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1.
Comput Biol Chem ; 89: 107372, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32911432

ABSTRACT

The SARS-CoV-2 virus is causing COVID-19 resulting in an ongoing pandemic with serious health, social, and economic implications. Much research is focused in repurposing or identifying new small molecules which may interact with viral or host-cell molecular targets. An important SARS-CoV-2 target is the main protease (Mpro), and the peptidomimetic α-ketoamides represent prototypical experimental inhibitors. The protease is characterised by the dimerization of two monomers each which contains the catalytic dyad defined by Cys145 and His41 residues (active site). Dimerization yields the functional homodimer. Here, our aim was to investigate small molecules, including lopinavir and ritonavir, α-ketoamide 13b, and ebselen, for their ability to interact with the Mpro. The sirtuin 1 agonist SRT1720 was also used in our analyses. Blind docking to each monomer individually indicated preferential binding of the ligands in the active site. Site-mapping of the dimeric protease indicated a highly reactive pocket in the dimerization region at the domain III apex. Blind docking consistently indicated a strong preference of ligand binding in domain III, away from the active site. Molecular dynamics simulations indicated that ligands docked both to the active site and in the dimerization region at the apex, formed relatively stable interactions. Overall, our findings do not obviate the superior potency with respect to inhibition of protease activity of covalently-linked inhibitors such as α-ketoamide 13b in the Mpro active site. Nevertheless, along with those from others, our findings highlight the importance of further characterisation of the Mpro active site and any potential allosteric sites.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Coronavirus Protease Inhibitors/pharmacology , Protein Multimerization/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Small Molecule Libraries/pharmacology , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Azoles/chemical synthesis , Azoles/chemistry , Azoles/pharmacology , Coronavirus 3C Proteases/metabolism , Coronavirus Protease Inhibitors/chemical synthesis , Coronavirus Protease Inhibitors/chemistry , Humans , Isoindoles , Ligands , Lopinavir/chemical synthesis , Lopinavir/chemistry , Lopinavir/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Organoselenium Compounds/chemical synthesis , Organoselenium Compounds/chemistry , Organoselenium Compounds/pharmacology , Ritonavir/chemical synthesis , Ritonavir/chemistry , Ritonavir/pharmacology , SARS-CoV-2/metabolism , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry
2.
Nanomedicine ; 25: 102172, 2020 04.
Article in English | MEDLINE | ID: mdl-32061722

ABSTRACT

We introduce the use of laser ablation to develop a multi-drug encapsulating theranostic nanoformulation for HIV-1 antiretroviral therapy. Laser ablated nanoformulations of ritonavir, atazanavir, and curcumin, a natural product that has both optical imaging and pharmacologic properties, were produced in an aqueous media containing Pluronic® F127. Cellular uptake was confirmed with the curcumin fluorescence signal localized in the cytoplasm. Formulations produced with F127 had improved water dispersibility, are ultrasmall in size (20-25 nm), exhibit enhanced cellular uptake in microglia, improve blood-brain barrier (BBB) crossing in an in vitro BBB model, and reduce viral p24 by 36 fold compared to formulations made without F127. This work demonstrates that these ultrasmall femtosecond laser-ablated nanoparticles are effective in delivering drugs across the BBB for brain therapy and show promise as an effective method to formulate nanoparticles for brain theranostics, reducing the need for organic solvents during preparation.


