1. Synthesis and efficacy of pyrvinium-inspired analogs against tuberculosis and malaria pathogens
- Author
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Puran Sigh Sijwali, Vagolu Siva Krishna, E. Vamshi Krishna, Gokulapriya Govindarajalu, Sunil Misra, Haridas B. Rode, Navin Adhikari, Dharmarajan Sriram, Vikas R. Gaikwad, and Uttam B. Karale
- 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 - 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.
- Published
- 2020