Design of novel dispirooxindolopyrrolidine and dispirooxindolopyrrolothiazole derivatives as potential antitubercular agents.
With the aim to develop new potent antitubercular agents, a series of novel dispirooxindolopyrrolidines and dispirooxindolopyrrolothiazoles have been synthesized via a three-component 1,3-dipolar cycloaddition of (Z)-3-arylidenebenzofuran-2-ones, substituted isatin derivatives and α-aminoacids. The stereochemistry of the spiroadducts has been confirmed by an X-ray diffraction analysis. All the target heterocycles were evaluated for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain and the most active compounds were subjected to cytotoxicity studies against (RAW 264.7) cell lines. Among them, twelve compounds showed potent anti-tubercular activity with MIC ranging from 1.56 to 6.25 μg/mL. In particular dispirooxindolopyrrolothiazole derivatives 5c and 5f were found to be the most active (MIC of 1.56 μg/mL) with a good safety profile (27.53% and 20.74% at 50 μM, respectively). This is the first report demonstrating the benzofuranone oxindole hybrids as potential antimycobacterial agents.
Laboratory of Heterocyclic Chemistry Natural Products and Reactivity/CHPNR, Department of Chemistry, Faculty of Science of Monastir, 5000 Monastir, Tunisia.
Chourouk
C
Mhiri
Laboratory of Heterocyclic Chemistry Natural Products and Reactivity/CHPNR, Department of Chemistry, Faculty of Science of Monastir, 5000 Monastir, Tunisia.
Sarra
S
Boudriga
Laboratory of Heterocyclic Chemistry Natural Products and Reactivity/CHPNR, Department of Chemistry, Faculty of Science of Monastir, 5000 Monastir, Tunisia. Electronic address: moheddine.askri@fsm.rnu.tn.
Moheddine
M
Askri
Institut UTINAM UMR-CNRS 6213, Université de Franche-Comté, 16 Route de Gray, 25030 Besançon, France.
Michael
M
Knorr
Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, Andhra Pradesh, India.
Dharmarajan
D
Sriram
Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, Andhra Pradesh, India.
Perumal
P
Yogeeswari
UMR-SRSMC 7565, University of Lorraine, 1 boulevard Arago, 57070 Metz, Technopôle, France.
Frédéric
F
Nana
Anorganische Chemie, Technische Universität Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany.
Christopher
C
Golz
Anorganische Chemie, Technische Universität Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany.
Carsten
C
Strohmann
D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000995:Antitubercular Agents; D011759:Pyrrolidines; D013141:Spiro Compounds; D013844:Thiazoles
1,3-Dipolar cycloaddition; Antimycobacterial activity; Cytotoxicity; Dispirooxindolopyrrolidines; Dispirooxindolopyrrolothiazoles