Novel phenanthridine amide analogs as potential anti-leishmanial agents: In vitro and in silico insights.

Autor: Nandikolla A; Department of Chemistry, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Hyderabad 500078, Telangana, India., Srinivasarao S; Department of Chemistry, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Hyderabad 500078, Telangana, India., Karan Kumar B; Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Pilani 333031, Rajasthan. India., Murugesan S; Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Pilani 333031, Rajasthan. India., Aggarwal H; Department of Chemistry, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Hyderabad 500078, Telangana, India., Balaña-Fouce R; Department of Biomedical Sciences, University of León, 24071 León, Spain., Melcón-Fernandez E; Department of Biomedical Sciences, University of León, 24071 León, Spain., Pérez-Pertejo Y; Department of Biomedical Sciences, University of León, 24071 León, Spain., Chandra Sekhar KVG; Department of Chemistry, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Hyderabad 500078, Telangana, India. Electronic address: kvgc@hyderabad.bits-pilani.ac.in.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2021 Dec; Vol. 117, pp. 105414. Date of Electronic Publication: 2021 Oct 09.
DOI: 10.1016/j.bioorg.2021.105414
Abstrakt: In the current work, sixteen novel amide derivatives of phenanthridine were designed and synthesized using 9-fluorenone, 4-Methoxy benzyl amine, and alkyl/aryl acids. The characterization of the title compounds was performed using LCMS, elemental analysis, 1 HNMR, 13 CNMR and single crystal XRD pattern was also developed for compounds A8. All the final analogs were screened in vitro for anti-leishmanial activity against promastigote form of L. infantum strain. Among the tested analogs, four compounds (A-06, A-11, A-12, and A-15) exhibited significant anti-leishmanial activity with EC 50 value ranges from 8.9 to 21.96 μM against amastigote forms of tested L. infantum strain with SI ranges of 1.0 to 4.3. From the activity results it was found that A-11 was the most active compound in both promastigote and amastigotes forms with EC 50 values 8.53 and 8.90 µM respectively. In-silico ADME prediction studies depicted that the titled compounds obeyed Lipinski's rule of five as that of the approved marketed drugs. The predicted in-silico toxicity profile also confirmed that the tested compounds were non-toxic. Finally, molecular docking and molecular dynamics study was also performed for significantly active compound (A-11) in order to study it's putative binding pattern at the active site of the selected leishmanial trypanothione reductase target as well as to understand the stability pattern of target-ligand complex for 100 ns. Single crystal XRD of compound A-08 revealed that the compound crystallizes in monoclinic C2/c space group and showed interesting packing arrangements.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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