Pyrimidine sulfonylacetanilides with improved potency against key mutant viruses of HIV-1 by specific targeting of a highly conserved residue.
Based on molecular simulation, the etravirine-VRX-480773 hybrids previously disclosed by our group were optimized to yield novel pyrimidine sulfonylacetanilides 8 with improved activity against a panel of seven clinically relevant single and double mutant strains of HIV-1. The improvement in potency in this in vitro model of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits the reverse transcriptase (RT), and represents a remarkable step forward in the development of anti-HIV drugs.
Department of Chemistry, Fudan University, Shanghai 200433, PR China.
Zheng-Yong
ZY
Wan
Department of Chemistry, Fudan University, Shanghai 200433, PR China.
Jin
J
Yao
Department of Chemistry, Fudan University, Shanghai 200433, PR China; Institute of Biomedical Science, Fudan University, Shanghai 200433, PR China.
Tian-Qi
TQ
Mao
Department of Chemistry, Fudan University, Shanghai 200433, PR China.
Xin-Long
XL
Wang
Department of Chemistry, Fudan University, Shanghai 200433, PR China.
Hai-Feng
HF
Wang
Department of Chemistry, Fudan University, Shanghai 200433, PR China.
Wen-Xue
WX
Chen
Department of Chemistry, Fudan University, Shanghai 200433, PR China. Electronic address: ahredy@126.com.
Hong
H
Yin
Department of Chemistry, Fudan University, Shanghai 200433, PR China; Institute of Biomedical Science, Fudan University, Shanghai 200433, PR China. Electronic address: rfchen@fudan.edu.cn.
Fen-Er
FE
Chen
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
Erik
E
De Clercq
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
Dirk
D
Daelemans
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
Christophe
C
Pannecouque
D000083:Acetanilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017124:Conserved Sequence / Q000187:drug effects*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000083:Acetanilides; D019380:Anti-HIV Agents; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; C039632:thioacetanilide
Antiviral agent; Biological activity; Highly conserved residue; Molecular hybridization; Molecular simulation