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1.
J Med Chem ; 67(12): 10306-10320, 2024 Jun 27.
Article in English | MEDLINE | ID: mdl-38872300

ABSTRACT

Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvß1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, in silico modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvß1 relative to several other integrin isoforms measured. Azabenzimidazolone 25 demonstrated antifibrotic efficacy in an in vivo rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvß1 inhibition.


Subject(s)
Drug Design , Receptors, Vitronectin , Animals , Rats , Humans , Receptors, Vitronectin/antagonists & inhibitors , Receptors, Vitronectin/metabolism , Structure-Activity Relationship , Liver Cirrhosis/drug therapy , Models, Molecular , Drug Discovery , Rats, Sprague-Dawley , Male , Crystallography, X-Ray , Benzimidazoles/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/chemical synthesis
2.
Eur J Med Chem ; 176: 162-174, 2019 Aug 15.
Article in English | MEDLINE | ID: mdl-31103897

ABSTRACT

Chagas disease is a neglected protozoan disease that affects more than eight million people in developing countries. Due to the limited number and toxicity profiles of therapies in current use, new drugs are urgently needed. In previous studies, we reported the isolation of two related antitrypanosomal neolignans from Nectandra leucantha (Lauraceae). In this work, a semi-synthetic library of twenty-three neolignan derivatives was prepared to explore synthetically accessible structure activity relationships (SAR) against Trypanosoma cruzi. Five compounds demonstrated activity against trypomastigotes (IC50 values from 8 to 64 µM) and eight showed activity against intracellular amastigotes (IC50 values from 7 to 16 µM). Eighteen derivatives demonstrated no mammalian cytotoxicity up to 200 µM. The phenolic acetate derivative of natural dehydrodieugenol B was effective against both parasite forms and eliminated 100% of amastigotes inside macrophages. This compound caused rapid and intense depolarization of the mitochondrial membrane potential, with decreased levels of intracellular reactive oxygen species being observed. Fluorescence assays demonstrated that this derivative affected neither the permeability nor the electric potential of the parasitic plasma membrane, an effect also corroborated by scanning electron microscopy studies. Structure-activity relationship studies (SARs) demonstrated that the presence of at least one allyl side chain on the biaryl ether core was important for antitrypanosomal activity, and that the free phenol is not essential. This set of neolignan derivatives represents a promising starting point for future Chagas disease drug discovery studies.


Subject(s)
Anisoles/pharmacology , Lignans/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Anisoles/chemical synthesis , Anisoles/chemistry , Anisoles/toxicity , Cell Line , Cell Membrane/drug effects , Humans , Lignans/chemical synthesis , Lignans/chemistry , Lignans/toxicity , Membrane Potential, Mitochondrial/drug effects , Mice, Inbred BALB C , Molecular Structure , Parasitic Sensitivity Tests , Reactive Oxygen Species/metabolism , Structure-Activity Relationship , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistry , Trypanocidal Agents/toxicity , Trypanosoma cruzi/growth & development , Trypanosoma cruzi/metabolism
3.
Bioorg Chem ; 89: 103002, 2019 08.
Article in English | MEDLINE | ID: mdl-31136901

ABSTRACT

Marine invertebrates are a rich source of small antiparasitic compounds. Among them, Macrorhynchia philippina is a chemically underexplored marine cnidarian. In the search for candidates against the neglected protozoan Chagas disease, we performed a bio-guided fractionation to obtain active compounds. The structural characterization of the active compound was determined using NMR analysis and MS and resulted in the isololiolide, a compound described for the first time in this species. It showed in vitro activity against both trypomastigote and intracellular amastigotes of Trypanosoma cruzi, with IC50 values of 32 µM and 40 µM, respectively, with no mammalian cytotoxicity (>200 µM). The lethal action was investigated in T. cruzi using different fluorophores to study: (i) mitochondrial membrane potential; (ii) plasma membrane potential and (iii) plasma membrane permeability. Our results demonstrated that isololiolide caused disruption of the plasma membrane integrity and a strong depolarization of the mitochondrial membrane potential, rapidly leading the parasite to death. Despite being considered a possible covalent inhibitor, safety in silico studies of isololiolide also considered neither mutagenic nor genotoxic potential. Additionally, isololiolide showed no resemblance to interference compounds (PAINS), and it succeeded in most filters for drug-likeness. Isololiolide is a promising candidate for future optimization against Chagas disease.


