(3Z)-3-(2-[4-(aryl)-1,3-thiazol-2-yl]hydrazin-1-ylidene)-2,3-dihydro-1H-indol-2-one derivatives as dual inhibitors of HIV-1 reverse transcriptase.
The HIV-1 Reverse Transcriptase (RT) is a validated and deeply explored biological target for the treatment of AIDS. However, only drugs targeting the RT-associated DNA polymerase (DP) function have been approved for clinical use. We designed and synthesised a new generation of HIV-1 RT inhibitors, based on the (3Z)-3-(2-[4-(aryl)-1,3-thiazol-2-yl]hydrazin-1-ylidene)-2,3-dihydro-1H-indol-2-one scaffold. These compounds are active towards both RT-associated functions, DNA polymerase and ribonuclease H. The structure, biological activity and mode of action of the new derivatives have been investigated. In particular, the nature of the aromatic group in the position 4 of the thiazole ring plays a key role in the modulation of the activity towards the two RT-associated functions.
Department of Life and Environmental Sciences, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy.
Rita
R
Meleddu
Department of Life and Environmental Sciences, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy.
Simona
S
Distinto
Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, SS554, 09042 Monserrato, Cagliari, Italy.
Angela
A
Corona
Department of Life and Environmental Sciences, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy.
Giulia
G
Bianco
Department of Life and Environmental Sciences, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy.
Valeria
V
Cannas
Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, SS554, 09042 Monserrato, Cagliari, Italy.
Francesca
F
Esposito
Dipartimento di Scienze della Salute, Università Magna Graecia di Catanzaro, Campus "S. Venuta", Viale Europa, 88100 Catanzaro, Italy.
Anna
A
Artese
Dipartimento di Scienze della Salute, Università Magna Graecia di Catanzaro, Campus "S. Venuta", Viale Europa, 88100 Catanzaro, Italy.
Stefano
S
Alcaro
Department of Organic Chemistry, Semmelweis University, Hogyes Endre utca 7, H-1092 Budapest, Hungary.
Peter
P
Matyus
Department of Organic Chemistry, Semmelweis University, Hogyes Endre utca 7, H-1092 Budapest, Hungary.
Dora
D
Bogdan
Department of Life and Environmental Sciences, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy.
Filippo
F
Cottiglia
Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, SS554, 09042 Monserrato, Cagliari, Italy.
Enzo
E
Tramontano
Department of Life and Environmental Sciences, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy. Electronic address: maccione@unica.it.
Elias
E
Maccioni
D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D016914:Ribonuclease H / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry
D007211:Indoles; D018894:Reverse Transcriptase Inhibitors; D013844:Thiazoles; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D004259:DNA-Directed DNA Polymerase; D016914:Ribonuclease H
(3Z)-3-(2-[4-(aryl)-1,3-thiazol-2-yl]hydrazin-1-ylidene)-2,3-dihydro-1H-indol-2-ones; Antiviral agents; HIV-1; HIV-1 RT dual inhibitors; Molecular modelling; RNase H