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Synthesis and efficacy of pyrvinium-inspired analogs against tuberculosis and malaria pathogens
- Source :
- Bioorganic & Medicinal Chemistry Letters. 30:127037
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- Herein, we report the synthesis and evaluation of pyrvinium-based antimalarial and antitubercular compounds. Pyrvinium is an FDA approved drug for the treatment of pinworm infection, and it has been reported to have antiparasitic and antimicrobial activities. Pyrvinium contains quinoline core coupled with pyrrole. We replaced the pyrrole with various aryl or heteroaryl substituents to generate pyrvinium analogs. The profiling of these compounds against malaria parasite P. falciparum 3D7 revealed analogs with better antimalarial activity than pyrvinium pamoate. Compound 14 and 16 showed IC50 of 23 nM and 60 nM against P. falciparum 3D7, respectively. These compounds were also effective against drug-resistant malaria parasite P. falciparum Dd2 with IC50 of 53 nM and 97 nM, respectively. The cytotoxicity against CHO-K1, HEK and NRK-49F cells revealed better selectivity index for these new analogs compared to pyrvinium. Additionally, this series of compounds showed activity against M. tuberculosis H37Rv; particularly compounds 10, 13, 14 and 16 showed equipotent antitubercular activity to that of pyrvinium pamoate. The compounds 14 and 16 should be taken forward as leads for further optimization.
- Subjects :
- Antiparasitic
medicine.drug_class
Plasmodium falciparum
Clinical Biochemistry
Antitubercular Agents
Pharmaceutical Science
Microbial Sensitivity Tests
Pharmacology
01 natural sciences
Biochemistry
Pyrvinium
Antimalarials
Pyrvinium Compounds
Structure-Activity Relationship
chemistry.chemical_compound
Pinworm infection
Parasitic Sensitivity Tests
Drug Discovery
medicine
Tuberculosis
Malaria, Falciparum
Cytotoxicity
Molecular Biology
IC50
Dose-Response Relationship, Drug
Molecular Structure
010405 organic chemistry
Chemistry
Organic Chemistry
Quinoline
Mycobacterium tuberculosis
Antimicrobial
medicine.disease
0104 chemical sciences
010404 medicinal & biomolecular chemistry
Molecular Medicine
Malaria
Subjects
Details
- ISSN :
- 0960894X
- Volume :
- 30
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Accession number :
- edsair.doi.dedup.....985d6b82193adf4ff1b265b499617420