Subject(s)
Carotenoids/pharmacology , Cnidaria/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Carotenoids/chemistry , Carotenoids/isolation & purification , Cell Line , Cell Membrane Permeability/drug effects , Dose-Response Relationship, Drug , Macrophages/drug effects , Membrane Potential, Mitochondrial/drug effects , Mice , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity Relationship , Trypanocidal Agents/chemistry , Trypanocidal Agents/isolation & purification
4.
Sci Rep ; 9(1): 6114, 2019 04 16.
Article in English | MEDLINE | ID: mdl-30992481

ABSTRACT

Leishmaniasis is a neglected disease that affects more than 12 million people, with a limited therapy. Plant-derived natural products represent a useful source of anti-protozoan prototypes. In this work, four derivatives were prepared from neolignans isolated from the Brazilian plant Nectandra leucantha, and their effects against intracellular amastigotes of Leishmania (L.) infantum evaluated in vitro. IC50 values between 6 and 35 µM were observed and in silico predictions suggested good oral bioavailability, no PAINS similarities, and ADMET risks typical of lipophilic compounds. The most selective (SI > 32) compound was chosen for lethal action and immunomodulatory studies. This compound caused a transient depolarization of the plasma membrane potential and induced an imbalance of intracellular Ca2+, possibly resulting in a mitochondrial impairment and leading to a strong depolarization of the membrane potential and decrease of ATP levels. The derivative also interfered with the cell cycle of Leishmania, inducing a programmed cell death-like mechanism and affecting DNA replication. Further immunomodulatory studies demonstrated that the compound eliminates amastigotes via an independent activation of the host cell, with decrease levels of IL-10, TNF and MCP-1. Additionally, this derivative caused no hemolytic effects in murine erythrocytes and could be considered promising for future lead studies.


Subject(s)
Anisoles/pharmacology , Antiprotozoal Agents/pharmacology , Leishmania infantum/drug effects , Leishmaniasis/drug therapy , Neglected Diseases/drug therapy , Animals , Anisoles/chemistry , Anisoles/isolation & purification , Anisoles/therapeutic use , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/isolation & purification , Antiprotozoal Agents/therapeutic use , Brazil , Cell Division/drug effects , Cell Line , DNA Replication/drug effects , Disease Models, Animal , Drug Evaluation, Preclinical , Energy Metabolism/drug effects , Erythrocytes/drug effects , Female , Hemolysis/drug effects , Humans , Inhibitory Concentration 50 , Lauraceae/chemistry , Leishmania infantum/cytology , Leishmania infantum/genetics , Leishmania infantum/metabolism , Leishmaniasis/parasitology , Male , Membrane Potential, Mitochondrial/drug effects , Mesocricetus , Mice , Neglected Diseases/parasitology , Primary Cell Culture , Reactive Oxygen Species , Toxicity Tests
5.
São Paulo; IAL; 2019. 15 p. ilus, graf, tab.
Non-conventional in Portuguese | LILACS, Sec. Est. Saúde SP, SESSP-IALPROD, Sec. Est. Saúde SP | ID: biblio-1007411

ABSTRACT

Leishmaniasis is a neglected disease that affects more than 12 million people, with a limited therapy. plant-derived natural products represent a useful source of anti-protozoan prototypes. In this work, four derivatives were prepared from neolignans isolated from the Brazilian plant Nectandra leucantha, and their effects against intracellular amastigotes of Leishmania (L.) infantum evaluated in vitro. IC50 values between 6 and 35 µM were observed and in silico predictions suggested good oral bioavailability, no pAINs similarities, and ADMet risks typical of lipophilic compounds. the most selective (sI > 32) compound was chosen for lethal action and immunomodulatory studies. this compound caused a transient depolarization of the plasma membrane potential and induced an imbalance of intracellular Ca2+, possibly resulting in a mitochondrial impairment and leading to a strong depolarization of the membrane potential and decrease of ATP levels. The derivative also interfered with the cell cycle of Leishmania, inducing a programmed cell death-like mechanism and affecting DNA replication. Further immunomodulatory studies demonstrated that the compound eliminates amastigotes via an independent activation of the host cell, with decrease levels of IL-10, TNF and MCP-1. Additionally, this derivative caused no hemolytic effects in murine erythrocytes and could be considered promising for future lead studies.


