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Vol. 31 No. 6 (2019): Vol 31 Issue 6

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Novel Pyrimidine Derivatives from 2,5-Dichloro-3-acetylthienyl Chalcones as Antifungal, Antitubercular and Cytotoxic Agents: Design, Synthesis, Biological Activity and Docking Study

https://doi.org/10.14233/ajchem.2019.21747
Bontha Venkata Subrahmanya Lokesh
Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia; AU College of Pharmaceutical Sciences, Andhra University, Visakhapatnam-530003, India
Y. Rajendra Prasad
AU College of Pharmaceutical Sciences, Andhra University, Visakhapatnam-530003, India
Afzal Basha Shaik
Department of Pharmaceutical Sciences, Vignan Pharmacy College, Vadlamudi-522213, India

Corresponding Author(s) : Bontha Venkata Subrahmanya Lokesh

lokeshb@ucsiuniversity.edu.my; bvslk71@yahoo.com

Asian Journal of Chemistry, Vol. 31 No. 6 (2019): Vol 31 Issue 6

Abstract

Twenty novel pyrimidine derivatives were synthesized from 2,5-dichloro-3-acetylthienyl chalcones by reacting with guanidine HCl in presence of KOH and ethanol under reflux for 6 h. Their structural characterizations were evaluated by ATR-FTIR, 1H NMR, 13C NMR, mass spectroscopy. They were also screened for antifungal, antitubercular and cytotoxicity activities. They were displayed good antifungal activity (MIC = 32-125 μg/mL) against Aspergillus niger and Candida tropicalis fungal species except compound 15 with 4"-pyridinyl moiety (MIC = 8.00 μg/mL) being more potent. Compound 5 with 2",4"-dichlorophenyl moiety was shown with good antitubercular activity (MIC = 6.2 μg/mL) against Mycobacterium tuberculosis H37Rv (MTB) stain. They have also tested for in vitro cytotoxicity activity against DU-145 prostate cancer cell lines. In which the compound 15 with 4"-pyridinyl moiety (IC50 = 2.0 ± 0.1 μg/mL) and compound 17 with 2"-pyrrolyl moiety (IC50 = 6.0 ± 0.1 μg/mL) possess highly potent antiprostate cancer properties. The molecular docking was done with the crystalline structure of mitochondrial 2-enoyl thioester reductase Etr1p/Etr2p heterodimer from Candida tropicalis fungal species with compound 15 (-7.80 kcal/mol) and shown greater binding affinity than fluconazole (-7.60 kcal/mol). Docking was performed with protein crystalline structure (PDB ID: 2WEE) of Mycobacterium tuberculosis H37Rv (MTB) stain and among all, compound 5 was exhibited good binding affinity (-6.90 kcal/mol), compared to pyrazinamide (-4.10 kcal/mol). The protein crystalline structure of a mutant androgen receptor (AR) ligand-binding domain (LBD) (PDB file: 1GS4) was tested with compounds 15 and 17 (-7.60 and -8.20 kcal/mol). They were exhibited good binding properties compared to methotrexate (-5.10 kcal/mol). Hence, these novel pyrimidine compounds are as lead compounds as antifungal, antitubercular and cytotoxic agents.

Keywords

2,5-Dichloro-3-acetylthiophene Novel pyrimidines Antifungal activity Antitubercular activity Cytotoxicity
Subrahmanya Lokesh, B. V., Prasad, Y. R., & Shaik, A. B. (2019). Novel Pyrimidine Derivatives from 2,5-Dichloro-3-acetylthienyl Chalcones as Antifungal, Antitubercular and Cytotoxic Agents: Design, Synthesis, Biological Activity and Docking Study. Asian Journal of Chemistry, 31(6), 1212–1220. https://doi.org/10.14233/ajchem.2019.21747
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