Optimization of diarylazines as anti-HIV agents with dramatically

Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.Fil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cisneros, José A.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados Unido

Thalidomide analogues: Tumor necrosis factor-alpha inhibitors and their evaluation as anti-inflammatory agents

A series of related thalidomide derivatives (2-9) were synthesized by microwave irradiation and evaluated for anti-inflammatory activity. Such activity was assessed in vivo and ex vivo. Compounds 2, 8 and 9 showed the highest levels of inhibition of TNF-α production. On rat paw edema and hyperalgesia assays, compound 9, (1,4-phthalazinedione) demonstrated the highest in vivo anti-inflammatory activity. Thus, compound 9 can be considered as a promising compound to be subjected to further modification to obtain new agents for the treatment of inflammatory diseases.Fil: Casal, Juan José. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bollini, Mariela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lombardo, Maria Elisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Investigaciones sobre Porfirinas y Porfirias. Universidad de Buenos Aires. Centro de Investigaciones sobre Porfirinas y Porfirias; ArgentinaFil: Bruno, Ana María. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Antimalarial activity of novel imidazoisoquinolinone derivatives correlates with heme binding affinity

A series of novel imidazoisoquinolinone derivatives were synthesized and evaluated for in vitro antimalarial efficacy against chloroquine sensitive GHA strain of Plasmodium falciparum. Compounds 2, 4, 6, 9, and 17 revealed moderate to good activities in the micromolar range. Binding interaction between these active compounds and heme were determined and correlated with antimalarial activity. A good correlation (r = 0.98) was observed between antimalarial activity and the heme dissociation constants (K d). These suggest that antimalarial mode of action of this class of compounds appears to be similar to that of chloroquine and involves the inhibition of hemozoin formation.Fil: Bollini, Mariela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Casal, Juan José. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Asís, Silvia Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; ArgentinaFil: Leal, Emilse Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; ArgentinaFil: Bruno, Ana María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; Argentin

Novel Polyoxometalate- Ionic Liquid with Antibacterial and Antifungal Properties. Feasibility of Its Implementation As a Multifunctional Thin Coating

The synthesis of hybrid materials, combining the properties of organic and inorganic components, results in composites with unique physical and chemical features. Polyoxometalates (POMs), i.e. inorganic anionic molecular metal oxides, are considered as promising future metallodrugs due to their antiviral, antitumoral and antibacterial activities. The combination of bulky organic cations with POMs results in composite ionic liquids (IL; melting point below 100°C) which combine the unique properties of both components. Pioneering studies have used composites of alkylammonium cations and POM anions for multifunctional water purification to remove toxic heavy materials, organic aromatics and microbes and for the inhibition of bio-corrosion on metal and stone surfaces due to coating formation.Fil: Enderle, Ana Gabriela. Universidad Nacional del Litoral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Streb, C.. Universitat Ulm; AlemaniaFil: Bollini, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Culzoni, Maria Julia. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Departamento de Química. Cátedra de Química Analítica; ArgentinaFil: Mitchell, S. G.. Universidad de Zaragoza; EspañaFil: Franco Castillo, I.. Universidad de Zaragoza; España2019 AIChE Annual MeetingOrlandoEstados UnidosAmerican Institute of Chemical Engineer

Trypanocidal activity of tioamide-sustituted imidazoisoquinolinones: Electrochemical properties and biological effects

