Estela Maris Freitas Muri

Hydroxamic Acids as Pharmacological Agents

A variety of hydroxamic acid derivatives have recently been touted for their potential use as inhibitors of hypertension, tumor growth, inflammation, infectious agents, asthma, arthritis, and more. Here we provide a comprehensive review of the basic medicinal chemistry and pharmacology of hydroxamic acid derivatives that have been examined as inhibitors of zinc metalloproteases, matrix metalloproteinases, leukotriene A(4) hydrolases, ureases, lipoxigenases, cyclooxygenases, as well as peptide deformilases.

Design and Synthesis of Heterocyclic Hydroxamic Acid Derivatives as Inhibitors of Helicobacter pylori Urease

Abstract Helicobacter pylori produces ammonia to help counter the acidic environment in the human stomach. The production of ammonia, essential for the microorganisms survival and virulence, is the product of enzymatic conversion of urea by the H. pyloris urease. Inhibition of urease activity by dipeptide hydroxamic acids has previously been demonstrated using a variety of fluorides, thiols and hydroxamic acids. Studies employing computer-aided drug design techniques have been utilized to suggest a novel series of heterocyclic hydroxamic acid derivatives as potential as urease inhibitors. The heterocyclic compounds 7a,b, 10b, 12b, 16b, and 19b have been designed, synthesized, and preliminarily tested as dipeptide mimics which offer a structure that is more biologically stable than that of the reported dipeptide inhibitors.

Isomannide derivatives as new class of inhibitors for human kallikrein 7.

Human kallikrein 7 (KLK7) is a potential target for the treatment of skin inflammation and cancer. Despite its potential, few KLK7-specific small-molecule inhibitors have been reported in the literature. As an extension of our program to design serine protease inhibitors, here we describe the in vitro assays and the investigation of the binding mechanism by molecular dynamics simulation of a novel class of pseudo-peptide inhibitors derived from isomannide. Of the inhibitors tested, two inhibited KLK7 with K(i) values in the low micromolar range (9g=1.8μM; 9j=3.0μM). Eadie-Hofstee and Dixon plots were used to evaluate the competitive mechanism of inhibition for the molecules. Calculated binding free energies using molecular MM/PB(GB)SA approach are in good agreement with experimental results, suggesting that the inhibitors share the same binding mode, which is stabilized by hydrophobic interactions and by a conserved network of hydrogen bonds. The promising results obtained in this study make these compounds valid leads for further optimization studies aiming to improve the potency of this new class of kallikrein inhibitors.

Molecular Modeling, Synthesis And Biological Evaluation of Heterocyclic Hydroxamic Acids Designed as Helicobacter Pylori Urease Inhibitors

Abstract: A computer-generated homology model of the antimicrobial target Helicobacter pylori urease was derived, using the x-ray crystal structure of Klebsiellaaerogenes as a template, in order to design novel urease inhibitors. Based on thesecomputational studies, several heterocyclic hydroxamic acid derivatives have beendesigned, synthesized, and examined for their ability to inhibit urease activity. Keywords: Helicobacter pylori , antimicrobial, urease, hydroxamic acids. INTRODUCTION Almost 90% of the human population is believedinfected with the spiral-shaped, Gram-negative bacterium Helicobacter pylori ( H. pylori ) , making it one of the mostinfectious agents known [1]. After numerous studies on thepathogenic role of this bacterium, it is now widely acceptedthat H. pylori is a major causative factor in peptic ulcerdiseases [2]. Antibiotic eradication therapies in the clinichave been shown to heal gastritis, provide a cure for manypatients suffering from peptic ulcers, and even generate aremission of MALT carcinomas. While the majority of

Hydroxamic Acids Designed as Inhibitors of Urease

Abstract: Urease is an enzyme responsible for the hydrolysis of urea into ammonia and carbamate. Humans infected by urease are exposed to a risk of chronic gastritis or cancer. Urease inhibitors have attracted a great deal of attention for the ir potential as new anti-ulcer drugs. Here, we describe the synthesis of series of hydroxamic acid compounds designed as in-hibitors of urease. Keywords: Hydroxamic acids, Urease, Gastritis, Inhibitors. INTRODUCTION Urease (urea amidohydrolase; E.C.3.5.1.5) is widely pre-sent in a variety of algae, bacteria, fungi and plants. Urease is a nickel-containing enzyme that catalyzes the hydrolysis of urea to produce ammonia and carbamate to protect the bacteria in the acidic environment through the elevation in pH [1,2a]. Humans infected by bacteria such as Helicobacter pylori ( H. pylori ) and Proteus mirabilis are exposed to a high risk of chronic gastritis [3]. The bacterium H. pylori has a major etiological role in human gastric carcinogenesis and has been classified as a class I carcinogen.

