ABSTRACT
Sixteen new C-terminally modified analogues of 2, a previously described potent and selective AT2R ligand, were designed, synthesized and evaluated for their affinity to the AT2R receptor. The introduction of large, hydrophobic substituents was shown to be beneficial and the most active compound (17, Ki=8.5 µM) was over 12-times more potent than the lead compound 2.
Subject(s)
Isoleucine/chemical synthesis , Isoleucine/metabolism , Receptor, Angiotensin, Type 2/metabolism , Animals , Drug Evaluation, Preclinical/methods , HEK293 Cells , Humans , Ligands , Oligopeptides/chemical synthesis , Oligopeptides/metabolism , Protein Binding/physiology , SwineABSTRACT
To study P1-P3 macrocyclizations of previously reported tertiary-alcohol-comprising HIV-1 protease inhibitors (PIs), three new 14- and 15-member macrocyclic PIs were designed, synthesized by ring-closing metathesis, and evaluated alongside with 10 novel linear PIs. Cocrystallized complexes of the macrocyclic PIs and the HIV-1 protease are presented, analyzed, and discussed. The macrocyclic structures exhibited higher activities than the linear precursors with Ki and EC50 values down to 3.1 nM and 0.37 µM, respectively.
Subject(s)
Alcohols/chemistry , Drug Design , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacology , HIV Protease/metabolism , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacology , Chemistry Techniques, Synthetic , Crystallography, X-Ray , HIV Protease/chemistry , HIV Protease Inhibitors/chemistry , Macrocyclic Compounds/chemistry , Models, Molecular , Protein ConformationABSTRACT
Using Ttou 84 as starting point, a novel class of biphenyl derivatives of imidazo[1,2-a]pyridine and imidazo[1,2-b]pyridazine was designed to optimize the inhibitory properties on the replication of the bovine viral diarrhoea virus (BVDV) and hepatitis C virus (HCV). Three sites of pharmacomodulation were chosen i.e. positions 2, 3 and 6 on the central heterocyclic core structure. From the 49 analogues tested, only compound 18j (3-(2'-hydroxybiphen-3-yl)-2-(2-methoxyphenyl)-6-(thien-3-yl)imidazo[1,2-b]pyridazine) showed antiviral activity in the HCV replicon system reminiscent of selective inhibition (60-70% inhibition). Compound 4f (3-(biphen-3-yl)-2-(4-fluorophenyl)-6-phenylthioimidazo[1,2-a]pyridine) proved to be the most selective inhibitor of BVDV replication and showed no or only marginal cross-resistance with known inhibitors of pestivirus replication. The cross-resistance profile of 4f might indicate that 4f does not interact with the same binding site as BPIP, VP32947, AG110 or LZ37. From 42 analogues tested against both viruses, QSAR studies were discussed in regard to BVDV antiviral activity.
Subject(s)
Antiviral Agents/pharmacology , Diarrhea Viruses, Bovine Viral/drug effects , Hepacivirus/drug effects , Imidazoles/pharmacology , Pyridazines/pharmacology , Pyridines/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Dose-Response Relationship, Drug , Imidazoles/chemical synthesis , Imidazoles/chemistry , Microbial Sensitivity Tests , Molecular Structure , Pyridazines/chemical synthesis , Pyridazines/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Quantitative Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
The NorA efflux pump lowers intracellular fluoroquinolone concentrations by expelling antibiotics through the membrane of Staphylococcus aureus. We identified 3-aryl-4-methyl-2-quinolin-2-ones as compounds able to restore the activity of the NorA substrate, ciprofloxacin, against resistant S. aureus strains, and acting as efflux pump inhibitors (EPI). In particular, 5-hydroxy-7-methoxy-4-methyl-3-phenylquinolin-2-one (6 c) presents both an EPI and an antimicrobial effect. Its efficacy and safety make it a potential candidate for further investigations.
Subject(s)
Anti-Bacterial Agents/pharmacology , Quinolones/chemistry , Staphylococcus aureus/drug effects , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/toxicity , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/metabolism , Cell Line , Cell Survival/drug effects , Ciprofloxacin/pharmacology , Drug Resistance, Multiple, Bacterial , Humans , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Multidrug Resistance-Associated Proteins/metabolism , Quinolones/pharmacology , Quinolones/toxicity , Staphylococcus aureus/metabolismABSTRACT
The synthesis of original imidazo[1,2-a]pyridines bearing a thioether side chain at the 3 position and diversely substituted on the 6 or 8 position, and their antiviral activities are reported. From the synthesized compounds, the imidazo[1,2-a]pyridines bearing a 5 membered heterocycle (thiophene, furane or pyrrole) in the 6 position or a phenylthio group in the 6 or 8 position were the most potent against human cytomegalovirus (CMV) and varicella-zoster virus (VZV), whereas several other congeners, while less potent, were more selective in their inhibitory activity against VZV and CMV. These compounds showed similar activity against thymidine kinase competent (TK+) and deficient (TK-) VZV strains, demonstrating a mechanism of action independent of the viral thymidine kinase.
Subject(s)
Antiviral Agents/chemical synthesis , Cytomegalovirus/drug effects , Herpesvirus 3, Human/drug effects , Imidazoles/pharmacology , Pyridines/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Survival/drug effects , Cells, Cultured , Cytomegalovirus Infections/drug therapy , Herpes Zoster/drug therapy , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Lung/cytology , Lung/embryology , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
The synthesis of original imidazo[1,2-a]pyridines bearing a phenethylthiomethyl side chain at the 3 position and a (hetero)aryl substituent on the 6 or 8 position, and their antiviral activities are reported. From the synthesized compounds, the 6-halogeno and 6-phenylimidazo[1,2-a]pyridine derivatives 4c-d and 5b were the most potent against human cytomegalovirus (CMV) and/or varicella-zoster virus (VZV), whereas several other congeners (i.e., 5e, 5g, 5i, 5l, 5n, 5p, 5q, and 5t), while less potent, were equally or more selective in their inhibitory activity against both VZV and CMV. These compounds showed similar activity against thymidine kinase competent (TK(+)) and deficient (TK(-)) VZV strains, demonstrating a mechanism of action independent of the viral thymidine kinase.
