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Phenotypic investigation of 4-nitrophenylacetyl- and 4-nitro-1H-imidazoyl-based compounds as antileishmanial agents

Published online by Cambridge University Press:  03 February 2022

Camila C. Santos ,
Huaisheng Zhang ,
Marcos M. Batista ,
Gabriel M. de Oliveira ,
Kelly C. Demarque ,
Natália L. da Silva ,
Otacílio C. Moreira ,
Ifedayo Victor Ogungbe  and
Maria de Nazaré Correia Soeiro Open the ORCID record for Maria de Nazaré Correia Soeiro [Opens in a new window]
Camila C. Santos
Affiliation:
Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), 21040-360 Rio de Janeiro, RJ, Brazil
Huaisheng Zhang
Affiliation:
Department of Chemistry, Jackson State University, Jackson, MS 39217-0510, USA
Marcos M. Batista
Affiliation:
Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), 21040-360 Rio de Janeiro, RJ, Brazil
Gabriel M. de Oliveira
Affiliation:
Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), 21040-360 Rio de Janeiro, RJ, Brazil
Kelly C. Demarque
Affiliation:
Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), 21040-360 Rio de Janeiro, RJ, Brazil
Natália L. da Silva
Affiliation:
Laboratory of Molecular Biology and Endemic Diseases, Oswaldo Cruz Institute (IOC/FIOCRUZ), 21040-360 Rio de Janeiro, RJ, Brazil
Otacílio C. Moreira
Affiliation:
Laboratory of Molecular Biology and Endemic Diseases, Oswaldo Cruz Institute (IOC/FIOCRUZ), 21040-360 Rio de Janeiro, RJ, Brazil
Ifedayo Victor Ogungbe*
Affiliation:
Department of Chemistry, Jackson State University, Jackson, MS 39217-0510, USA
Maria de Nazaré Correia Soeiro*
Affiliation:
Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), 21040-360 Rio de Janeiro, RJ, Brazil
*
Authors for correspondence: Ifedayo Victor Ogungbe, E-mail: ifedayo.v.ogungbe@jsums.edu; Maria de Nazaré Correia Soeiro, E-mail: soeiro@ioc.fiocruz.br
Authors for correspondence: Ifedayo Victor Ogungbe, E-mail: ifedayo.v.ogungbe@jsums.edu; Maria de Nazaré Correia Soeiro, E-mail: soeiro@ioc.fiocruz.br
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Abstract

Cutaneous leishmaniasis (CL) is a spectrum of clinical manifestations characterized by severe skin ulcerations that leads to social stigma. There are limited treatment options for CL, and the available drugs are becoming less efficacious due to drug resistance. More efficacious and safer antileishmanial drugs are needed. In this study, the biological effect of seven synthetically accessible nitroaromatic compounds was evaluated in vitro against amastigotes of Leishmania amazonensis, followed by in vivo evaluation using mouse models of CL. Two compounds (6 and 7) were active against amastigotes in vitro [half-maximal effective concentration (EC50): 4.57 ± 0.08 and 9.19 ± 0.68 μm, respectively], with selectivity indexes >50, and the other compounds were not selective. In vivo, compounds 6 and 7 (10 mg kg−1, twice a day for 14 days) failed to reduce skin lesion sizes and parasite loads determined by light microscopy of lesion imprints and quantitative polymerase chain reaction. Nevertheless, the in vitro leishmanicidal efficacy sustained their use as templates for nitroimidazole-based antileishmanial drug discovery programmes focusing on analogues with more suitable properties.

Keywords

Cutaneous leishmaniasisin vitro experimental chemotherapyin vivoLeishmania amazonensisshape-based virtual screening
Type
Research Article
Information
Parasitology , Volume 149 , Issue 4 , April 2022 , pp. 490 - 495
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Copyright
Copyright © The Author(s), 2022. Published by Cambridge University Press