Pseudo-peptides derived from isomannide: inhibitors of serine proteases.

In this paper, we describe the synthesis of a novel class of pseudo-peptides derived from isomannide and several oxazolones as potential inhibitors of serine proteases as well as preliminary pharmacological assays for hepatitis C. Hepatitis C, dengue and West Nile fever are among the most important flaviviruses that share one important serine protease enzyme. Serine proteases belong to the most studied class of proteolytic enzymes and are a primary target in the drug development field. Several pseudo-peptides were obtained in good yields from the reaction of isomannide and oxazolones, and their anti-HCV potential using the HCV replicon-based assay was shown.

Pseudo-peptides derived from isomannide as potential inhibitors of serine proteases.

Summary.Hepatitis C, Dengue and West Nile virus are among of the most important flaviviruses that share one important serine protease enzyme. Serine proteases belong to the most studied class of proteolytic enzymes, and are a primary target in the drug development field. In this paper, we describe the synthesis and preliminary molecular modeling studies of a novel class of N-t-Boc amino acid amides derived of isomannide as potential serine proteases inhibitors.

Isomannide-Based Peptidomimetics as Inhibitors for Human Tissue Kallikreins 5 and 7

Human kallikrein 5 (KLK5) and 7 (KLK7) are potential targets for the treatment of skin inflammation and cancer. Previously, we identified isomannide derivatives as potent and competitive KLK7 inhibitors. The introduction of N-protected amino acids into the isomannide-based scaffold was studied. Some KLK5 inhibitors with submicromolar affinity (K i values of 0.3-0.7 μM) were identified, and they were 6- to 13-fold more potent than our previous hits. Enzyme kinetics studies and the determination of the mechanism of inhibition confirmed that the new isomannide-based derivatives are competitive inhibitors of both KLK5 and KLK7. Molecular docking and MD simulations of selected inhibitors into the KLK5 binding site provide insight into the molecular mechanism by which these compounds interact with the enzyme. The promising results obtained in this study open new prospects on the design and synthesis of highly specific KLK5 and KLK7 inhibitors.

Molecular dynamics simulations of the free and inhibitor-bound cruzain systems in aqueous solvent: insights on the inhibition mechanism in acidic pH.

The major cysteine protease of Trypanosoma cruzi, cruzain (CRZ), has been described as a therapeutic target for Chagas’ disease, which affects millions of people worldwide. Thus, a series of CRZ inhibitors has been studied, including a new competitive inhibitor, Nequimed176 (NEQ176). Nevertheless, the structural and dynamic basis for CRZ inhibition remains unclear. Hoping to contribute to this ever-growing understanding of timescale dynamics in the CRZ inhibition mechanism, we have performed the first study using 100 ns of molecular dynamics (MD) simulations of two CRZ systems in an aqueous solvent under pH 5.5: CRZ in the apo form (ligand free) and CRZ complexed to NEQ176. According to the MD simulations, the enzyme adopts an open conformation in the apo form and a closed conformation in the NEQ176–CRZ complex. We also suggest that this closed conformation is related to the hydrogen-bonding interactions between NEQ176 and CRZ, which occurs through key residues, mainly Gly66, Met68, Asn69, and Leu160. In addition, the cross-correlation analysis shows evidence of the correlated motions among Ala110–Asp140, Leu160–Gly189, and Glu190–Gly215 subdomains, as well as, the movements related to Ala1–Thr59 and Asp60–Pro90 regions seem to be crucial for CRZ activity.

Synthesis, biological evaluation and molecular modeling of pseudo-peptides based statine as inhibitors for human tissue kallikrein 5.

Human kallikrein 5 (KLK5) is a potential target for the treatment of skin inflammation and cancer. A new series of statine based peptidomimetic compounds were designed and synthesized through simple and efficient reactions. Some KLK5 inhibitors (2a-c compounds) were identified with nanomolar affinity showing Ki values of 0.12-0.13 μM. Our molecular modeling studies suggest that the inhibitors binding at the KLK5 through H-bond interactions with key residues (mainly His108, Gln242, Gly243, Ser245, and Ser260), disrupting the correlated motions mainly among the Ile67-Tyr127, Glu128-Val187, and Gly237-Ser293 subdomains, which seems to be crucial for KLK5 activity. Therefore, we believe that these findings will significantly facilitate our understanding of the conformational dynamics in the course of KLK5 inhibition and, consequently, the development of more potent molecules as alternative for cancer treatment.