PMID- 15185725
OWN - NLM
STAT- MEDLINE
DCOM- 20041124
LR  - 20170214
IS  - 0956-3202 (Print)
IS  - 0956-3202 (Linking)
VI  - 15
IP  - 2
DP  - 2004 Mar
TI  - Design and synthesis of novel dihydroxyindole-2-carboxylic acids as HIV-1 
      integrase inhibitors.
PG  - 67-81
AB  - In a search for new HIV-1 integrase (IN) inhibitors, we synthesized and evaluated 
      the biological activity of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) and a 
      series of its derivatives. These compounds were designed as conformationally 
      constrained analogues of the acrylate moiety of caffeic acid phenethyl ester 
      (CAPE). DHICA, an intermediate in the biosynthesis of melanins, was prepared as a 
      monomeric unit by a novel synthetic route. In order to perform coherent SAR 
      studies, two series of DHICA amides were synthesized. First, to validate the 
      utility of a previously identified three-point pharmacophore based on CAPE in 
      inhibitor design, we prepared a series of benzyl- or phenylethylamine substituted 
      derivatives lacking and containing hydroxyl groups. Second, dimers of DHICA 
      containing various aminoalkylamine linkers were also prepared with a goal to 
      increase potency. All compounds were tested against purified IN and the C65S 
      mutant in enzyme-based assays. They were also tested for cytotoxicity in an 
      ovarian carcinoma cell line and antiviral activity in HIV-1-infected CEM cells. 
      Seven compounds inhibited catalytic activities of purified IN with IC50 values 
      below 10 microM. Further computational docking studies were performed to 
      determine the title compounds' mode of interaction with the IN active site. The 
      residues K156, K159 and D64 were the most important for potency against purified 
      IN.
FAU - Sechi, Mario
AU  - Sechi M
AD  - Dipartimento Farmaco Chimico Tossicologico, Universita di Sassari, Sassari, 
      Italy. mario.sechi@uniss.it
FAU - Angotzi, Gianfranco
AU  - Angotzi G
FAU - Dallocchio, Roberto
AU  - Dallocchio R
FAU - Dessi, Alessandro
AU  - Dessi A
FAU - Carta, Fabrizio
AU  - Carta F
FAU - Sannia, Luciano
AU  - Sannia L
FAU - Mariani, Alberto
AU  - Mariani A
FAU - Fiori, Stefano
AU  - Fiori S
FAU - Sanchez, Tino
AU  - Sanchez T
FAU - Movsessian, Leah
AU  - Movsessian L
FAU - Plasencia, Carmen
AU  - Plasencia C
FAU - Neamati, Nouri
AU  - Neamati N
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Antivir Chem Chemother
JT  - Antiviral chemistry & chemotherapy
JID - 9009212
RN  - 0 (HIV Integrase Inhibitors)
RN  - 0 (Indoles)
RN  - 4790-08-3 (5,6-dihydroxy-2-indolylcarboxylic acid)
RN  - EC 2.7.7.- (HIV Integrase)
SB  - IM
MH  - Catalysis/drug effects
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Computer Simulation
MH  - Drug Design
MH  - Drug Evaluation, Preclinical
MH  - Female
MH  - HIV/drug effects
MH  - HIV Integrase/*drug effects
MH  - HIV Integrase Inhibitors/*chemical synthesis/chemistry/pharmacology
MH  - Humans
MH  - Indoles/*chemical synthesis/chemistry
MH  - Models, Molecular
MH  - Molecular Structure
MH  - Structure-Activity Relationship
EDAT- 2004/06/10 05:00
MHDA- 2004/12/16 09:00
CRDT- 2004/06/10 05:00
PHST- 2004/06/10 05:00 [pubmed]
PHST- 2004/12/16 09:00 [medline]
PHST- 2004/06/10 05:00 [entrez]
AID - 10.1177/095632020401500203 [doi]
PST - ppublish
SO  - Antivir Chem Chemother. 2004 Mar;15(2):67-81. doi: 10.1177/095632020401500203.