Bioisosteric replacement and scaffold hopping are powerful strategies in drug design useful for rationally modifying a hit compound towards novel lead therapeutic agents. Recently, we reported a series of thie- nopyrimidinones that compromise dynamics at the p66/p51 HIV-1 reverse transcriptase (RT)-associated Ribonuclease H (RNase H) dimer interface, thereby allosterically interrupting catalysis by altering the active site geometry. Although they exhibited good submicromolar activity, the isosteric replacement of the thio- phene ring, a potential toxicophore, is warranted. Thus, in this article, the most active 2-(3,4-dihydroxy- phenyl)-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one 1 was selected as the hit scaffold and several isosteric substitutions of the thiophene ring were performed. A novel series of highly active RNase H allo- steric quinazolinone inhibitors was thus obtained. To determine their target selectivity, they were tested against RT-associated RNA-dependent DNA polymerase (RDDP) and integrase (IN). Interestingly, none of the compounds were particularly active on (RDDP) but many displayed micromolar to submicromolar activity against IN.

Scaffold hopping and optimisation of 3’,4’-dihydroxyphenyl- containing thienopyrimidinones: synthesis of quinazolinone derivatives as novel allosteric inhibitors of HIV-1 reverse transcriptase-associated ribonuclease H

Tocco, Graziella;Esposito, Francesca;Caboni, Pierluigi;Laus, Antonio;Corona, Angela;Tramontano, Enzo
2020-01-01

Abstract

Bioisosteric replacement and scaffold hopping are powerful strategies in drug design useful for rationally modifying a hit compound towards novel lead therapeutic agents. Recently, we reported a series of thie- nopyrimidinones that compromise dynamics at the p66/p51 HIV-1 reverse transcriptase (RT)-associated Ribonuclease H (RNase H) dimer interface, thereby allosterically interrupting catalysis by altering the active site geometry. Although they exhibited good submicromolar activity, the isosteric replacement of the thio- phene ring, a potential toxicophore, is warranted. Thus, in this article, the most active 2-(3,4-dihydroxy- phenyl)-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one 1 was selected as the hit scaffold and several isosteric substitutions of the thiophene ring were performed. A novel series of highly active RNase H allo- steric quinazolinone inhibitors was thus obtained. To determine their target selectivity, they were tested against RT-associated RNA-dependent DNA polymerase (RDDP) and integrase (IN). Interestingly, none of the compounds were particularly active on (RDDP) but many displayed micromolar to submicromolar activity against IN.
2020
Bioisosters
HIV-1 virus
integrase
RNase H
RNase H allosteric inhibitors
Anti-HIV Agents
Catalytic Domain
Drug Design
HIV Reverse Transcriptase
Humans
Models, Molecular
Protein Binding
Protein Multimerization
Pyrimidinones
Quinazolinones
Reverse Transcriptase Inhibitors
Ribonuclease H, Human Immunodeficiency Virus
Structure-Activity Relationship
Thiophenes
Bioisosters; RNase H allosteric inhibitors; HIV-1 virus; RNase H; Integrase
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11584/299906
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