Subject(s)
Drug Compounding , HIV Infections/drug therapy , Nanoparticles/chemistry , Theranostic Nanomedicine/trends , Atazanavir Sulfate/chemical synthesis , Atazanavir Sulfate/chemistry , Atazanavir Sulfate/pharmacology , Blood-Brain Barrier/drug effects , Curcumin/chemical synthesis , Curcumin/chemistry , Curcumin/pharmacology , Drug Carriers/chemical synthesis , Drug Carriers/chemistry , Drug Carriers/pharmacology , HIV Infections/virology , HIV-1/drug effects , HIV-1/pathogenicity , Humans , Laser Therapy , Nanoparticles/therapeutic use , Precision Medicine , Ritonavir/chemical synthesis , Ritonavir/chemistry , Ritonavir/pharmacology
3.
J Enzyme Inhib Med Chem ; 35(1): 629-638, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32037904

ABSTRACT

Phialophora verrucosa causes several fungal human diseases, mainly chromoblastomycosis, which is extremely difficult to treat. Several studies have shown that human immunodeficiency virus peptidase inhibitors (HIV-PIs) are attractive candidates for antifungal therapies. This work focused on studying the action of HIV-PIs on peptidase activity secreted by P. verrucosa and their effects on fungal proliferation and macrophage interaction. We detected a peptidase activity from P. verrucosa able to cleave albumin, sensitive to pepstatin A and HIV-PIs, especially lopinavir, ritonavir and amprenavir, showing for the first time that this fungus secretes aspartic-type peptidase. Furthermore, lopinavir, ritonavir and nelfinavir reduced the fungal growth, causing remarkable ultrastructural alterations. Lopinavir and ritonavir also affected the conidia-macrophage adhesion and macrophage killing. Interestingly, P. verrucosa had its growth inhibited by ritonavir combined with either itraconazole or ketoconazole. Collectively, our results support the antifungal action of HIV-PIs and their relevance as a possible alternative therapy for fungal infections.


Subject(s)
Antifungal Agents/pharmacology , Aspartic Acid Proteases/antagonists & inhibitors , HIV Protease Inhibitors/pharmacology , Macrophages/drug effects , Phialophora/drug effects , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Aspartic Acid Proteases/metabolism , Carbamates/chemical synthesis , Carbamates/chemistry , Carbamates/pharmacology , Dose-Response Relationship, Drug , Furans , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/chemistry , Humans , Lopinavir/chemical synthesis , Lopinavir/chemistry , Lopinavir/pharmacology , Macrophages/metabolism , Microbial Sensitivity Tests , Molecular Structure , Phialophora/enzymology , Phialophora/growth & development , Ritonavir/chemical synthesis , Ritonavir/chemistry , Ritonavir/pharmacology , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacology
4.
Bioorg Med Chem ; 28(6): 115349, 2020 03 15.
Article in English | MEDLINE | ID: mdl-32044230

ABSTRACT

Identification of structural determinants required for potent inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) could help develop safer drugs and more effective pharmacoenhancers. We utilize a rational inhibitor design to decipher structure-activity relationships in analogues of ritonavir, a highly potent CYP3A4 inhibitor marketed as pharmacoenhancer. Analysis of compounds with the R1 side-group as phenyl or naphthalene and R2 as indole or naphthalene in different stereo configuration showed that (i) analogues with the R2-naphthalene tend to bind tighter and inhibit CYP3A4 more potently than the R2-phenyl/indole containing counterparts; (ii) stereochemistry becomes a more important contributing factor, as the bulky side-groups limit the ability to optimize protein-ligand interactions; (iii) the relationship between the R1/R2 configuration and preferential binding to CYP3A4 is complex and depends on the side-group functionality/interplay and backbone spacing; and (iv) three inhibitors, 5a-b and 7d, were superior to ritonavir (IC50 of 0.055-0.085 µM vs. 0.130 µM, respectively).


Subject(s)
Cytochrome P-450 CYP3A Inhibitors/pharmacology , Cytochrome P-450 CYP3A/metabolism , Ritonavir/pharmacology , Cytochrome P-450 CYP3A Inhibitors/chemical synthesis , Cytochrome P-450 CYP3A Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Hydrophobic and Hydrophilic Interactions , Molecular Structure , Ritonavir/chemical synthesis , Ritonavir/chemistry , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 28(14): 2379-2381, 2018 08 01.
Article in English | MEDLINE | ID: mdl-29934245

ABSTRACT

With the help of Surflex-Dock calculation, two ritonavir analogs in which one thioazole unit was replaced by selenazole have been designed and synthesized. The key selenazole structure was constructed from ß-azido diselenide through a cascade diselenide cleavage/selenocarbonylation/Staudinger reduction/aza-Wittig reaction and a following MnO2 oxidation. The accordingly prepared compounds exhibited good anti-HIV-1 (IIIB) activities comparable to that of the original ritonavir, as well as the positive SI values.


