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Drug screening using shape-based virtual screening and in vitro experimental models of cutaneous Leishmaniasis

Published online by Cambridge University Press:  07 October 2020

Camila Cardoso Santos ,
Marcos Meuser Batista ,
Asma Inam Ullah ,
Tummala Rama Krishna Reddy  and
Maria de Nazaré Correia Soeiro Open the ORCID record for Maria de Nazaré Correia Soeiro [Opens in a new window]
Camila Cardoso Santos
Affiliation:
Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), CEP21040-360, Rio de Janeiro, RJ, Brazil
Marcos Meuser Batista
Affiliation:
Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), CEP21040-360, Rio de Janeiro, RJ, Brazil
Asma Inam Ullah
Affiliation:
The Medicines Research Group, School of Health, Sport and Bioscience, College of Applied Health and Communities, University of East London, Stratford Campus, Water Lane, London, UK
Tummala Rama Krishna Reddy
Affiliation:
The Medicines Research Group, School of Health, Sport and Bioscience, College of Applied Health and Communities, University of East London, Stratford Campus, Water Lane, London, UK
Maria de Nazaré Correia Soeiro*
Affiliation:
Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), CEP21040-360, Rio de Janeiro, RJ, Brazil
*
Author for correspondence: Maria de Nazaré Correia Soeiro, E-mail: [email protected]
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Abstract

Cutaneous leishmaniasis (CL) is one of the most disregarded tropical neglected disease with the occurrence of self-limiting ulcers and triggering mucosal damage and stigmatizing scars, leading to huge public health problems and social negative impacts. Pentavalent antimonials are the first-line drug for CL treatment for over 70 years and present several drawbacks in terms of safety and efficacy. Thus, there is an urgent need to search for non-invasive, non-toxic and potent drug candidates for CL. In this sense, we have implemented a shape-based virtual screening approach and identified a set of 32 hit compounds. In vitro phenotypic screenings were conducted using these hit compounds to check their potential leishmanicidal effect towards Leishmania amazonensis (L. amazonensis). Two (Cp1 and Cp2) out of the 32 compounds revealed promising antiparasitic activities, exhibiting considerable potency against intracellular amastigotes present in peritoneal macrophages (IC50 values of 9.35 and 7.25 μm, respectively). Also, a sterile cidality profile was reached at 20 μm after 48 h of incubation, besides a reasonable selectivity (≈8), quite similarly to pentamidine, a diamidine still in use clinically for leishmaniasis. Cp1 with an oxazolo[4,5-b]pyridine scaffold and Cp2 with benzimidazole scaffold could be developed by lead optimization studies to enhance their leishmanicidal potency.

Keywords

Cutaneous leishmaniasisin vitro experimental chemotherapyLeishmania amazonensisshape-based virtual screening
Type
Research Article
Information
Parasitology , Volume 148 , Issue 1 , January 2021 , pp. 98 - 104
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Copyright
Copyright © The Author(s) 2020. Published by Cambridge University Press

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