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

摘要

Twenty novel pyrimidine derivatives were synthesized from 2,5-dichloro-3-acetylthienyl chalcones by reacting with guanidine HC1 in presence of KOH and ethanol under reflux for 6 h.Their structural characterizations were evaluated by ATR-FTIR,~1H NMR,~(13)C 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/rnL)against Mycobacterium tuberculosis H_(37)Rv(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(IC_(50)= 2.0 ±0.1 ug/mL)and compound 17 with 2”-pyrrolyl moiety(IC_(50)= 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 Etrlp/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.