Conversion of antibacterial quinolone drug levofloxacin to potent cytotoxic agents

Author:

Ahadi Hamideh1,Shokrzadeh Mohammad2,Hosseini‐khah Zahra3,Ghassemi Barghi Nasrin2ORCID,Ghasemian Majid4,Emami Saeed5ORCID

Affiliation:

1. Department of Medicinal Chemistry, Student Research Committee, Faculty of Pharmacy Mazandaran University of Medical Sciences Sari Iran

2. Department of Toxicology and Pharmacology, Faculty of Pharmacy Mazandaran University of Medical Sciences Sari Iran

3. Diabetes Research Center Mazandaran University of Medical Sciences Sari Iran

4. Department of Clinical Biochemistry, Faculty of Medicine Ahvaz Jundishapur University of Medical Sciences Ahvaz Iran

5. Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy Mazandaran University of Medical Sciences Sari Iran

Abstract

AbstractLevofloxacin, the optical S‐(‐) isomer of ofloxacin, is a broad‐spectrum antibacterial agent widely used to control various infections caused by Gram‐positive and Gram‐negative bacteria. While the COOH group is necessary for antibacterial activity, its modification can offer anticancer activity to the fluoroquinolone framework. Therefore, several levofloxacin carboxamides 11a‐j and 12 containing 5‐substituted‐1,3,4‐thiadiazole residue were synthesized and screened in vitro for their anticancer activity. The in vitro MTT viability assay revealed that the most compounds had significant activity against cancer cells MCF‐7, A549, and SKOV3. In particular, the 3‐chloro‐ and 4‐fluoro‐ benzyl derivatives (11b and 11h), with IC50 values of 1.69–4.76 μM were as potent as or better than doxorubicin. It should be noted that the mother quinolone levofloxacin showed no activity on the tested cancer cell lines. The SAR analysis demonstrated that the 3‐chloro or 4‐fluoro substituent on the S‐benzyl moiety had positive effect on the activity. Further in vitro evaluations of the most promising compounds 11b and 11h by flow cytometric analysis and comet test revealed the ability of compounds in the induction of apoptosis and blockage of the cell proliferation at the G1‐phase by nuclear fragmentation and DNA degradation in cancer cells. The obtained results demonstrated that the alteration of 6‐COOH functional group in the levofloxacin structure and conjugation with a proper heterocyclic pharmacophore is a good strategy to obtain new anticancer agents.

Funder

Mazandaran University of Medical Sciences

Publisher

Wiley

Subject

Health, Toxicology and Mutagenesis,Toxicology,Molecular Biology,Molecular Medicine,Biochemistry,General Medicine

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