Synthesis and Identification of Pentathiepin-Based Inhibitors of Sporothrix brasiliensis

doi:10.3390/antibiotics8040249

. 2019 Dec 3;8(4):249.

doi: 10.3390/antibiotics8040249.

Synthesis and Identification of Pentathiepin-Based Inhibitors of Sporothrix brasiliensis

Christopher R M Asquith¹, Ana C S Machado², Luisa H M de Miranda², Lidia S Konstantinova^{3

4}, Rodrigo Almeida-Paes⁵, Oleg A Rakitin^{3

4}, Sandro A Pereira²

Affiliations

¹ Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Laboratory of Clinical Research in Dermatozoonoses on Domestic Animals (LAPCLIN-DERMZOO), Evandro Chagas National Institute of Infectious Diseases (INI), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-360, Brazil.
³ Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia.
⁴ Nanotechnology Education and Research Center, South Ural State University, Lenina Ave. 76, 454080 Chelyabinsk, Russia.
⁵ Mycology Laboratory, INI, Fiocruz, Rio de Janeiro 21040-360, Brazil.

PMID: 31816950
PMCID: PMC6963766
DOI: 10.3390/antibiotics8040249

Synthesis and Identification of Pentathiepin-Based Inhibitors of Sporothrix brasiliensis

Christopher R M Asquith et al. Antibiotics (Basel). 2019.

. 2019 Dec 3;8(4):249.

doi: 10.3390/antibiotics8040249.

Authors

Christopher R M Asquith¹, Ana C S Machado², Luisa H M de Miranda², Lidia S Konstantinova^{3

4}, Rodrigo Almeida-Paes⁵, Oleg A Rakitin^{3

4}, Sandro A Pereira²

Affiliations

¹ Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Laboratory of Clinical Research in Dermatozoonoses on Domestic Animals (LAPCLIN-DERMZOO), Evandro Chagas National Institute of Infectious Diseases (INI), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro 21040-360, Brazil.
³ Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia.
⁴ Nanotechnology Education and Research Center, South Ural State University, Lenina Ave. 76, 454080 Chelyabinsk, Russia.
⁵ Mycology Laboratory, INI, Fiocruz, Rio de Janeiro 21040-360, Brazil.

PMID: 31816950
PMCID: PMC6963766
DOI: 10.3390/antibiotics8040249

Abstract

Sporothrix brasiliensis is the causative agent of zoonotic sporotrichosis in Brazil and is currently referred to as the most virulent species among those of clinical importance within the genus. Sporotrichosis is an emergent disease that has come to the forefront over two decades with a recent hot spot of sporotrichosis infection emerging in the state of Rio de Janeiro. The source of these infections is now at epidemic proportions with more than 4000 cases reported in Rio de Janeiro, Brazil, alone since 1998. We developed a focused library of a rare pentathiepin ring system and identified a potent substitution pattern that yielded compounds 21 and 22. These compounds were more potent than itraconazole which is the current standard of care for sporotrichosis.

Keywords: 1,2,3,4,5-pentathiepin; anti-fungal; sporotrichosis; sulfur heterocycle; varacin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Previously reported anti-fungal compounds.

**Figure 2**
Previously reported biologically active pentathiepin compounds.

**Scheme 1**
Synthesis route to pentathiepin derivatives: reagents and conditions. (a) 1,4-Diaza-bicyclo (2.2.2)octane (DABCO), S₂Cl₂, CHCl₃, 0 °C to rt; 48 h, reflux 2 h (**13,** 30% and **18,** 3%); (b) DABCO, S₂Cl₂, CHCl₃, 0 °C; 48 h (16, 36%; 19, 40% and 20, 62%); (c) DABCO, S₂Cl₂, CHCl₃, 20 °C; 48 h (21,18%; 23, 38% and 22,16%); (d) S₂Cl₂ (0.8 eq), CHCl₃, 0 °C; 48 h (24, 70%).

