in cats, in addition to recurrences and reinfections, characterizing zoonotic sporotrichosis as a matter of large relevance to public health [3,10]

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