Novel 1-[2-(diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles as HIV-1 non-nucleoside reverse transcriptase inhibitors. A structure-activity relationship investigation.
1-[2-(Diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles (DAMNIs) is a novel family of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) active at submicromolar concentration. Replacement of one phenyl ring of 1-[2-(diphenylmethoxy)ethyl]-2-methyl-5-nitroimidazole (4) with heterocyclic rings, such as 2-thienyl or 3-pyridinyl, led to novel DAMNIs with increased activity. In HIV-1 WT cell-based assay the racemic 1-{2-[alpha-(thiophen-2-yl)phenylmethoxy]ethyl}-2-methyl-5-nitroimidazole (7) (EC(50) = 0.03 microM) proved 5 times more active than compound 4. Docking experiments showed that the introduction of a chiral center would not affect the binding of both (R)-7 and (S)-7. The internal scoring function of the Autodock program calculated the same inhibition constant (K(i) = 7.9 nM) for the two enantiomers. Compounds 7 (ID(50) = 8.25 microM) were found more active than efavirenz (ID(50) = 25 microM) against the viral RT carrying the K103N mutation, suggesting for these compounds a potential use in efavirenz based anti-AIDS regimens.
Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università di Roma La Sapienza, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
Gabriella
G
De Martino
Giuseppe
G
La Regina
Alessandra
A
Di Pasquali
Rino
R
Ragno
Alberto
A
Bergamini
Chiara
C
Ciaprini
Anna
A
Sinistro
Giovanni
G
Maga
Emmanuele
E
Crespan
Marino
M
Artico
Romano
R
Silvestri
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D008958:Models, Molecular; D008968:Molecular Conformation; D019829:Nevirapine / Q000737:chemistry; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D009593:Nitroimidazoles; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D054303:HIV Reverse Transcriptase