title: Synthesis and evaluation of novel marine bromopyrrole alkaloid-based derivatives as potential antidepressant agents.
abstract: Herein, we report synthesis and screening of a series of twenty derivatives of bromopyrrole alkaloids with aroyl hydrazone feature for antidepressant activity by forced swim test (FST), tail suspension test (TST), and actophotometer method. The molecules were further evaluated for in vitro human MAO's inhibitory activities. The tested compounds exhibited moderate to good antidepressant activity compared with standard fluoxetine. Among these, most promising antidepressant derivatives 5b (%DID = 60.48), 5e (%DID = 59), and 5j (%DID = 74.86) reduced immobility duration of 50-70% at 30 mg/kg dose levels in FST. Further, derivative 5b, 5e, and 5j displayed good antidepressant activity with %DID value of 47.50, 46.62, and 52.49, respectively, in TST compared with standard fluoxetine (66.56% DID). Compound 5b showed high in vitro MAO-A potency and selectivity (Ki MAO-A (μM) = 2.4 ± 0.99, SI = 0.06) with promising pharmacological activity recognizing its potential as antidepressant lead candidate for further drug development. Study revealed that the presence of halogen atoms such as chlorine and fluorine at ortho- and/or para-position of phenyl ring and N-alkylation of pyrrole core is favored features for antidepressant activity.
authors.affiliation: Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa.
authors.forename: Rajesh A
authors.initials: RA
authors.lastname: Rane
authors.forename: Shital
authors.initials: S
authors.lastname: Napahde
authors.forename: Pavan Kumar
authors.initials: PK
authors.lastname: Bangalore
authors.forename: Niteshkumar U
authors.initials: NU
authors.lastname: Sahu
authors.forename: Nishant
authors.initials: N
authors.lastname: Shah
authors.forename: Yogesh A
authors.initials: YA
authors.lastname: Kulkarni
authors.forename: Kalyani
authors.initials: K
authors.lastname: Barve
authors.forename: Leena
authors.initials: L
authors.lastname: Lokare
authors.forename: Rajshekhar
authors.initials: R
authors.lastname: Karpoormath
mesh_terms: D000470:Alkaloids / Q000737:chemistry; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D059001:Aquatic Organisms; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D019417:Hindlimb Suspension; D006801:Humans; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry; D023382:Toxicity Tests, Acute
chemical_list: D000470:Alkaloids; D000928:Antidepressive Agents; D008996:Monoamine Oxidase Inhibitors; D011758:Pyrroles; D008995:Monoamine Oxidase
keywords: MAOs inhibitors; antidepressant activity; aroyl hydrazones; bromopyrrole alkaloids