A facile stereoselective synthesis of dispiro-indeno pyrrolidine/pyrrolothiazole-thiochroman hybrids and evaluation of their antimycobacterial, anticancer and AchE inhibitory activities

Chelliah Bharkavi; Sundaravel Vivek Kumar; Mohamed Ashraf Ali; Hasnah Osman; Shanmugam Muthusubramanian; Subbu Perumal

doi:10.1016/j.bmc.2016.09.044

A facile stereoselective synthesis of dispiro-indeno pyrrolidine/pyrrolothiazole-thiochroman hybrids and evaluation of their antimycobacterial, anticancer and AchE inhibitory activities

Bioorg Med Chem. 2016 Nov 15;24(22):5873-5883. doi: 10.1016/j.bmc.2016.09.044. Epub 2016 Sep 19.

Authors

Chelliah Bharkavi¹, Sundaravel Vivek Kumar¹, Mohamed Ashraf Ali², Hasnah Osman³, Shanmugam Muthusubramanian⁴, Subbu Perumal⁵

Affiliations

¹ Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai, Tamil Nadu 625 021, India.
² School of Chemical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia; New Drug Discovery Research, Department of Medicinal Chemistry, Sunrise University, Alwar, Rajasthan 301030, India.
³ School of Chemical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
⁴ Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai, Tamil Nadu 625 021, India. Electronic address: muthumanian2001@yahoo.com.
⁵ Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai, Tamil Nadu 625 021, India. Electronic address: subbu.perum@gmail.com.

PMID: 27687968
DOI: 10.1016/j.bmc.2016.09.044

Abstract

A facile stereoselective synthesis of novel dispiro indeno pyrrolidine/pyrrolothiazole-thiochroman hybrids has been achieved by 1,3-dipolar cycloaddition of azomethine ylides, generated in situ from ninhydrin and sarcosine/thiaproline, on a series of 3-benzylidenethiochroman-4-ones. The synthesised compounds were screened for their antimycobacterial, anticancer and AchE inhibition activities. Compound 4l (IC₅₀ 1.07μM) has been found to exhibit the most potent antimycobacterial activity compared to cycloserine (12 times), pyrimethamine (37 times) and ethambutol (IC₅₀ <1.56μM) and 6l (IC₅₀=2.87μM) is more active than both cycloserine (4 times) and pyrimethamine (12 times). Three compounds, 4a, 6b and 6i, display good anticancer activity against CCRF-CEM cell lines. Compounds 6g and 4g display maximum AchE inhibitory activity with IC₅₀ values of 1.10 and 1.16μmol/L respectively.

Keywords: 1,3-Dipolar cycloaddition; AchE inhibition; Azomethine ylides; CCRF-CEM; Dispiro heterocycles; M. tuberculosis H(37)Rv.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / metabolism*
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Chromones / chemistry
Chromones / pharmacology
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Indenes / chemistry
Indenes / pharmacology
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Mycobacterium tuberculosis / drug effects*
Pyrrolidines / chemistry
Pyrrolidines / pharmacology
Spiro Compounds / chemistry
Spiro Compounds / pharmacology
Stereoisomerism
Structure-Activity Relationship
Thiazoles / chemistry
Thiazoles / pharmacology

Substances

Anti-Bacterial Agents
Antineoplastic Agents
Cholinesterase Inhibitors
Chromones
Indenes
Pyrrolidines
Spiro Compounds
Thiazoles
Acetylcholinesterase
pyrrolidine