Design and Synthesis of New Potent<i>C</i><sub>2</sub>-Symmetric HIV-1 Protease Inhibitors. Use of<scp>l</scp>-Mannaric Acid as a Peptidomimetic Scaffold

Alterman, Mathias; Björsne, Magnus; Mühlman, Anna; Classon, Björn; Kvarnström, Ingemar; Danielson, U. Helena; Markgren, Per-Olof; Nillroth, Ulrika; Unge, Torsten; Hallberg, A.; Samuelsson, Bertil

doi:10.1021/jm970777b

Cited by 72 publications

(75 citation statements)

References 44 publications

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“…In the mid 1990s, we initiated a medicinal chemistry program aimed at developing potent HIV-1 inhibitors that should be inexpensive to prepare. The stereochemistry of l-mannitol was exploited, and in a short synthetic route, some highly potent C 2 -symmetric, C-terminally duplicated inhibitors with a central 1,2-dihydroxyethylene transition-state bioisostere were directly produced (e.g., inhibitors 1 and 2, Scheme 1) [43].…”

Section: Linear 12-dihydroxyethylene-based Inhibitorsmentioning

confidence: 99%

Controlled Microwave Heating as an Enabling Technology: Expedient Synthesis of Protease Inhibitors in Perspective

2007

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Since the early days of organic chemistry, oil baths, hot plates, metal blocks, and isomantles have been the heating devices of choice for driving chemical reactions. Over the last years, microwave heating has evolved as a well-demonstrated alternative to classic heating with the potential to emerge as the preferred heating method in organic synthesis. In this perspective, we will illustrate that microwave heating has an edge over conventional heating also in medicinal and high-throughput chemistry applications, enabling both an expanded reaction range and the diminishing of reaction times from many hours or days down to minutes. By focusing on the development of protease inhibitors, we present a series of successful lead optimizations starting from complex core structures and using controlled microwave heating as the energy source. In short, hundreds of protease inhibitors have been quickly synthesized under microwave irradiation since the start of our high-speed program back in 1998.

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Section: Linear 12-dihydroxyethylene-based Inhibitorsmentioning

confidence: 99%

Controlled Microwave Heating as an Enabling Technology: Expedient Synthesis of Protease Inhibitors in Perspective

2007

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“…168 In addition to the 2-hydroxyethylene scaffold, the L-mannaric scaffold has also proved to be a promising scaffold for the design of potent C2-symmetric HIV-1 protease inhibitors. 169 These diol-based HIV-1 protease inhibitors show excellent antiviral activity in cell culture, also in the presence of 40% human serum. 170 Their resistance profile, i.e., activity against HIV strains resistant to other peptidomimetic inhibitors of HIV protease remains to be determined.…”

Section: H I V P R O T E a S E I N H I B I T O R Smentioning

confidence: 99%

New anti‐HIV agents and targets

Clercq

2002

Medicinal Research Reviews

210

127

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Virtually all the compounds that are currently used or are subject of advanced clinical trials for the treatment of HIV infections, belong to one of the following classes: (i) nucleoside reverse transcriptase inhibitors (NRTIs): i.e., zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine and nucleotide reverse transcriptase inhibitors (NtRTIs) (i.e., tenofovir disoproxil fumarate); (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e., nevirapine, delavirdine, efavirenz, emivirine; and (iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir. In addition to the reverse transcriptase and protease reaction, various other events in the HIV replicative cycle can be considered as potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polycarboxylates, polyoxometalates, polynucleotides, and negatively charged albumins); (ii) viral entry, through blockade of the viral coreceptors CXCR4 (i.e., bicyclam (AMD3100) derivatives) and CCR5 (i.e., TAK-779 derivatives); (iii) virus-cell fusion, through binding to the viral envelope glycoprotein gp41 (T-20, T-1249); (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2'-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA)]; (v) proviral DNA integration, through integrase inhibitors such as 4-aryl-2,4-dioxobutanoic acid derivatives; (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (flavopiridol, fluoroquinolones). Also, various new NRTIs, NNRTIs, and PIs have been developed that possess, respectively: (i) improved metabolic characteristics (i.e., phosphoramidate and cyclosaligenyl pronucleotides by-passing the first phosphorylation step of the NRTIs), (ii) increased activity ["second" or "third" generation NNRTIs ( i.e., TMC-125, DPC-083)] against those HIV strains that are resistant to the "first" generation NNRTIs, or (iii), as in the case of PIs, a different, modified peptidic (i.e., azapeptidic (atazanavir)) or non-peptidic scaffold (i.e., cyclic urea (mozenavir), 4-hydroxy-2-pyrone (tipranavir)). Non-peptidic PIs may be expected to inhibit HIV mutant strains that have become resistant to peptidomimetic PIs.

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“…2 Some are also used for the treatment of HIV infection. [3][4][5] Several workers investigated the s-triazine nucleus in the scope of potential therapeutic agents for diseases due to bacteria [6][7][8][9] cancer, [10][11][12] antitumor [13][14] and malaria. [15][16] The above literature survey led us to consider the s-triazine nucleus as a possible scaffold.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and antimicrobial evaluation of s-triazinyl urea and thiourea derivatives

Kaswala¹,

Chikhalia²,

Shah³

et al. 2009

Arkivoc

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A series of urea and thiourea derivatives of s-triazine have been developed based on high yielding nucleophilic substitution of 2,4,6-trichloro-1,3,5-triazine by 4-hydroxy coumarin, cyclopropylamine and ammonia at suitable conditions. These were further treated with various substituted aryl isocyanate and aryl isothiocyanate. All the synthesized compounds were evaluated for their antibacterial activities against various Gram-positive and Gram-negative strains of bacteria. A few compounds showed good to superior in vitro antibacterial activity against S.aureus, B.subtilis, E.coli and P.aeruginosa respectively. The new synthesized compounds were characterized using IR, 1 H-NMR and elemental analysis.

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Design and Synthesis of New PotentC₂-Symmetric HIV-1 Protease Inhibitors. Use ofl-Mannaric Acid as a Peptidomimetic Scaffold

Cited by 72 publications

References 44 publications

Controlled Microwave Heating as an Enabling Technology: Expedient Synthesis of Protease Inhibitors in Perspective

Controlled Microwave Heating as an Enabling Technology: Expedient Synthesis of Protease Inhibitors in Perspective

New anti‐HIV agents and targets

Design, synthesis and antimicrobial evaluation of s-triazinyl urea and thiourea derivatives

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Design and Synthesis of New PotentC2-Symmetric HIV-1 Protease Inhibitors. Use ofl-Mannaric Acid as a Peptidomimetic Scaffold

Cited by 72 publications

References 44 publications

Controlled Microwave Heating as an Enabling Technology: Expedient Synthesis of Protease Inhibitors in Perspective

Controlled Microwave Heating as an Enabling Technology: Expedient Synthesis of Protease Inhibitors in Perspective

New anti‐HIV agents and targets

Design, synthesis and antimicrobial evaluation of s-triazinyl urea and thiourea derivatives

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Design and Synthesis of New PotentC₂-Symmetric HIV-1 Protease Inhibitors. Use ofl-Mannaric Acid as a Peptidomimetic Scaffold