Synthesis and comparison of in vitro dual anti-infective activities of novel naphthoquinone hybrids and atovaquone.
Bioorg Chem
; 114: 105118, 2021 09.
Article
in En
| MEDLINE
| ID: mdl-34216896
ABSTRACT
A principal factor that contributes towards the failure to eradicate leishmaniasis and tuberculosis infections is the reduced efficacy of existing chemotherapies, owing to a continuous increase in multidrug-resistant strains of the causative pathogens. This accentuates the dire need to develop new and effective drugs against both plights. A series of naphthoquinone-triazole hybrids was synthesized and evaluated in vitro against Leishmania (L.) and Mycobacterium tuberculosis (Mtb) strains. Their cytotoxicities were also evaluated, using the human embryonic kidney cell line (HEK-293). The hybrids were found to be non-toxic towards human cells and had demonstrated micromolar cellular antileishmanial and antimycobacterial potencies. Hybrid 13, i.e. 2-{[1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl]methoxy}naphthalene-1,4-dione was the most active of all. It was found with MIC90 0.5 µM potency against Mtb in a protein free medium, and with half-maxima inhibitory concentrations (IC50) of 0.81 µM and 1.48 µM against the infective promastigote parasites of L. donavani and L. major, respectively, with good selectivity towards these pathogens (SI 22 - 65). Comparatively, the clinical naphthoquinone, atovaquone, although less cytotoxic, was found to be two-fold less antimycobacterial potent, and six- to twelve-fold less active against leishmania. Hybrid 13 may therefore stand as a potential anti-infective hit for further development in the search for new antitubercular and antileishmanial drugs. Elucidation of its exact mechanism of action and molecular targets will constitute future endeavour.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Naphthoquinones
/
Atovaquone
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Leishmania
/
Mycobacterium tuberculosis
/
Antiprotozoal Agents
/
Antitubercular Agents
Limits:
Humans
Language:
En
Journal:
Bioorg Chem
Year:
2021
Type:
Article
Affiliation country:
South Africa