Sulfonamide derivatives containing dihydropyrazole moieties selectively and potently inhibit MMP-2/MMP-9: Design, synthesis, inhibitory activity and 3D-QSAR analysis.
New series of sulfonamide derivatives containing a dihydropyrazole moieties inhibitors of MMP-2/MMP-9 were discovered using structure-based drug design. Synthesis, antitumor activity, structure-activity relationship and optimization of physicochemical properties were described. In vitro the bioassay results revealed that most target compounds showed potent inhibitory activity in the enzymatic and cellular assays. Among the compounds, compound 3i exhibited the most potent inhibitory activity with IC50 values of 0.21 μM inhibiting MMP-2 and 1.87 μM inhibiting MMP-9, comparable to the control positive compound CMT-1 (1.26 μM, 2.52 μM). Docking simulation was performed to position compound 3i into the MMP-2 active site to determine the probable binding pose. Docking simulation was further performed to position compound 3i into the MMP-2 active site to determine the probable binding model the 3D-QSAR models were built for reasonable design of MMP-2/MMP-9 inhibitors at present and in future.
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
Xiao-Qiang
XQ
Yan
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
Zhong-Chang
ZC
Wang
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
Zhen
Z
Li
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
Peng-Fei
PF
Wang
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
Han-Yue
HY
Qiu
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
Long-Wang
LW
Chen
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
Xiao-Yuan
XY
Lu
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
Peng-Cheng
PC
Lv
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China. Electronic address: zhuhl@nju.edu.cn.
Hai-Liang
HL
Zhu
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
3D-QSAR; Anticancer; Docking; MMP-2/MMP-9; Sulfonamide derivatives