download report - Istituto Pasteur

P a r t i c i p a n t s :
Marino Artico, Roberto Di Santo, Roberta Costi, professors;
Giuseppe La Regina, Rino Ragno, researchers;
Gabriella De Martino, post-doc fellow; Antonio Coluccia,
Francesco Piscitelli, PhD students.
C o l l a b o r a t i o n s :
Università di Roma Tor Vergata (Prof. Alberto Bergamini, Dr.
Chiara Ciaprini, Dr. Anna Sinistro); Istituto di Genetica
Molecolare, CNR, Pavia (Dr. Giovanni Maga, Dr. Emmanuele
Crespan); NCI at Bethesda, NIH, USA (Prof. Yves Pommier);
Rega Institute for Medical Research, K.U., Leuven, Belgium (Dr.
Jean Balzarini); Welsh School of Pharmacy, Cardiff University,
UK (Dr. Andrea Brancale, Dr. John Disson, Dr. Maria Chiara
Barbera); NCI at Frederick, NIH, Maryland, USA (Prof. Ernest
Hamel, Dr. Michael C. Edler).
Report of activity
Anti-HIV-1 Agents
Human immunodeficiency virus (HIV) is the etiological
agent of acquired immunodeficiency syndrome
(AIDS). More than 20 antiretroviral drugs
are available and fall into six classes: nucleoside and
nucleotide reverse transcriptase inhibitors (NRTIs),
non-nucleoside reverse transcriptase inhibitors
(NNRTIs), protease inhibitors (PIs), fusion
inhibitors (FIs), integrase inhibitors (INIs), and
CCR5 coreceptor antagonist. Three (recommended)
or four antiretroviral drugs are combined in the
highly active antiretroviral therapy (HAART) that
proved to be effective in reducing morbidity and
mortality of HIV-infected people. However,
HAART is unable to eradicate the viral infection;
the needed long-term or permanent treatments
favor the emergence of drug resistance, toxicity, and
unwanted side effects.
Principal investigator: Romano Silvestri
Professor of Medicinal Chemistry
Dipartimento di Chimica e Tecnologie del Farmaco
Tel: (+39) 06 49913800; Fax: (+39) 06 491491
romano.silvestri@uniroma1.it
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New antimicrobial and antiviral agents - AREA 6
Indole nucleus as a selected pharmacophore for the design of novel
highly potent anti-viral agents active against HIV-1 (RT and IN
inhibitors) and also capable to inhibit HCV and tumor cell replication
Non-Nucleoside Reverse Transcriptase
Inhibitors.
NNRTIs have received a huge attention because of
low toxicity and favorable pharmacokinetics properties,
being four NNRTIs approved for AIDS
treatment (nevirapine, delavirdine, efavirenz, and
etravirine). However, the emergence of drug
resistance remains a pressing problem. Our studies
on sulfone NNRTIs led to the development of
potent indolylarylsulfones (IASs). Continuing our
efforts to develop IASs with improved activity
against the viral mutants, we planned the synthesis
of new derivatives bearing two halogen atoms at
the indole ring. New IASs were obtained starting
from the appropriate ethyl pyruvate phenylhydrazone,
obtained according to the method of Japp-
Klingemann, that was treated with polyphosphoric
acid to furnish the corresponding ethyl 1H-indole-
2-carboxylate (Fischer’s indole synthesis).
Reaction of the indole ester with the appropriate
phenylthiosuccinimide in the presence of boron
trifluoride diethyl etherate afforded the corresponding
ethyl 3-(phenylthio)-1H-indole-2-carboxylate,
that was oxidated to sulfone and transformed
into carboxamide by treating with 3-chloroperoxybenzoic
acid and ammonium hydroxide, respectively.
IASs bearing the 4,5-difluoro or 5-chloro-4-fluoro
substitution pattern at the indole ring were
potent inhibitors of HIV-1 WT and the NNRTIresistant
strains Y181C and K103N-Y181C. These
compounds were highly effective against the 112
and the AB1 strains in lymphocytes and inhibited
at nanomolar concentration the multiplication of
the IIIBBa-L strain in macrophages. 5-Chloro-3-
(3,5-dimethylphenylsulfonyl)-4-fluoro-1H-indole-
2-carboxamide was exceptionally potent against
RT WT and RTs carrying the K103N, Y181I, and
L100I mutations. The synthesis of new derivatives
characterized by natural and unnatural aminoacids
at the 2-carboxamide and different electron-with-