title: Synthesis of new secretory phospholipase A2-inhibitory indole containing isoxazole derivatives as anti-inflammatory and anticancer agents.
abstract: Secretory phospholipase A2 (sPLA2) is an important enzyme that plays a key role in various inflammatory diseases including cancer and its inhibitors have been developed as preventive or therapeutic agents. In the present study, a series of new indole containing isoxazole derivatives (10a-10o) is synthesized and evaluated for their sPLA2 inhibitory activities. All compounds (10a-10o) showed significant sPLA2 inhibition activities both in vitro and in vivo studies which is substantiated in in silico studies. Among all the tested compounds, 10o showed potent sPLA2 inhibition activity, that is comparable or more to ursolic acid (positive control). Further studies demonstrated that 10o showed in vitro antiproliferative activity when tested against MCF-7 breast and DU145 prostate cancer cells. Furthermore, compounds 10a-10o obeyed lipinsky's rule of 5 and suggesting druggable properties. The in vitro, in vivo and in silico results are encouraging and warrant pre-clinical studies to develop sPLA2-inhibitory compound 10o as novel therapeutic agent for various inflammatory disorders and several malignancies.
authors.affiliation: Centre for Research and Development, PRIST University, Thanjavur 613 403, Tamilnadu, India.
authors.forename: Srinivasa Rao
authors.initials: SR
authors.lastname: Pedada
authors.affiliation: Department of Biochemistry, Institute of Science, GITAM University, Visakhapatnam 530 045, Andhra Pradesh, India.
authors.forename: Nagendra Sastry
authors.initials: NS
authors.lastname: Yarla
authors.affiliation: Department of Chemistry, Arts, Commerce and Science College, Nandgaon 423 196, Maharashtra, India.
authors.forename: Pawan J
authors.initials: PJ
authors.lastname: Tambade
authors.affiliation: Toxinology/Toxicology and Drug Discovery Unit, Center for Emerging Technologies, Jain Global Campus, Jain University, Ramanagara 562 112, Karnataka, India.
authors.forename: Bhadrapura Lakkappa
authors.initials: BL
authors.lastname: Dhananjaya
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Larkin Health Sciences Institute, Miami, FL 33169, USA.
authors.forename: Anupam
authors.initials: A
authors.lastname: Bishayee
authors.affiliation: Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad 500 046, Telangana, India.
authors.forename: Kalle M
authors.initials: KM
authors.lastname: Arunasree
authors.affiliation: Department of Biotechnology, Sri Krishnadevaraya University, Anantapuramu 515 003, Andhra Pradesh, India.
authors.forename: Gundala Harold
authors.initials: GH
authors.lastname: Philip
authors.affiliation: Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad 500 046, Telangana, India; Department of Biotechnology, Sri Krishnadevaraya University, Anantapuramu 515 003, Andhra Pradesh, India.
authors.forename: Gangappa
authors.initials: G
authors.lastname: Dharmapuri
authors.affiliation: "GALLY" International Biomedical Research Consulting LLC, San Antonio, TX 78229, USA; School of Health Sciences and Healthcare Administration, University of Atlanta, E. Johns Crossing, #175, Johns Creek, GA 30097, USA; Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Russia.
authors.forename: Gjumrach
authors.initials: G
authors.lastname: Aliev
authors.affiliation: Pharmacology Division, University College of Pharmaceutical Sciences, Andhra University, Visakhapatnam 530003, Andhra Pradesh, India.
authors.forename: Swathi
authors.initials: S
authors.lastname: Putta
authors.affiliation: Department of Biochemistry, Sarada Vilas College, Mysore 570004, Karnataka, India. Electronic address: dr.gururaja@gmail.com.
authors.forename: Gururaja
authors.initials: G
authors.lastname: Rangaiah
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D017208:Rats, Wistar
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D007211:Indoles; D007555:Isoxazoles; D054497:Phospholipases A2, Secretory
keywords: Anti-inflammatory activity; Anticancer; Indole; Isooxazole; Secretory phospholipase A(2)