title: Synthesis and immunopotentiating activity of novel isoxazoline functionalized coumarins.
abstract: A novel series (13) of isoxazoline functionalized coumarins was synthesized through 1,3-dipolar cyclization of nitrile oxides with Allylated coumarins. Synthesis of effective and target selective immunostimulators through conjugation of diversely substituted isoxazolines and 7-hydroxycoumarins is the focus of the present article. The proposed synthetic scheme was observed to be highly regiospecific yielding attempted conjugates in good yield (>90%). Kinetic resolution of the racemates was carried out by employing lipase B from Candida antarctica (CALB). The synthesized compounds were screened in vitro and in vivo for their biological activities viz. toxicity and impact on splenocyte proliferation (T- and B-cell proliferation), antibody production (HA titre), delayed-type hypersensitivity reaction (DTH), T-cell subtypes (CD4 and CD8), cytokine production (IL-2, IFN-γ, and IL-4) and NO (macrophage) production. Our results establish that isoxazoline functionalized coumarins exhibit excellent immune potentiating activity especially compounds 2, 4 and 8 whose activity is more than that of Levimasole as standard. The structure activity relations are explained in light of the structural/functional aspects of tested compounds. To the best of our knowledge the presented work is first of its kind and is presaged to prove very useful for the design and synthesis of bis-heterocycle based novel, therapeutically selective and effective immunopotentiators.
authors.affiliation: Medicinal Chemistry Division, Indian Institute of Integrative Medicine, Jammu, India. Electronic address: tabsismail@gmail.com.
authors.forename: Tabasum
authors.initials: T
authors.lastname: Ismail
authors.affiliation: Department of Chemistry, Jamia Hamdard University, New Delhi, India.
authors.forename: Syed
authors.initials: S
authors.lastname: Shafi
authors.affiliation: Medicinal Chemistry Division, Indian Institute of Integrative Medicine, Jammu, India.
authors.forename: Swarn
authors.initials: S
authors.lastname: Singh
authors.affiliation: Medicinal Chemistry Division, Indian Institute of Integrative Medicine, Jammu, India.
authors.forename: Tabasum
authors.initials: T
authors.lastname: Sidiq
authors.affiliation: Medicinal Chemistry Division, Indian Institute of Integrative Medicine, Jammu, India.
authors.forename: Anamika
authors.initials: A
authors.lastname: Khajuria
authors.affiliation: Medicinal Chemistry Division, Indian Institute of Integrative Medicine, Jammu, India.
authors.forename: Abdul
authors.initials: A
authors.lastname: Rouf
authors.affiliation: Medicinal Chemistry Division, Indian Institute of Integrative Medicine, Jammu, India.
authors.forename: Mahipal
authors.initials: M
authors.lastname: Yadav
authors.affiliation: Medicinal Chemistry Division, Indian Institute of Integrative Medicine, Jammu, India.
authors.forename: Varma
authors.initials: V
authors.lastname: Saikam
authors.affiliation: Medicinal Chemistry Division, Indian Institute of Integrative Medicine, Jammu, India.
authors.forename: Parvinder Pal
authors.initials: PP
authors.lastname: Singh
authors.affiliation: Department of Chemistry, Jamia Hamdard University, New Delhi, India.
authors.forename: Mohammad Sarwar
authors.initials: MS
authors.lastname: Alam
authors.affiliation: Department of Chemistry, Guru Nanak Dev University, Amritsar, India.
authors.forename: Nasarul
authors.initials: N
authors.lastname: Islam
authors.affiliation: Department of Pharmaceutical Chemistry, Jamia Hamdard University, New Delhi, India.
authors.forename: Kalicharan
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Vaccine Immunology Laboratory, NPC Division, Indian Institute of Chemical Technology, Hyderabad, India. Electronic address: hmskumar@gmail.com.
authors.forename: Halmuthur Mahabalarao Sampath
authors.initials: HMS
authors.lastname: Kumar
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000187:drug effects; D002478:Cells, Cultured; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016207:Cytokines / Q000187:drug effects; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000188:drug therapy; D007107:Immune System / Q000187:drug effects; D007555:Isoxazoles / Q000737:chemistry; D008214:Lymphocytes / Q000187:drug effects; D013329:Structure-Activity Relationship; D000069436:Toxicological Phenomena / Q000187:drug effects
chemical_list: D000276:Adjuvants, Immunologic; D000906:Antibodies; D003374:Coumarins; D016207:Cytokines; D007555:Isoxazoles
keywords: 2-Isoxazoline; 7-Hydroxycoumarin; Bis-heterocycles; Immunopotentiation; Kinetic resolution