**Figure 3**
Growth of *Sporothrix brasiliensis* isolate 8584 treated with compound 24 at (A) 0.5 µg/mL (0.172 μM); (B) 0.25 µg/mL (0.086 μM); (C) 0.12 µg/mL (0.041 μM); (D) 0.06 µg/mL (0.020 μM); (E) 0.03 µg/mL (0.010 μM); (F) 0.015 µg/mL (0.005 μM).

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[1] Dias N.M., Oliveira M.M., Santos C., Zancope-Oliveira R.M., Lima N. Sporotrichosis caused by Sporothrix Mexicana, Portugal. Emerg. Infect. Dis. 2011;17:1975–1976. doi: 10.3201/eid1710.110737. - DOI - PMC - PubMed

[2] Dias N.M., Oliveira M.M., Santos C., Zancope-Oliveira R.M., Lima N. Sporotrichosis caused by Sporothrix Mexicana, Portugal. Emerg. Infect. Dis. 2011;17:1975–1976. doi: 10.3201/eid1710.110737. - DOI - PMC - PubMed

[3] Schenck B.R. On refractory subcutaneous abscesses casued by a fungus possibly related to the sporotricha. Bull. Johns Hopkins Hosp. 1898;93:286.

[4] Schenck B.R. On refractory subcutaneous abscesses casued by a fungus possibly related to the sporotricha. Bull. Johns Hopkins Hosp. 1898;93:286.

[5] Gremião I.D., Miranda L.H., Reis E.G., Rodrigues A.M., Pereira S.A. Zoonotic epidemic of sporotrichosis: Cat to human transmission. PLoS Pathog. 2017;13:e1006077. doi: 10.1371/journal.ppat.1006077. - DOI - PMC - PubMed

[6] Gremião I.D., Miranda L.H., Reis E.G., Rodrigues A.M., Pereira S.A. Zoonotic epidemic of sporotrichosis: Cat to human transmission. PLoS Pathog. 2017;13:e1006077. doi: 10.1371/journal.ppat.1006077. - DOI - PMC - PubMed

[7] Barros M.B., Schubach Ade O., do Valle A.C., Gutierrez Galhardo M.C., Conceição-Silva F., Schubach T.M., Reis R.S., Wanke B., Marzochi K.B., Conceição M. Cat-transmitted sporotrichosis epidemic in Rio de Janeiro, Brazil: Description of a series of cases. J. Clin. Infect. Dis. 2004;38:529–535. doi: 10.1086/381200. - DOI - PubMed

[8] Barros M.B., Schubach Ade O., do Valle A.C., Gutierrez Galhardo M.C., Conceição-Silva F., Schubach T.M., Reis R.S., Wanke B., Marzochi K.B., Conceição M. Cat-transmitted sporotrichosis epidemic in Rio de Janeiro, Brazil: Description of a series of cases. J. Clin. Infect. Dis. 2004;38:529–535. doi: 10.1086/381200. - DOI - PubMed

[9] Almeida-Paes R., de Oliveira M.M., Freitas D.F., do Valle A.C., Zancopé-Oliveira R.M., Gutierrez-Galhardo M.C. Sporotrichosis in Rio de Janeiro, Brazil: Sporothrix brasiliensis is associated with atypical clinical presentations. PLoS Negl. Trop. Dis. 2014;8:e3094. doi: 10.1371/journal.pntd.0003094. - DOI - PMC - PubMed

[10] Almeida-Paes R., de Oliveira M.M., Freitas D.F., do Valle A.C., Zancopé-Oliveira R.M., Gutierrez-Galhardo M.C. Sporotrichosis in Rio de Janeiro, Brazil: Sporothrix brasiliensis is associated with atypical clinical presentations. PLoS Negl. Trop. Dis. 2014;8:e3094. doi: 10.1371/journal.pntd.0003094. - DOI - PMC - PubMed

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Synthesis and Identification of Pentathiepin-Based Inhibitors of Sporothrix brasiliensis

Affiliations

Synthesis and Identification of Pentathiepin-Based Inhibitors of Sporothrix brasiliensis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

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Cited by

References

LinkOut - more resources

Full Text Sources