title: Synthesis and evaluation of anticancer and antiobesity activity of 1-ethoxy carbonyl-3,5-bis (3'-indolyl methylene)-4-pyperidone analogs.
abstract: A series of eleven novel bisindole derivatives were synthesized and screened for anticancer and antiobesity potentials in in vitro mode. The reaction of 1-ethoxy carbonyl 4-pyperidone 1a with indole-3-carboxaldehyde 1b in presence of catalytic amount of piperidine gave 2 which was N-alkylated with different benzyl halides in the presence of potassium carbonate to afford compounds 3a-3k in quantitative yields. Among the compounds tested for anticancer activity against different human cancer cell lines, 3f significantly inhibited HepG2 cell line (IC50 7.33 μM) when compared with standard doxorubicin (IC50 10.15 μM). Compounds 3e (IC50 2.75 μM), 3f (IC50 4.21 μM) and 3i (IC50 15.98 μM) showed better activity than the standard curcumin (IC50 23.54 μM) against A549 cell line. Also, among the synthesized compounds, 3g (IC50 14.89 μM), 3c (IC50 56.41 μM) and 3i (IC50 30.88 μM) have potentially inhibited enzyme lipase when compared to standard Orlistat (IC50 62.25 μM). In in silico docking assays, piperidones 3e, 3f, 3i, 3c and 3a showed higher binding affinity towards anti-cancer target of A549 (3e: -11.1, 3f: -10.3, 3c: -11.3, 3i: -11.2 kcal/mol), HepG2 (3f: -10.5 kcal/mol), HeLa (3d: -10.0 kcal/mol) and SKOV3 (3f: -8.4 kcal/mol) cell lines better than standard drug doxorubicin. Docking to lipase protein for compounds 3i, 3g and 3c showed scores of -11.1, -10.7 and -10.5 kcal/mol when compared to that of standard drug Orlistat with -6.9 kcal/mol.
authors.affiliation: Natural Product Chemistry, CSIR-Central Institute of Medicinal and Aromatic Plants-Research Centre, Boduppal, Hyderabad 500092, Telangana, India.
authors.forename: Komuraiah
authors.initials: K
authors.lastname: Buduma
authors.affiliation: Toxicology Unit, Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, Telangana, India.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Chinde
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, Telangana, India.
authors.forename: Anand Kumar
authors.initials: AK
authors.lastname: Dommati
authors.affiliation: Metabolic and Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India.
authors.forename: Pooja
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Metabolic and Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India.
authors.forename: Aparna
authors.initials: A
authors.lastname: Shukla
authors.affiliation: Natural Product Chemistry, CSIR-Central Institute of Medicinal and Aromatic Plants-Research Centre, Boduppal, Hyderabad 500092, Telangana, India.
authors.forename: K V N Satya
authors.initials: KVNS
authors.lastname: Srinivas
authors.affiliation: Natural Product Chemistry, CSIR-Central Institute of Medicinal and Aromatic Plants-Research Centre, Boduppal, Hyderabad 500092, Telangana, India.
authors.forename: Niranjana Kumar
authors.initials: NK
authors.lastname: Arigari
authors.affiliation: Metabolic and Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, Uttar Pradesh, India.
authors.forename: Feroz
authors.initials: F
authors.lastname: Khan
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, Telangana, India.
authors.forename: Ashok Kumar
authors.initials: AK
authors.lastname: Tiwari
authors.affiliation: Toxicology Unit, Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, Telangana, India.
authors.forename: Paramjit
authors.initials: P
authors.lastname: Grover
authors.affiliation: Natural Product Chemistry, CSIR-Central Institute of Medicinal and Aromatic Plants-Research Centre, Boduppal, Hyderabad 500092, Telangana, India. Electronic address: koteshkumarj@yahoo.com.
authors.forename: Kotesh Kumar
authors.initials: KK
authors.lastname: Jonnala
mesh_terms: D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008049:Lipase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D010881:Piperidones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010881:Piperidones; D008049:Lipase
keywords: Anticancer activity; Antiobesity activity; Bisindole; Docking studies; Pyperidone