Subject(s)
Anti-HIV Agents/pharmacology , Azoles/pharmacology , HIV Protease Inhibitors/pharmacology , HIV/drug effects , Organoselenium Compounds/pharmacology , Ritonavir/pharmacology , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Azoles/chemistry , Dose-Response Relationship, Drug , Drug Design , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/chemistry , Manganese Compounds/chemistry , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Organoselenium Compounds/chemistry , Oxidation-Reduction , Oxides/chemistry , Ritonavir/chemical synthesis , Ritonavir/chemistry , Structure-Activity Relationship
6.
Eur J Pharm Sci ; 95: 111-121, 2016 Dec 01.
Article in English | MEDLINE | ID: mdl-27181836

ABSTRACT

The objective of this study was to prepare ritonavir (RTV) nanosuspensions, an anti-HIV protease inhibitor, to solve its poor water solubility issues. The microfluidization method with a pre-treatment step was used to obtain the nanosuspensions. Design of Experiment (DoE) approach was performed in order to understand the effect of the critical formulation parameters which were selected as polymer type (HPMC or PVP), RTV to polymer ratio, and number of passes. Interactions between the formulation variables were evaluated according to Univariate ANOVA. Particle size, particle size distribution and zeta potential were selected as dependent variables. Scanning electron microscopy, X-ray powder diffraction, and differential scanning calorimetry were performed for the in vitro characterization after lyophilization of the optimum nanosuspension formulation. The saturation solubility was examined in comparison with coarse powder, physical mixture and nanosuspension. In vitro dissolution studies were conducted using polyoxyethylene 10 lauryl ether (POE10LE) and biorelevant media (FaSSIF and FeSSIF). The results showed nanosuspensions were partially amorphous and spherically shaped with particle sizes ranging from 400 to 600nm. Moreover, 0.1-0.4 particle size distribution and about -20mV zeta potential values were obtained. The nanosuspension showed a significantly increased solubility when compared to coarse powder (3.5 fold). Coarse powder, physical mixture, nanosuspension and commercial product dissolved completely in POE10LE; however, cumulative dissolved values reached ~20% in FaSSIF for the commercial product and nanosuspension. The nanosuspension showed more than 90% drug dissolved in FeSSIF compared to the commercial product which showed ~50% in the same medium. It was determined that RTV dissolution was increased by nanosuspension formulation. We concluded that DoE approach is useful to develop nanosuspension formulation to improve solubility and dissolution rate of RTV.


Subject(s)
Microfluidic Analytical Techniques/methods , Nanoparticles/chemistry , Polymers/chemical synthesis , Ritonavir/chemical synthesis , Drug Stability , Nanoparticles/analysis , Particle Size , Polymers/analysis , Ritonavir/analysis , Suspensions , X-Ray Diffraction/methods
7.
Org Lett ; 9(2): 267-70, 2007 Jan 18.
Article in English | MEDLINE | ID: mdl-17217281

ABSTRACT

An efficient procedure for the directed reductive amination of beta-hydroxy-ketones (3) for the stereoselective preparation of 1,3-syn-amino alcohols (6) is reported. The operationally simple protocol uses Ti(iOPr)4 for coordination of the intermediate imino alcohol (5) and PMHS as the reducing agent. The method was expanded to an asymmetric aldol reductive amination sequence to allow a highly convergent synthesis of the hydroxy-amine core of the HIV-protease inhibitors ritonavir and lopinavir. [reaction: see text].


