PMID- 34358070
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210809
IS  - 1424-8247 (Print)
IS  - 1424-8247 (Electronic)
IS  - 1424-8247 (Linking)
VI  - 14
IP  - 7
DP  - 2021 Jul 5
TI  - Preclinical Studies in Anti-Trypanosomatidae Drug Development.
LID - 10.3390/ph14070644 [doi]
LID - 644
AB  - The trypanosomatid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania 
      are the causative agents of human African trypanosomiasis, Chagas Disease and 
      Leishmaniasis, respectively. These infections primarily affect poor, rural 
      communities in the developing world, and are responsible for trapping sufferers 
      and their families in a disease/poverty cycle. The development of new 
      chemotherapies is a priority given that existing drug treatments are problematic. 
      In our search for novel anti-trypanosomatid agents, we assess the 
      growth-inhibitory properties of >450 compounds from in-house and/or "Pathogen 
      Box" (PBox) libraries against L. infantum, L. amazonensis, L.braziliensis, T. 
      cruzi and T. brucei and evaluate the toxicities of the most promising agents 
      towards murine macrophages. Screens using the in-house series identified 17 
      structures with activity against and selective toward Leishmania: Compounds 
      displayed 50% inhibitory concentrations between 0.09 and 25 muM and had 
      selectivity index values >10. For the PBox library, ~20% of chemicals exhibited 
      anti-parasitic properties including five structures whose activity against L. 
      infantum had not been reported before. These five compounds displayed no toxicity 
      towards murine macrophages over the range tested with three being active in an in 
      vivo murine model of the cutaneous disease, with 100% survival of infected 
      animals. Additionally, the oral combination of three of them in the in vivo 
      Chagas disease murine model demonstrated full control of the parasitemia. 
      Interestingly, phenotyping revealed that the reference strain responds 
      differently to the five PBox-derived chemicals relative to parasites isolated 
      from a dog. Together, our data identified one drug candidate that displays 
      activity against Leishmania and other Trypanosomatidae in vitro and in vivo, 
      while exhibiting low toxicity to cultured mammalian cells and low in vivo acute 
      toxicity.
FAU - Perdomo, Cintya
AU  - Perdomo C
AD  - Laboratorio de Moleculas Bioactivas, Departamento de Ciencias Biologicas, CENUR 
      Litoral Norte, Universidad de la Republica, Paysandu 60000, Uruguay.
FAU - Aguilera, Elena
AU  - Aguilera E
AUID- ORCID: 0000-0002-1052-687X
AD  - Grupo de Quimica Organica Medicinal, Instituto de Quimica Biologica, Facultad de 
      Ciencias, Universidad de la Republica, Montevideo 11400, Uruguay.
FAU - Corvo, Ileana
AU  - Corvo I
AD  - Laboratorio de Moleculas Bioactivas, Departamento de Ciencias Biologicas, CENUR 
      Litoral Norte, Universidad de la Republica, Paysandu 60000, Uruguay.
FAU - Faral-Tello, Paula
AU  - Faral-Tello P
AD  - Institut Pasteur de Montevideo, Unidad de Biologia Molecular, Montevideo 11400, 
      Uruguay.
FAU - Serna, Elva
AU  - Serna E
AD  - Departamento de Medicina Tropical, Instituto de Investigaciones en Ciencias de la 
      Salud, Universidad Nacional de Asuncion, San Lorenzo 2169, Paraguay.
FAU - Robello, Carlos
AU  - Robello C
AD  - Institut Pasteur de Montevideo, Unidad de Biologia Molecular, Montevideo 11400, 
      Uruguay.
AD  - Departamento de Bioquimica, Facultad de Medicina, Universidad de la Republica, 
      Montevideo 11800, Uruguay.
FAU - Wilkinson, Shane R
AU  - Wilkinson SR
AUID- ORCID: 0000-0002-8474-1943
AD  - Queen Mary Pre-Clinical Drug Discovery Group, School of Biological and Chemical 
      Sciences, Queen Mary University of London, London E1 4NS, UK.
FAU - Yaluff, Gloria
AU  - Yaluff G
AUID- ORCID: 0000-0002-7568-4756
AD  - Departamento de Medicina Tropical, Instituto de Investigaciones en Ciencias de la 
      Salud, Universidad Nacional de Asuncion, San Lorenzo 2169, Paraguay.
FAU - Alvarez, Guzman
AU  - Alvarez G
AUID- ORCID: 0000-0001-8385-6100
AD  - Laboratorio de Moleculas Bioactivas, Departamento de Ciencias Biologicas, CENUR 
      Litoral Norte, Universidad de la Republica, Paysandu 60000, Uruguay.
LA  - eng
GR  - ID435/CSIC (Comision Sectorial de Investigacion Cientifica) I+D 2016/
PT  - Journal Article
DEP - 20210705
PL  - Switzerland
TA  - Pharmaceuticals (Basel)
JT  - Pharmaceuticals (Basel, Switzerland)
JID - 101238453
PMC - PMC8308625
OTO - NOTNLM
OT  - Pathogen box
OT  - anti-trypanosomatid
OT  - arylidene ketones
OT  - thiazolidene hydrazines
OT  - veterinary isolates
COIS- The authors declare no conflict of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript, or in the decision to publish the result.
EDAT- 2021/08/07 06:00
MHDA- 2021/08/07 06:01
PMCR- 2021/07/05
CRDT- 2021/08/06 17:18
PHST- 2021/06/02 00:00 [received]
PHST- 2021/06/28 00:00 [revised]
PHST- 2021/06/30 00:00 [accepted]
PHST- 2021/08/06 17:18 [entrez]
PHST- 2021/08/07 06:00 [pubmed]
PHST- 2021/08/07 06:01 [medline]
PHST- 2021/07/05 00:00 [pmc-release]
AID - ph14070644 [pii]
AID - pharmaceuticals-14-00644 [pii]
AID - 10.3390/ph14070644 [doi]
PST - epublish
SO  - Pharmaceuticals (Basel). 2021 Jul 5;14(7):644. doi: 10.3390/ph14070644.