1,3-Oxazine-2-one derived dual-targeted molecules against replicating and non-replicating forms of Mycobacterium tuberculosis

Anand Babu Velappan; Dhanunjaya Kesamsetty; Dhrubajyoti Datta; Rui Ma; Natarajan Hari; Scott G Franzblau; Joy Debnath

doi:10.1016/j.ejmech.2020.112835

1,3-Oxazine-2-one derived dual-targeted molecules against replicating and non-replicating forms of Mycobacterium tuberculosis

Eur J Med Chem. 2020 Dec 15:208:112835. doi: 10.1016/j.ejmech.2020.112835. Epub 2020 Sep 13.

Authors

Anand Babu Velappan¹, Dhanunjaya Kesamsetty¹, Dhrubajyoti Datta², Rui Ma³, Natarajan Hari⁴, Scott G Franzblau³, Joy Debnath⁵

Affiliations

¹ Department of Chemistry, SCBT, SASTRA Deemed to Be University, Tamilnadu, 613401, India.
² Department of Chemistry, Indian Institute of Science Education and Research, Pune, Maharashtra, 411008, India.
³ Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St, Chicago, IL, 60612, USA.
⁴ NMR Laboratory, SCBT, SASTRA Deemed to Be University, Tamilnadu, 613401, India.
⁵ Department of Chemistry, SCBT, SASTRA Deemed to Be University, Tamilnadu, 613401, India. Electronic address: joydebnath@scbt.sastra.edu.

PMID: 32977201
DOI: 10.1016/j.ejmech.2020.112835

Abstract

The high mortality rate and increasing prevalence of resistant Mtb are the major concerns for the Tuberculosis (TB) treatment in this century. To curtail the prevalence of resistant Mtb, we have prepared 1,3-oxazine-2-one based dual targeted molecules. Compound 67 and 68 were found to be equally active against replicating and non-replicatiing form of Mtb (MIC_MABA 3.48 and 2.97 μg/ml; MIC_LORA 2.94 and 2.15 μg/ml respectively). They had found to suppress the biosynthesis of alfa, methoxy and keto-mycolate completely, as well as inhibit enzymatic activity of MenG (IC₅₀ = 9.11 and 6.25 μg/ml respectively for H37Ra; IC₅₀ = 11.76 and 10.88 μg/ml respectively for M smegmatis).

Keywords: 1,3-Oxazine-2-one; MenG enzyme; Mycobacterium tuberculosis; Mycolic acid.

MeSH terms

Antitubercular Agents / chemical synthesis
Antitubercular Agents / pharmacology*
Antitubercular Agents / toxicity
Bacterial Proteins / antagonists & inhibitors
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / toxicity
Leukocytes, Mononuclear / drug effects
Methyltransferases / antagonists & inhibitors
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium smegmatis / drug effects
Mycobacterium tuberculosis / drug effects*
Mycolic Acids / metabolism
Oxazines / chemical synthesis
Oxazines / pharmacology*
Oxazines / toxicity
Structure-Activity Relationship

Substances

Antitubercular Agents
Bacterial Proteins
Enzyme Inhibitors
Mycolic Acids
Oxazines
Methyltransferases