Subject(s)
Amino Alcohols/chemical synthesis , HIV Protease Inhibitors/chemical synthesis , Ketones/chemistry , Pyrimidinones/chemical synthesis , Ritonavir/chemical synthesis , Amination , Amino Alcohols/chemistry , HIV Protease Inhibitors/chemistry , Lopinavir , Molecular Structure , Organometallic Compounds/chemistry , Oxidation-Reduction , Pyrimidinones/chemistry , Ritonavir/chemistry , Stereoisomerism , Titanium/chemistry
8.
Cienc. tecnol. pharm ; 16(1): 17-21, ene. 2006. tab
Article in Es | IBECS | ID: ibc-66295

ABSTRACT

El estudio se ha diseñado con objeto de determinarla interacción entre el ritonavir y el saquinavirdurante su absorción gastrointestinal.Para ello, se han realizado estudios de perfusiónen el intestino delgado completo de ratasWistar, con distintas proporciones de los dosfármacos. Los resultados obtenidos demuestranque la constante aparente de velocidad deabsorción (kap) del ritonavir disminuye, aunqueno significativamente, cuando la concentraciónde saquinavir es al menos un 40% superiora la de ritonavir. Asimismo, la kap saquinavirdisminuye cuando la concentración de ritonavires un 25% superior a la de saquinavir,si bien estas diferencias no son significativas.El mismo comportamiento se observa cuandola concentración de ritonavir es un 40% inferiora la de saquinavir, lo que indicaría que la incorporacióndel saquinavir se modifica por el ritonavir.Se requieren estudios adicionales paradilucidar el mecanismo concreto de interacciónentre los dos fármacos


The study has been designed in order to determinatethe interaction between the ritonavirand the saquinavir during its gastrointestinalabsorption. For it, perfusion studies have beencarried out in the whole intestine of the Wistarrats, with different proportions of the two drugs.The results obtained demonstrate that the apparentabsorption rate constant (kap) of the ritonavirit diminishes, although not significantly,when the saquinavir concentration is at least40% superior to that of ritonavir. Also, the kapsaquinavir diminishes when the ritonavir concentrationis 25% superior to that of saquinavir,although these differences are not significant.The same behavior is observed when the ritonavirconcentration is 40 % smaller to that ofsaquinavir, what would indicate that the incorporationof the saquinavir modifies for the ritonavir.Additional studies are required to elucidatethe concrete mechanism of interactionamong the two drugs


Subject(s)
Rats , Animals , Ritonavir/pharmacology , Ritonavir/pharmacokinetics , Ritonavir/therapeutic use , Saquinavir/pharmacology , Saquinavir/pharmacokinetics , Intestinal Absorption , Models, Animal , Ritonavir/chemistry , Ritonavir/chemical synthesis , Saquinavir/chemistry , Saquinavir/chemical synthesis , Saquinavir/therapeutic use
9.
Org Lett ; 8(1): 51-4, 2006 Jan 05.
Article in English | MEDLINE | ID: mdl-16381565

ABSTRACT

[reaction: see text] The base-catalyzed hydroazidation of alpha'-amino alpha,beta-unsaturated ketones with in situ generated hydrazoic acid was found to proceed with high stereoselectivity in favor of the syn product. The stereoselectivity is controlled by the configuration of the enone and syn/anti ratios up to 7:1 were obtained with secondary and tertiary amines at low temperature. By this route the diamino alcohol core of HIV-PR inhibitors ritonavir and lopinavir was synthesized in 37% yield from phenylalanine.