Subject(s)
Cells , Disease , Leishmania
6.
Article in Portuguese | LILACS, Sec. Est. Saúde SP, SESSP-IALPROD, Sec. Est. Saúde SP, SESSP-IALACERVO | ID: biblio-1007421

ABSTRACT

Chagas disease is a neglected protozoan disease that affects more than eight million people in developing countries. Due to the limited number and toxicity profiles of therapies in current use, new drugs are urgently needed. In previous studies, we reported the isolation of two related antitrypanosomal neo- lignans from Nectandra leucantha (Lauraceae). In this work, a semi-synthetic library of twenty-three neolignan derivatives was prepared to explore synthetically accessible structure activity relationships (SAR) against Trypanosoma cruzi. Five compounds demonstrated activity against trypomastigotes (IC50 values from 8 to 64 mM) and eight showed activity against intracellular amastigotes (IC50 values from 7 to 16 mM). Eighteen derivatives demonstrated no mammalian cytotoxicity up to 200 mM. The phenolic ac- etate derivative of natural dehydrodieugenol


Subject(s)
Trypanosoma cruzi , Disease , Chagas Disease
7.
Bioorg Med Chem Lett ; 28(10): 1887-1891, 2018 06 01.
Article in English | MEDLINE | ID: mdl-29655979

ABSTRACT

During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK2. A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design and physical properties-based design resulted in replacement of a highly hydrophobic poly fluorinated aryl ring by a simple trifluoromethyl that led to identification of compound 6 with much improved physicochemical properties. Subsequent SAR studies led to the synthesis of new pyran analog 7 with improved cell potency. Further optimization of pharmacokintetics properties by increasing permeability with appropriate fluorinated alkyl led to compound 8 as a potent, selective AKT inhibitors that blocks the phosphorylation of GSK3ß in vivo and had robust, dose and concentration dependent efficacy in the U87MG tumor xenograft model.


Subject(s)
Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Pyrimidinones/chemistry , Animals , Binding Sites , Cell Line, Tumor , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Mice , Molecular Dynamics Simulation , Neoplasms/drug therapy , Neoplasms/pathology , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Structure, Tertiary , Proto-Oncogene Proteins c-akt/metabolism , Pyrimidinones/pharmacology , Pyrimidinones/therapeutic use , Stereoisomerism , Structure-Activity Relationship , Transplantation, Heterologous
8.
Org Lett ; 10(4): 613-6, 2008 Feb 21.
Article in English | MEDLINE | ID: mdl-18205373

ABSTRACT

A scaleable synthesis of the potent histone deacetylase (HDAC) inhibitor FK228 is described. A reliable strategy for preparing the key beta-hydroxy mercapto heptenoic acid partner was accomplished in nine steps and 13% overall yield. A Noyori asymmetric hydrogen-transfer reaction established the hydroxyl stereochemistry in >99:1 er via the reduction of a propargylic ketone.


Subject(s)
Depsipeptides/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors , Depsipeptides/chemistry , Depsipeptides/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Molecular Structure
9.
Org Lett ; 8(18): 4051-4, 2006 Aug 31.
Article in English | MEDLINE | ID: mdl-16928071

ABSTRACT

7-Hydroxy-quinine was synthesized by an asymmetric aldol reaction that establishes the C8 and C9 stereochemistry, followed by construction of the 3-vinyl-quinuclidine azabicyclo[2.2.2]octane by C3-C4 ring closure using an intramolecular palladium-mediated allylic alkylation with excellent regio- and diastereoselectivity. This is the first report of a ketone-enolate-stereocontrolled allylic alkylation mediated by palladium. The title compound and a dehydro-quinine analogue were evaluated for antimalarial activity.


Subject(s)
Ketones/chemistry , Palladium/chemistry , Quinine/chemistry , Quinuclidines/chemical synthesis , Alkylation , Catalysis , Molecular Structure
10.
J Am Chem Soc ; 127(18): 6504-5, 2005 May 11.
Article in English | MEDLINE | ID: mdl-15869250

ABSTRACT

The total synthesis of (+)-dihydrocompactin via an intramolecular ionic Diels-Alder reaction that proceeds with remote stereocontrol is described. This reaction proceeds by an intermediate vinyl-oxocarbenium ion (6), the conformational constraints of which lead to the observed asymmetric induction. The sense of asymmetric induction appears contrasteric and is explained by the proposed reactive conformation shown in Figure 1.


Subject(s)
Lovastatin/analogs & derivatives , Lovastatin/chemical synthesis , Ions , Models, Molecular , Molecular Conformation , Stereoisomerism
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