Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Sep 8:137:126-138.
doi: 10.1016/j.ejmech.2017.05.026. Epub 2017 May 10.

QSAR-driven design, synthesis and discovery of potent chalcone derivatives with antitubercular activity

Marcelo N Gomes  1 , Rodolpho C Braga  1 , Edyta M Grzelak  2 , Bruno J Neves  3 , Eugene Muratov  4 , Rui Ma  2 , Larry L Klein  2 , Sanghyun Cho  2 , Guilherme R Oliveira  5 , Scott G Franzblau  6 , Carolina Horta Andrade  7
Affiliations

QSAR-driven design, synthesis and discovery of potent chalcone derivatives with antitubercular activity

Marcelo N Gomes et al. Eur J Med Chem. .

Abstract

New anti-tuberculosis (anti-TB) drugs are urgently needed to battle drug-resistant Mycobacterium tuberculosis strains and to shorten the current 6-12-month treatment regimen. In this work, we have continued the efforts to develop chalcone-based anti-TB compounds by using an in silico design and QSAR-driven approach. Initially, we developed SAR rules and binary QSAR models using literature data for targeted design of new heteroaryl chalcone compounds with anti-TB activity. Using these models, we prioritized 33 compounds for synthesis and biological evaluation. As a result, 10 heteroaryl chalcone compounds (4, 8, 9, 11, 13, 17-20, and 23) were found to exhibit nanomolar activity against replicating mycobacteria, low micromolar activity against nonreplicating bacteria, and nanomolar and micromolar against rifampin (RMP) and isoniazid (INH) monoresistant strains (rRMP and rINH) (<1 μM and <10 μM, respectively). The series also show low activity against commensal bacteria and generally show good selectivity toward M. tuberculosis, with very low cytotoxicity against Vero cells (SI = 11-545). Our results suggest that our designed heteroaryl chalcone compounds, due to their high potency and selectivity, are promising anti-TB agents.

Keywords: Anti-TB agents; Chalcone; In silico design; Nitroaromatic compounds; QSAR; Tuberculosis.

PubMed Disclaimer

Figures

Figure 1
Figure 1
MMP analysis of molecular pairs of chalcones and chalcone-like compounds with anti-TB activity reported in the literature.
Figure 2
Figure 2
Derived SAR rules for chalcones with anti-TB activity. Modifications in blue shading increase the activity; with red – decrease the activity.
Scheme 1
Scheme 1
Synthesis of chalcones and chalcone-like derivatives. Reagents and conditions: (i) H2SO4 conc., AcOH, reflux, 100 °C, 4 – 24 h; (1) acetophenones, (2) nitrofuraldehyde or nitrothiophenecarboxaldehyde, (3–25) analogs nitrofurans or nitrotiophenes. (ii) 20% NaOH, EtOH, room temperature, 10 h; (1) acetophenones; (2) aromatics aldehydes; (26–35) phenyl analogs, furan or pyrrole.
See this image and copyright information in PMC

References

    1. Palmer BD, Sutherland HS, Blaser A, Kmentova I, Franzblau SG, Wan B, Wang Y, Ma Z, Denny Wa, Thompson AM. Synthesis and Structure-Activity Relationships for Extended Side Chain Analogues of the Antitubercular Drug (6 S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5 H-imidazo[2,1-b][1,3]oxazine (PA-824) J. Med. Chem. 2015;58:3036–3059. doi: 10.1021/jm501608q. - DOI - PubMed
    1. Martins F, Santos S, Ventura C, Elvas-Leitão R, Santos L, Vitorino S, Reis M, Miranda V, Correia HF, Aires-de-Sousa J, Kovalishyn V, Latino DaRS, Ramos J, Viveiros M. Design, synthesis and biological evaluation of novel isoniazid derivatives with potent antitubercular activity. Eur. J. Med. Chem. 2014;81:119–138. doi: 10.1016/j.ejmech.2014.04.077. - DOI - PubMed
    1. WHO. [accessed October 28, 2015];Global Tuberculosis 2015. 2015 http://www.who.int/tb/publications/global_report/en/
    1. Tang J, Yam W-C, Chen Z. Mycobacterium tuberculosis infection and vaccine development. Tuberculosis. 2016;98:30–41. doi: 10.1016/j.tube.2016.02.005. - DOI - PubMed
    1. Cole ST, Riccardi G. New tuberculosis drugs on the horizon. Curr. Opin. Microbiol. 2011;14:570–576. doi: 10.1016/j.mib.2011.07.022. - DOI - PubMed

MeSH terms