Subject(s)
Azides/chemistry , HIV Protease Inhibitors/chemical synthesis , Pyrimidinones/chemical synthesis , Ritonavir/chemical synthesis , HIV Protease Inhibitors/chemistry , Lopinavir , Pyrimidinones/chemistry , Ritonavir/chemistry , Stereoisomerism
10.
Bioorg Med Chem Lett ; 15(24): 5499-503, 2005 Dec 15.
Article in English | MEDLINE | ID: mdl-16203141

ABSTRACT

As part of our efforts to identify potent HIV-1 protease inhibitors that are active against resistant viral strains, structural modification of the azacyclic urea (I) was undertaken by incorporating acyl groups as P(1)' ligands. The extensive SAR study has yielded a series of N-acyl azacyclic ureas (II), which are highly potent against both wild-type and multiple PI-resistant viral strains.


Subject(s)
HIV Protease Inhibitors/chemical synthesis , HIV-1/drug effects , Aza Compounds/chemical synthesis , Aza Compounds/pharmacology , Drug Design , Drug Resistance, Multiple , HIV Protease Inhibitors/therapeutic use , Ligands , Microbial Sensitivity Tests , Models, Molecular , Ritonavir/chemical synthesis , Ritonavir/therapeutic use , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemical synthesis , Urea/pharmacology
11.
Pharm Dev Technol ; 10(2): 291-7, 2005.
Article in English | MEDLINE | ID: mdl-15926678

ABSTRACT

The thermodynamically most stable polymorph under ambient conditions is almost without exception the most desirable crystalline form for development by a pharmaceutical company. It is, therefore, beneficial to discover and to characterize this polymorph at the earliest possible stage of development. A screen for discovering the stable polymorph of a pharmaceutical compound early in the drug discovery-development process is developed and described. In this screen, a small amount of compound is suspended in a diverse group of solvents for two weeks in an effort to crystallize the most stable polymorph. The solubility of the compound in each solvent utilized in the stable polymorph screen is also simultaneously determined using a simple gravimetric method. Ritonavir and an early development candidate (Pfizer compound A) are used as model compounds to demonstrate the utility of the screen for finding the stable polymorph early in the drug discovery-development process.


Subject(s)
Drug Design , Pharmaceutical Preparations/chemistry , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Isomerism , Pharmaceutical Solutions , Ritonavir/chemical synthesis , Ritonavir/chemistry , Solvents , Spectrum Analysis, Raman , Thermodynamics , X-Ray Diffraction
12.
J Org Chem ; 67(24): 8635-43, 2002 Nov 29.
Article in English | MEDLINE | ID: mdl-12444650

ABSTRACT

A stereoselective synthesis of hydroxyethylene dipeptide isosteres based on the 1,4-diamino-2-hydroxybutane structure is described. Horner-Emmons olefination of phosphonates derived from alpha-amino acids, stereoselective reduction of the resulting enones to allylic alcohols, and syn epoxidation of the latter lead to enantiomerically pure 1-amino-2-hydroxy-3,4-epoxybutanes, key intermediates in the synthesis. Reductive cleavage of the epoxy alcohols with Red-Al proceeds in a highly regioselective way, giving 1-amino-2,4-dihydroxybutanes, from which diamino alcohol hydroxyethylene isosteres are obtained by selective protection of the secondary 2-hydroxy group, via cyclization to 1,3-oxazolidinone, and further elaboration of the 4-hydroxy. Both C-2 epimers of 1,4-diamino-2-hydroxybutanes are accessible by appropriate choice of the conditions for cyclization. The approach is demonstrated by the synthesis of a series of six hydroxyethylene dipeptide isosteres, including the diamino alcohol core of potent HIV-protease inhibitor ritonavir 18 and its C-2 epimer 11a.


Subject(s)
Alcohols/chemistry , Butanols/chemistry , Combinatorial Chemistry Techniques , Dipeptides/chemical synthesis , HIV Protease Inhibitors/chemical synthesis , Ritonavir/analogs & derivatives , Ritonavir/chemical synthesis , Catalysis , Dipeptides/chemistry , HIV Protease Inhibitors/chemistry , Lopinavir , Molecular Structure , Pyrimidinones/chemistry , Stereoisomerism
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