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References

Alcântara, LM, Ferreira, TC, Gadelha, FR and Miguel, DC (2018) Challenges in drug discovery targeting TriTryp diseases with an emphasis on leishmaniasis. International Journal for Parasitology: Drugs and Drug Resistance 8, 430–439.Google ScholarPubMed
Alvar, J, Vélez, ID, Bern, C, Herrero, M, Desjeux, P, Cano, J, Jannin, J and de Boer, M (2012) Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE 7, e35671. doi: 10.1371/journal.pone.0035671CrossRefGoogle ScholarPubMed
Baileyid, F, Mondragon-Shem, K, Haines, LR, Olabi, A, Alorfi, A, Ruiz-Postigo, JA, Alvar, J, Hotez, P, Adams, ER, Vélez, ID, Al-Salem, W, Eaton, J, Acosta-Serrano, Á and Molyneux, DH (2019) Cutaneous leishmaniasis and co-morbid major depressive disorder: a systematic review with burden estimates. PLoS Neglected Tropical Diseases 13, 1–22.Google Scholar
Cardoso Santos, C, Meuser Batista, M, Inam Ullah, A, Rama Krishna Reddy, T and Soeiro, MdNC (2021) Drug screening using shape-based virtual screening and in vitro experimental models of cutaneous leishmaniasis. Parasitology 148, 98–104.10.1017/S0031182020001900CrossRefGoogle ScholarPubMed
Caridha, D, Vesely, B, Van Bocxlaer, K, Arana, B, Mowbray, CE, Rafati, S, Uliana, S, Reguera, R, Kreishman-Deitrick, M, Sciotti, R and Buffet, P (2019) Route map for the discovery and pre-clinical development of new drugs and treatments for cutaneous leishmaniasis. International Journal for Parasitology: Drugs and Drug Resistance 11, 106–117.Google ScholarPubMed
de Vries, HJC, Reedijk, SH and Schallig, HDFH (2015) Cutaneous leishmaniasis: recent developments in diagnosis and management. American Journal of Clinical Dermatology 16, 99–109.CrossRefGoogle ScholarPubMed
Drugs for Neglected Diseases Initiative (2020) Target product profile for cutaneous leishmaniasis. Retrieved from DNDi website: https://dndi.org/diseases/cutaneous-leishmaniasis/target-product-profile/ (accessed 30 January 2021).Google Scholar
Feitosa, LM, da Silva, ER, Hoelz, LVB, Souza, DL, Come, JAASS, Cardoso-Santos, C, Batista, MM, Soeiro, MDNC, Boechat, N and Pinheiro, LCS (2019) New pyrazolopyrimidine derivatives as Leishmania amazonensis arginase inhibitors. Bioorganic and Medicinal Chemistry 27, 3061–3069. doi: 10.1016/j.bmc.2019.05.026CrossRefGoogle ScholarPubMed
Gleeson, MP (2008) Generation of a set of simple, interpretable ADMET rules of thumb. Journal of Medicinal Chemistry 51, 817–834.CrossRefGoogle ScholarPubMed
Godinho, JLP, Simas-Rodrigues, C, Silva, R, Ürmenyi, TP, De Souza, W and Rodrigues, JCF (2012) Efficacy of miltefosine treatment in Leishmania amazonensis-infected BALB/c mice. International Journal of Antimicrobial Agents 39, 326–331.CrossRefGoogle ScholarPubMed
Katsuno, K, Burrows, JN, Duncan, K, van Huijsduijnen, RH, Kaneko, T, Kita, K, Mowbray, CE, Schmatz, D, Warner, P and Slingsby, BT (2015) Hit and lead criteria in drug discovery for infectious diseases of the developing world. Nature Reviews Drug Discovery 14, 751–758. doi: 10.1038/nrd4683CrossRefGoogle ScholarPubMed
Lainson, R, Shaw, JJ, Silveira, FT, de Souza, AAA, Braga, RR and Ishikawa, EAY (1994) The dermal leishmaniases of Brazil, with special reference to the eco-epidemiology of the disease in Amazonia. Memorias do Instituto Oswaldo Cruz 89, 435–443.10.1590/S0074-02761994000300027CrossRefGoogle Scholar
Martins, ALGP, Barreto, JA, Lauris, JRP and Martins, ACGP (2014) American tegumentary leishmaniasis: correlations among immunological, histopathological and clinical parameters. Anais Brasileiros de Dermatologia 89, 52–58.10.1590/abd1806-4841.20142226CrossRefGoogle ScholarPubMed
Mikus, J and Steverding, D (2000) A simple colorimetric method to screen drug cytotoxicity against Leishmania using the dye Alamar Blue®. Parasitology International 48, 265–269.10.1016/S1383-5769(99)00020-3CrossRefGoogle Scholar