Three thioamide-substituted imidazoisoquinolinones, which possess an heterocyclic center similar to tryptanthrin and are named C1, C2 and C3, were studied regarding: a) its in vitro anti-Trypanosoma cruzi activity, b) its cytotoxicity and electrochemical behaviour and c) its effect on cell viability, redox state and mitochondrial function . The assayed compounds showed a significant activity against the proliferative forms, but only C1 showed activity on the trypomastigote form (for C1, IC50 epi = 1.49 µM; IC50 amas = 1.74 µM and IC50 try = 34.89 µM). The presence of an antioxidant compound such as ascorbic acid or dithiotreitol induced a three-fold increase in the antiparasitic activity, whereas glutathione had a dual effect depending on its concentration. Our results indicate that these compounds, which exhibited low toxicity to the host cells, can be reduced inside the parasite by means of the pool of low molecular weight thiols, causing oxidative stress and parasite death by apoptosis. The antiparasitic activity of the compounds studied could be explained by a loss of the capacity of the antioxidant defense system of the parasite to keep its intracellular redox state. C1 could be considered a good candidate for in vivo evaluation .Fil: Frank, Fernanda Maria. Consejo Nacional de Investigaciones Cienti­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "Profesor R. A. Margni"; ArgentinaFil: Ciccarelli, Allejandra Beatriz. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Centro de Investigacion Sobre Porfirinas y Porfirias; ArgentinaFil: Bollini, Mariela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; ArgentinaFil: Bruno, Ana M.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Orgánica; ArgentinaFil: Batlle, Alcira Maria del C.. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Centro de Investigacion Sobre Porfirinas y Porfirias; ArgentinaFil: Lombardo, Maria Elisa. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Centro de Investigacion Sobre Porfirinas y Porfirias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentin

Structure-based evaluation of C5 derivatives in the catechol diether series targeting HIV-1 reverse transcriptase

Using a computationally driven approach, a class of inhibitors with picomolar potency known as the catechol diethers were developed targeting the non-nucleoside-binding pocket of HIV-1 reverse transcriptase. Computational studies suggested that halogen-bonding interactions between the C5 substituent of the inhibitor and backbone carbonyl of conserved residue Pro95 might be important. While the recently reported crystal structures of the reverse transcriptase complexes confirmed the interactions with the non-nucleoside-binding pocket, they revealed the lack of a halogen-bonding interaction with Pro95. To understand the effects of substituents at the C5 position, we determined additional crystal structures with 5-Br and 5-H derivatives. Using comparative structural analysis, we identified several conformations of the ethoxy uracil dependent on the strength of a van der Waals interaction with the Cγ of Pro95 and the C5 substitution. The 5-Cl and 5-F derivatives position the ethoxy uracil to make more hydrogen bonds, whereas the larger 5-Br and smaller 5-H position the ethoxy uracil to make fewer hydrogen bonds. EC50 values correlate with the trends observed in the crystal structures. The influence of C5 substitutions on the ethoxy uracil conformation may have strategic value, as future derivatives can possibly be modulated to gain additional hydrogen-bonding interactions with resistant variants of reverse transcriptase.Fil: Frey, Kathleen M.. University of Yale; Estados UnidosFil: Gray, William T.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gallardo Macias, Ricardo. University of Yale; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados Unido

Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase

Reverse transcriptase (RT) from the human immunodeficiency virus continues to be an attractive drug target for antiretroviral therapy. June 2022 will commemorate the 30th anniversary of the first Human Immunodeficiency Virus (HIV) RT crystal structure complex that was solved with non-nucleoside reverse transcriptase inhibitor nevirapine. The release of this structure opened opportunities for designing many families of non-nucleoside reverse transcriptase inhibitors (NNRTIs). In paying tribute to the first RT-nevirapine structure, we have developed several compound classes targeting the non-nucleoside inhibitor binding pocket of HIV RT. Extensive analysis of crystal structures of RT in complex with the compounds informed iterations of structure-based drug design. Structures of seven additional complexes were determined and analyzed to summarize key interactions with residues in the non-nucleoside inhibitor binding pocket (NNIBP) of RT. Additional insights comparing structures with antiviral data and results from molecular dynamics simulations elucidate key interactions and dynamics between the nucleotide and non-nucleoside binding sites.Fil: Frey, Kathleen M.. University of Yale; Estados UnidosFil: Bertoletti, Nicole. University of Yale; Estados UnidosFil: Chan, Albert H.. University of Yale; Estados UnidosFil: Ippolito, Joseph A.. University of Yale; Estados UnidosFil: Bollini, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados Unido

Extension into the entrance channel of HIV-1 reverse transcriptase—Crystallography and enhanced solubility

