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Design, Synthesis and Biological Evaluation of Novel Heterocyclic Fluoroquinolone Citrate Conjugates as Potential Inhibitors of Topoisomerase IV: A Computational Molecular Modeling Study

Author(s):

Tejeswara Rao Allaka, Naresh Kumar Katari, Sreekantha B. Jonnalagadda, Vasavi Malkhed and Jaya Shree Anireddy*   Pages 1 - 20 ( 20 )

Abstract:


Background & Objective: A facile and efficient method for the synthesis of novel derivatives of FQ citrate conjugates with 1,2,4-triazoles and 1,3,4-oxadiazole scaffolds 8-11 using conventional as well as microwave irradiation methods was reported. Based on these original building blocks the new derivatives of 3, 7-disubstituted fluoroquinolones bearing the oxadiazolyl-triazole groups were obtained. These invaluable derivatives are of great interest in medicinal and pharmaceutical studies because of their important biological properties.

Methods: All the reactions were examined under conventional as well as microwave mediated conditions. The structures of obtained compounds were confirmed by 1H NMR, 13C NMR, IR HRMS spectroscopy and elemental analysis. The antibacterial, antifungal activity of these compounds was screened against Gram-positive, Gram-negative bacteria and fungal stains by agar well diffusion method. Cytotoxic assay of the title compounds was evaluated against cervical carcinoma cell line (HeLa) by using MTT assay. The crystal structure of Quinolone-DNA cleavage complex of type IV topoisomerase from S. pneumoniae (PDB ID: 3RAE) complex were obtained from the Protein Database (PDB, http://www.rcsb.org). Molecular properties prediction-drug likeness by Molinspiration and Molsoft software, lipophilicity and solubility parameters using Osiris program.

Results: A novel approach to the synthesis of benzylthio-1,2,4-triazole, 1,3,4-oxadiazoles core with regioisomeric norfloxacin citrate conjugates was developed. Among the title compounds 11b, 10a reveals pronounced activity against S. pneumoniae with minimum inhibitory concentrations 0.89, 0.96 mg/mL and MBCs of 2.95, 2.80 mg/mL respectively. Minimum fungicidal concentration (MFC) have been determined for each compound against two fungal strains. Compound 11b showed maximum anticancer activity against HeLa cell line with IC50 value 11.3 ± 0.41 comparable to standard drug DXN. For binding mode active site residues and docking energies (ΔG =-7.9 Kcal/mol) for ligand 9b exhibited highest hydrogen bonding (3.59274 A˚), Pi–Alkyl (5.14468 A˚) interactions with amino acid LEU479 of 3RAE protein. The compounds followed the Lipinski ‘Rule of five’ were synthesized for antimicrobial and anticancer screening as oral bioavailable drugs/leads. Maximum drug likeness model score 1.52, 1.41 was found for compounds 10d, 11b.

Conclusion: The present work, through simple synthetic approaches, led to the development of novel hybrids of fluoroquinolone containing citrate-triazole-oxadiazole pharmacophores that exhibited remarkable biological activities against different microorganisms and cell line. The compounds showed suitable drug like properties and are expected to present good bioavailability profile. An efficient combination of molecular modeling and biological activity provided an insight into QSAR guide lines that could aid in further development and optimization of the norfloxacin derivatives.

Keywords:

Citrate conjugates, Fluoroquinolone, Oxadiazolyl-Triazoles, Biological activities, Computational mutagenesis, Molecular docking studies

Affiliation:

Centre for Chemical Sciences and Technology, Institute of Science & Technology, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, Telangana 500085, Department of Chemistry, GITAM School of Technology, GITAM University, HTP campus, Rudraram, Medak, Telangana 502329, School of Chemistry & Physics, University of KwaZulu-Natal, Westville Campus, P Bag X 54001, Durban 4000, Department of Chemistry, University College of Science, Saifabad, Osmania University, Hyderabad, Telangana 500004, Centre for Chemical Sciences and Technology, Institute of Science & Technology, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, Telangana 500085



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