Research on anti-HIV-1 agents. Part 2: Solid-phase synthesis, biological evaluation and molecular modeling studies of 2,5,6-trisubstituted-4(3H)-pyrimidinones targeting HIV-1 reverse transcriptase

Botta, Maurizio; Corelli, Federico; Maga, Giovanni; Manetti, Fabrizio; Renzulli, Michela L.; Spadari, Silvio

doi:10.1016/s0040-4020(01)00815-8

Cited by 44 publications

(18 citation statements)

References 33 publications

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“…In order to exploit the high flexibility of the pharmacophoric structure I, we became involved in the application of solid phase techniques for the development of combinatorial libraries. In a first note, 25 we reported the development of a flexible linker for the solid phase synthesis of different pyrimidinone derivatives (Scheme 1). The carbonate moiety used to attach the heterocyclic moiety to the solid support (Merrifield resin) can be selectively cleaved to afford compounds 7a-c.…”

Section: Towards New Anti-hiv Derivativesmentioning

confidence: 99%

Towards new methodologies for the synthesis of biologically interesting 6-substituted pyrimidines and 4(3H)-pyrimidinones

Petricci¹,

Mugnaini²,

Radi³

et al. 2006

Arkivoc

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The present paper describes the application of modern combinatorial and microwave assisted techniques for the lead discovery and optimization of novel non-nucleoside HIV-1-RT inhibitors. Starting from the parallel solid phase synthesis of highly substituted pyrimidinone derivatives, compound 12c was identified as interesting lead compound for further structure optimizations. The generation and screening of a small virtual combinatorial library led to the optimization of the lead structure 12c to give highly active derivatives (against HIV1-RT wild-type and mutant strains) in the nanomolar range. Moreover, a straightforward three-step parallel solution phase approach was developed for the generation of a small library of novel 4-dialkylamino-2-methylsulfonyl-6-vinylpyrimidines which were obtained in high yield after a simple ethyl acetate extraction with no need of further purification. Surprisingly, some of these derivatives showed a new competitive inhibition of HIV1-RT never reported in the literature for this class of compounds. Molecular modeling calculations were also performed to investigate the binding mode of all synthesized compounds onto the non-nucleoside reverse transcriptase inhibitor binding site and to rationalize the relationships between their chemical structure and activity.

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Section: Towards New Anti-hiv Derivativesmentioning

confidence: 99%

Towards new methodologies for the synthesis of biologically interesting 6-substituted pyrimidines and 4(3H)-pyrimidinones

Petricci¹,

Mugnaini²,

Radi³

et al. 2006

Arkivoc

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“…The preparation by solid phase synthesis starting from Merrifield resin of a small library of 2,6-disubstituted-and 2,5,6-trisubstituted-4(3H) pyrimidinones has been described by Botta and coworkers (Fig. (8)) [38]. The new pyrimidinones have been tested in vitro for their ability to Pascual et al used an other approach to generate a virtual library of 125 396 compounds by combining all fragments present in the published 180-compound family [34].…”

Section: Non-nucleoside Reverse Transcriptase Inhibitors (Nnrtis)mentioning

confidence: 99%

Combinatorial Chemistry as a Tool for Targeting Different Stages of the Replicative HIV-1 Cycle

Mugnaini¹,

Petricci²,

Corelli³

et al. 2005

CCHTS

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In the present era, acquired immunodeficiency syndrome (AIDS) is the most fatal disorder for which no completely successful chemotherapy has been developed so far. The pandemic spread of this disease has prompted an unprecedented scientific and clinical effort to understand and combat it. A number of targets has been identified to stop the replication of the virus at different stages of its life cycle: Reverse Transcriptase (RT), protease (PR) and CCR5 are the most promising targets. Although highly active antiretroviral therapy (HAART) has been effective in reducing the mortality and morbidity in recent years, adverse side effects of the chemotherapy, patient non-compliance and the development of viral resistance remain major problems. With the aim to find better drug candidates with minor adverse side effects in recent years, several groups have investigated combinatorial approaches for the generation of libraries of HIV PR inhibitors while only few contributions to the preparation of libraries of HIV Reverse Transcriptase (RT) and CCR5 inhibitors are available. This review summarizes the recent developments of combinatorial chemistry in this area.

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“…1 A number of synthetic pharmacophores based upon the pyrimidyl structure exhibit antibacterial, antimicrobial, anticancer, anti-HIV-1 and anti-rubella virus activities. 2 Among them, 2,4,6-triaminopyrimidine (TAP) (Fig. 1) is also an outstanding medicine raw material, which has been widely used to synthesize anti-cancer drugs, such as methotrexate and dyrenium.…”

Section: Introductionmentioning

confidence: 99%

Electrochemical Behavior and Voltammetric Determination of 2,4,6-Triaminopyrimidine at Glassy Carbon Electrode Modified with Multi-Walled Carbon Nanotubes/Nafion

et al. 2010

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Research on anti-HIV-1 agents. Part 2: Solid-phase synthesis, biological evaluation and molecular modeling studies of 2,5,6-trisubstituted-4(3H)-pyrimidinones targeting HIV-1 reverse transcriptase

Cited by 44 publications

References 33 publications

Towards new methodologies for the synthesis of biologically interesting 6-substituted pyrimidines and 4(3H)-pyrimidinones

Towards new methodologies for the synthesis of biologically interesting 6-substituted pyrimidines and 4(3H)-pyrimidinones

Combinatorial Chemistry as a Tool for Targeting Different Stages of the Replicative HIV-1 Cycle

Electrochemical Behavior and Voltammetric Determination of 2,4,6-Triaminopyrimidine at Glassy Carbon Electrode Modified with Multi-Walled Carbon Nanotubes/Nafion

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