Discovery of novel antitubercular agents: design, synthesis and insights into the binding interactions

Dharmarajsinh N. Rana^a*; Mahesh T. Chhabria^b; Nisha K. Shah^a; Pathik S. Brahmkshatriya^c

^a Department of Chemistry, Gujarat University, Ahmedabad; ^b Department of Pharmaceutical Chemistry, L M College of Pharmacy, Ahmedabad; ^c Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic and Center for Biomolecules and Complex Systems, Flemingovo na´m. 2, 166 10 Prague 6, Czech Republic

Email: drsynmedchem@gmail.com

Abstract:

Tuberculosis (TB) infection, caused by Mycobacterium tuberculosis, is the second major cause of death due to an infectious disease in adults worldwide with nine million new cases and close to 2.0 million deaths annually.¹  On top of this, the recent cases of totally drug-resistant tuberculosis have raised alarming concerns on the existing drug regimen implying urgent need to discover newer antitubercular agents with newer molecular mechanism of action.² In the present study, we designed and synthesized a series of novel substituted pyrazoline derivatives and evaluated them for their in vitro antitubercular  activity  against  both  the  viral  and  multidrug-resistant  tuberculosis  (MDR-TB) strains showed that most of the target compounds displayed potent activity in the range of MIC ~0.625 to 25 μg/mL.  Few compound were found to be equipotent to isoniazid against viral strain of MTB (MIC = 0.625 μg/mL). One of the compounds displayed better potency  than isoniazid against MDR-TB (MIC = 3.25 μg/mL).Molecular docking provided useful insights into the binding interactions of target compounds in the active site of enoyl-ACP reductase, the molecular target of isoniazid. The docked  compounds  occupied  the  same  hydrophobic  binding  pocket  and  interacted  mostly  by dispersion interactions with the neighboring residues Met103, Met155, Tyr158, Met199, Ile202, Ile215 and Leu218.

Keywords: Antitubercular, docking, benzoxazole, pyrazoline, enolyl-ACP reductase

References:

1.   Chhabria, M.; Patel, S.; Jani, M. Anti-Infect. Agents Med. Chem. 2010, 9, 59–103.

2.   Udwadia, Z. F.; Amale, R. A.; Ajbani, K. K.; Rodrigues, C. Clin. Infect. Dis. 2012, 54, 579–581.