A5033705171- HIV/AIDS drug development and treatment
- Biochemical and Molecular Research
- HIV Research and Treatment
- Hepatitis C virus research
- Quinazolinone synthesis and applications
- Synthesis and Reactivity of Heterocycles
- Hepatitis B Virus Studies
- Monoclonal and Polyclonal Antibodies Research
- Click Chemistry and Applications
- Histone Deacetylase Inhibitors Research
- Parasites and Host Interactions
- Chemical Synthesis and Analysis
- Parasite Biology and Host Interactions
- Synthesis and Biological Evaluation
- Trypanosoma species research and implications
- Synthetic Organic Chemistry Methods
- Peptidase Inhibition and Analysis
- Signaling Pathways in Disease
- Venomous Animal Envenomation and Studies
- Research on Leishmaniasis Studies
- Malaria Research and Control
- Analytical Chemistry and Chromatography
- Pharmacological Effects and Toxicity Studies
- Antimicrobial Peptides and Activities
- HIV-related health complications and treatments
IRBM Science Park
2004-2020
United States Military Academy
2007-2012
University of Würzburg
2008-2009
University of Messina
2008-2009
Institute of Molecular Biology and Pathology
2007
University of Siena
1998
Human immunodeficiency virus type-1 (HIV-1) integrase is one of the three virally encoded enzymes required for replication and therefore a rational target chemotherapeutic intervention in treatment HIV-1 infection. We report here discovery Raltegravir, first HIV-integrase inhibitor approved by FDA HIV It derives from evolution 5,6-dihydroxypyrimidine-4-carboxamides N-methyl-4-hydroxypyrimidinone-carboxamides, which exhibited potent inhibition catalyzed strand transfer process. Structural...
This paper describes the synthesis of a new class peptidomimetic cysteine protease inhibitors based on 1,4-benzodiazepine scaffold and an electrophilic vinyl sulfone moiety. The former was introduced internally to peptide sequence that mimics fragment d-Ser-Gly; latter built P1-P1′ site reacts as classical "Michael acceptor", leading alkylated enzyme by irreversible addition thiol group active cysteine. introduction moiety has been accomplished olefin cross-metathesis, powerful tool for...
A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using molecular modeling-derived strategy. Building on the profile previous clinical compounds and exploring linker regions series allowed for optimization broad genotype mutant enzyme potency, cellular activity, rat liver exposure following oral dosing. These studies led identification candidate 15 (MK-5172), which is active against 1-3 clinically relevant enzymes has good plasma...
This paper describes the synthesis and biological evaluation of a new class peptidomimetic falcipain-2 inhibitors based on 1,4-benzodiazepine scaffold combined with various α,β-unsaturated electrophilic functions such as vinyl-ketone, -amide, -ester, -nitrile. The profile reactivity this derivatives has been evaluated 4c, containing vinyl ester warhead, proved to be highly potent selective inhibitor.
Human immunodeficiency virus type-1 (HIV-1) integrase, one of the three constitutive viral enzymes required for replication, is a rational target chemotherapeutic intervention in treatment AIDS that has also recently been confirmed clinical setting. We report here on design and synthesis N-benzyl-5,6-dihydroxypyrimidine-4-carboxamides as class agents which exhibits potent inhibition HIV-integrase-catalyzed strand transfer process. In current study, structural modifications these molecules...
The human immunodeficiency virus type-1 (HIV-1) encodes three enzymes essential for viral replication: a reverse transcriptase, protease, and an integrase. latter is responsible the integration of genome into and, therefore, represents attractive target chemotherapeutic intervention against AIDS. A drug based on this mechanism has not yet been approved. Benzyl-dihydroxypyrimidine-carboxamides were discovered in our laboratories as novel metabolically stable class agents that exhibits potent...
HIV integrase is one of the three enzymes encoded by genome and essential for viral replication, but inhibitors as marketed drugs have just very recently started to emerge. In this study, we show evolution from N-methylpyrimidinone structure bicyclic pyrimidinones. Introduction a suitably substituted amino moiety modulated physical−chemical properties molecules conferred nanomolar activity in inhibition spread HIV-1 infection cell culture. An extensive SAR study led sulfamide (R)-22b, which...
The identification of a new series P. falciparum growth inhibitors is described. Starting from known human class I HDAC SAR exploration based on inhibitory activity in parasite and cells-based assays led to the compounds with submicromolar inhibition (EC50 < 500 nM) good selectivity over cells (up >50-fold). Inhibition parasital HDACs as mechanism action this selective supported by hyperacetylation studies.
Schistosomiasis, one of the most prevalent neglected parasitic diseases affecting humans and animals, is caused by Platyhelminthes genus Schistosoma. Schistosomes are only trematodes to have evolved sexual dimorphism constant pairing with a male essential for maturation female. Pairing required full development two major female organs, ovary vitellarium that involved in production different cell types such as oocytes vitellocytes, which represent core elements whole egg machinery. Sexually...
The application of class I HDAC inhibitors as cancer therapies is well established, but more recently their development for nononcological indications has increased. We report here on the generation improved selective human based an ethylketone zinc binding group (ZBG) in place hydroxamic acid that features majority inhibitors. also describe a novel set HDAC3 isoform show stronger potency and selectivity than most commonly used tool compound RGFP966. These compounds are again alternative ZBG...
Novel anti-schistosomal multi-stage drugs are needed because only a single drug, praziquantel, is available for the treatment of schistosomiasis and poorly effective on larval juvenile stages parasite. Schistosomes have complex life-cycle multiple developmental in intermediate definitive hosts. Acetylation deacetylation histones play pivotal roles chromatin structure regulation transcription eukaryotic cells. Histone deacetylase (HDAC) inhibitors modulate acetylation several other proteins...
Our laboratories recently reported the discovery of P2-P4 macrocyclic inhibitors HCV NS3/4A protease, characterized by high levels potency and liver exposure. Within this novel class inhibitors, we here describe identification a structurally diverse series compounds featuring 2-amino-1,3-thiazole as replacement carbamate in P4. Optimization studies focused on structural modifications P3, P2, P1 regions macrocycle well linker chain resulted several analogues excellent enzyme cellular...
19F-nuclear magnetic resonance (NMR) has been extensively used in a drug-discovery programme to support the selection of candidates for further development. Data on an early lead compound, N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (compound A (+)), and MK-0518 (N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide), potent inhibitor...
2-Phenyl-5,6-dihydroxypyrimidine-4-carboxylic acids were discovered as specific inhibitors of the NS5B polymerase Hepatitis C Virus. In-depth structure-activity investigations at ortho and meta positions phenyl ring undertaken, compounds with greatly improved activity over original lead have been discovered. Keywords: hcv ns5b rna polymerase, dihydroxypyrimidines, sar, inhibitors, amides, ureas
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