Nagle, A, Biggart, A, Be, C, Srinivas, H, Hein, A, Caridha, D, Sciotti, RJ, Pybus, B, Kreishman-Deitrick, M, Bursulaya, B, Lai, YH, Gao, MY, Liang, F, Mathison, CJN, Liu, X, Yeh, V, Smith, J, Lerario, I, Xie, Y, Chianelli, D, Gibney, M, Berman, A, Chen, YL, Jiricek, J, Davis, LC, Liu, X, Ballard, J, Khare, S, Eggimann, FK, Luneau, A, Groessl, T, Shapiro, M, Richmond, W, Johnson, K, Rudewicz, PJ, Rao, SPS, Thompson, C, Tuntland, T, Spraggon, G, Glynne, RJ, Supek, F, Wiesmann, C and Molteni, V (2020) Discovery and characterization of clinical candidate LXE408 as a kinetoplastid-selective proteasome inhibitor for the treatment of leishmaniases. Journal of Medicinal Chemistry 63, 10773–10781.10.1021/acs.jmedchem.0c00499CrossRefGoogle ScholarPubMed
Okwor, I and Uzonna, J (2016) Social and economic burden of human leishmaniasis. American Journal of Tropical Medicine and Hygiene 94, 489–493.CrossRefGoogle ScholarPubMed
Pires, DEV, Blundell, TL and Ascher, DB (2015) pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. Journal of Medicinal Chemistry 58, 4066–4072.CrossRefGoogle ScholarPubMed
Ribeiro-Romão, RP, Saavedra, AF, Da-Cruz, AM, Pinto, EF and Moreira, OC (2016) Development of real-time PCR assays for evaluation of immune response and parasite load in golden hamster (Mesocricetus auratus) infected by Leishmania (Viannia) braziliensis. Parasites and Vectors 9, 1–12.CrossRefGoogle ScholarPubMed
Romanha, AJ, de Castro, SL, Soeiro, M, Lannes-Vieira, J, Ribeiro, I, Talvani, A, Bourdin, B, Blum, B, Olivieri, B, Zani, C, Spadafora, C, Chiari, E, Chatelain, E, Chaves, G, Calzada, JE, Bustamante, JM, Freitas-Junior, LH, Romero, LI, Bahia, MT, Lotrowska, M, Soares, M, Andrade, SG, Armstrong, T, Degrave, W and Andrade, ZdA (2010) In vitro and in vivo experimental models for drug screening and development for Chagas disease. Memorias do Instituto Oswaldo Cruz 105, 233–238.10.1590/S0074-02762010000200022CrossRefGoogle ScholarPubMed
Ruoti, M, Oddone, R, Lampert, N, Orué, E, Miles, MA, Alexander, N, Rehman, AM, Njord, R, Shu, S, Brice, S, Sinclair, B and Krentel, A (2013) Mucocutaneous leishmaniasis: knowledge, attitudes, and practices among Paraguayan communities, patients, and health professionals. Journal of Tropical Medicine, ID 538629. doi: 10.1155/2013/538629Google ScholarPubMed
Santos, CC, Lionel, JR, Peres, RB, Batista, MM, da Silva, PB, de Oliveira, GM, da Silva, CF, Batista, DGJ, Souza, SMO, Andrade, CH, Neves, BJ, Braga, RC, Patrick, DA, Bakunova, SM, Tidwell, RR and Soeiro, MdNC (2018) In vitro, in silico, and in vivo analyses of novel aromatic amidines against Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy 62, e02205-17.10.1128/AAC.02205-17CrossRefGoogle ScholarPubMed
Santos, CC, Zhang, H, Batista, MM, de Oliveira, GM, Demarque, KC, da Silva-Gomes, NL, Moreira, OC, Ogungbe, IV and Soeiro, MdNC (2020) In vitro and in vivo evaluation of an adamantyl-based phenyl sulfonyl acetamide against cutaneous leishmaniasis models of Leishmania amazonensis. Antimicrobial Agents and Chemotherapy 64, e01188-20.CrossRefGoogle ScholarPubMed
Van Bocxlaer, K, Caridha, D, Black, C, Vesely, B, Leed, S, Sciotti, RJ, Wijnant, GJ, Yardley, V, Braillard, S, Mowbray, CE, Ioset, JR and Croft, SL (2019) Novel benzoxaborole, nitroimidazole and aminopyrazoles with activity against experimental cutaneous leishmaniasis. International Journal for Parasitology: Drugs and Drug Resistance 11, 129–138.Google ScholarPubMed
Weisz, G (2006) Making medical history. Bulletin of the History of Medicine 80, 153–159.CrossRefGoogle Scholar
World Health Organization, Regional Office for the Eastern Mediterranean (2020) Infectious agent (s) WHO case definition incubation period communicability period epidemiology and risk factors Situation in countries affected by crisis in Syria. pp. 1–7.Google Scholar
Wyllie, S, Roberts, AJ, Norval, S, Patterson, S, Foth, BJ, Berriman, M, Read, KD and Fairlamb, AH (2016) Activation of bicyclic nitro-drugs by a novel nitroreductase (NTR2) in Leishmania. PLoS Pathogens 12, e1005971.10.1371/journal.ppat.1005971CrossRefGoogle Scholar
Zhang, H, Collins, J, Nyamwihura, R, Ware, S, Kaiser, M and Ogungbe, IV (2018) Discovery of a quinoline-based phenyl sulfone derivative as an antitrypanosomal agent. Bioorganic and Medicinal Chemistry Letters 28, 1647–1651.CrossRefGoogle ScholarPubMed
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