Non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-RT) are reported that feature extension into the entrance channel near Glu138. Complexes of the parent anilinylpyrimidine 1 and the morpholinoethoxy analog 2j with HIV-RT have received crystallographic characterization confirming the designs. Measurement of aqueous solubilities of 2j, 2k, the parent triazene 2a, and other NNRTIs demonstrate profound benefits for addition of the morpholinyl substituent.Fil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Frey, Kathleen M.. University of Yale. School of Medicine; Estados UnidosFil: Cisneros, José A.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale. School of Medicine; Estados UnidosFil: Das, Kalyan. Rutgers University; Estados UnidosFil: Bauman, Joseph D.. Rutgers University; Estados UnidosFil: Arnold, Eddy. Rutgers University; Estados UnidosFil: Anderson, Karen S.. University of Yale. School of Medicine; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados Unido

Potent inhibitors active against HIV reverse transcriptase with K101P, a mutation conferring rilpivirine resistance

Catechol diether compounds have nanomolar antiviral and enzymatic activity against HIV with reverse transcriptase (RT) variants containing K101P, a mutation that confers high-level resistance to FDA-approved non-nucleoside inhibitors efavirenz and rilpivirine. Kinetic data suggests that RT (K101P) variants are as catalytically fit as wild-type and thus can potentially increase in the viral population as more antiviral regimens include efavirenz or rilpivirine. Comparison of wild-type structures and a new crystal structure of RT (K101P) in complex with a leading compound confirms that the K101P mutation is not a liability for the catechol diethers while suggesting that key interactions are lost with efavirenz and rilpivirine.Fil: Gray, William T.. University of Yale; Estados UnidosFil: Frey, Kathleen M.. University of Yale; Estados UnidosFil: Laskey, Sarah B.. University Johns Hopkins; Estados UnidosFil: Mislak, Andrea C.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Lee, Won Gil. University of Yale; Estados UnidosFil: Bollini, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Yale; Estados UnidosFil: Siliciano, Robert F.. University Johns Hopkins; Estados Unidos. Howard Hughes Medial Institute; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados Unido

De novo design approaches targeting an envelope protein pocket to identify small molecules against dengue virus

Dengue fever is a mosquito-borne viral disease that has become a major public health concern worldwide. This disease presents with a wide range of clinical manifestations, from a mild cold-like illness to the more serious hemorrhagic dengue fever and dengue shock syndrome. Currently, neither an approved drug nor an effective vaccine for the treatment are available to fight the disease. The envelope protein (E) is a major component of the virion surface. This protein plays a key role during the viral entry process, constituting an attractive target for the development of antiviral drugs. The crystal structure of the E protein reveals the existence of a hydrophobic pocket occupied by the detergent n-octyl-β-d-glucoside (β-OG). This pocket lies at the hinge region between domains I and II and is important for the low pH-triggered conformational rearrangement required for the fusion of the virion with the host's cell. Aiming at the design of novel molecules which bind to E and act as virus entry inhibitors, we undertook a de novo design approach by “growing” molecules inside the hydrophobic site (β-OG). From more than 240000 small-molecules generated, the 2,4 pyrimidine scaffold was selected as the best candidate, from which one synthesized compound displayed micromolar activity. Molecular dynamics-based optimization was performed on this hit, and thirty derivatives were designed in silico, synthesized and evaluated on their capacity to inhibit dengue virus entry into the host cell. Four compounds were found to be potent antiviral compounds in the low-micromolar range. The assessment of drug-like physicochemical and in vitro pharmacokinetic properties revealed that compounds 3e and 3h presented acceptable solubility values and were stable in mouse plasma, simulated gastric fluid, simulated intestinal fluid, and phosphate buffered saline solution.Fil: Leal, Emilse Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Adler, Natalia Sol. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Fernandez, Gabriela Araceli. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Gebhard, Leopoldo German. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Battini, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Aucar, María Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Videla, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Monge, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Hernández de los Ríos, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Acosta Dávila, John. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Morell, María L.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Cordo, Sandra Myriam. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: García, Cybele C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Gamarnik, Andrea Vanesa. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cavasotto, Claudio Norberto. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Universidad Austral; ArgentinaFil: Bollini, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentin