Antileishmanial activity of novel indolyl–coumarin hybrids: Design, synthesis, biological evaluation, molecular docking study and in silico ADME prediction

• Published in: Bioorganic & medicinal chemistry letters 2016-02, Vol.26 (3), p.829-835
• Main Authors: Sangshetti, Jaiprakash N., Kalam Khan, Firoz A., Kulkarni, Abhishek A., Patil, Rajendra H., Pachpinde, Amol M., Lohar, Kishan S., Shinde, Devanand B.
• Format: Article
• Language: English
• Subjects: Antileishmanial; Antioxidant; Antioxidants - chemistry; Antioxidants - metabolism; Antioxidants - pharmacology; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - metabolism; Antiprotozoal Agents - pharmacology; Binding Sites; Cell Survival - drug effects; Coumarins - chemical synthesis; Coumarins - chemistry; Coumarins - pharmacokinetics; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; HeLa Cells; Ho3+ doped CoFe2O4 nanoparticles; Humans; Indolyl–coumarin hybrids; Inhibitory Concentration 50; Leishmania - drug effects; Leishmania - enzymology; Molecular Docking Simulation; Molecular docking studies; Oxidoreductases - antagonists & inhibitors; Oxidoreductases - metabolism; Protein Structure, Tertiary; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - metabolism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.12.085

[Display omitted] In present work we have designed and synthesized total twelve novel 3-(3-(1H-indol-3-yl)-3-phenylpropanoyl)-4-hydroxy-2H-chromen-2-one derivatives 13(a–l) using Ho3+ doped CoFe2O4 nanoparticles as catalyst and evaluated for their potential antileishmanial and antioxidant activities. The compounds 13a, 13d and 13h were found to possess significant antileishmanial activity (IC50 value=95.50, 95.00 and 99.00μg/mL, respectively) when compared to the standard sodium stibogluconate (IC50=490.00μg/mL). The compounds 13a (IC50=12.40μg/mL), 13d (IC50=13.49μg/mL), 13g (IC50=13.24μg/mL) and 13l (IC50=13.74μg/mL) had shown good antioxidant activity when compared with standards butylated hydroxy toluene (IC50=16.5μg/mL) and ascorbic acid (IC50=12.8μg/mL). After performing molecular docking studies, it was found that compounds 13a and 13d had potential to inhibit pteridine reductase 1 enzyme. In silico ADME pharmacokinetic parameters had shown promising results and none of the synthesized compounds had violated Lipinski’s rule of five. Thus, suggesting that compounds from the present series can serve as important gateway for the design and development of new antileishmanial as well as antioxidant agent.