Eliezer J. Barreiro

Bioisosterism : A useful strategy for molecular modification and drug design

This review aim to demonstrate the role of bioisosterism in rational drug design as well as in the molecular modification and optimization process aiming to improve pharmacodynamic and pharmacokinetic properties of lead compounds. Bioisosterism is a strategy of Medicinal Chemistry for the rational design of new drugs, applied with a lead compound (LC) as a special process of molecular modification (1). The LC should be of a completely well known chemical structure and possess an equally well known mechanism of action, if possible at the level of topographic interaction with the receptor, including knowledge of all of its pharmacophoric group. Furthermore, the pathways of metabolic inactivation (2), as well as the main determining structural factors of the physicochemical properties which regulate the bioavailability, and its side effects, whether directly or not, should be known so as to allow for a broad prediction of the definition of the bioisosteric relation to be used. The success of this strategy in developing new substances which are therapeutically attractive has observed a significant growth in distinct therapeutic classes, being amply used by the pharmaceutical industry to discover new analogs of therapeutic innovations commercially attractive (me-too), and also as a tool useful in the molecular modification. There may be innumerous reasons for the use of bioisosterism to design new drugs, including the necessity to improve pharmacological activity, gain selectivity for a determined receptor or enzymatic isoform subtype - with simultaneous reduction of certain adverse effects -, or even optimize the pharmacokinetics the LC might present. In this paper, we will discuss bioisosterism as a strategy of molecular modification, showing its importance in building a new series of congeners compounds designed as candidate of new drugs, giving examples of successful cases in distinct therapeutic classes (3-7).

Molecular hybridization: a useful tool in the design of new drug prototypes.

Molecular hybridization is a new concept in drug design and development based on the combination of pharmacophoric moieties of different bioactive substances to produce a new hybrid compound with improved affinity and efficacy, when compared to the parent drugs. Additionally, this strategy can result in compounds presenting modified selectivity profile, different and/or dual modes of action and reduced undesired side effects. So, in this paper, we described several examples of different strategies for drug design, discovery and pharmacomodulation focused on new innovative hybrid compounds presenting analgesic, anti-inflammatory, platelet anti-aggregating, anti-infectious, anticancer, cardio- and neuroactive properties.

Privileged Structures: A Useful Concept for the Rational Design of New Lead Drug Candidates

Privileged structures are defined as molecular frameworks which are able of providing useful ligands for more than one type of receptor or enzyme target by judicious structural modifications. In the present work, we describe some examples and applications of the usefulness of the privileged structure concept for the structural design of new drug candidates, by discussing the eligibility of such motifs, including the identification of the N-acylhydrazone template as privileged structures.

The Methylation Effect in Medicinal Chemistry

The Methylation Effect in Medicinal Chemistry Eliezer J. Barreiro,* Arthur E. K€ummerle, and Carlos A. M. Fraga Laborat orio de Avaliac-~ao e Síntese de Subst̂ancias Bioativas (LASSBio), Faculdade de Farm acia, Universidade Federal do Rio de Janeiro, CCS, Cidade Universit aria, CP 68.006, 21941-902 Rio de Janeiro, RJ, Brazil Programa de P os-Graduac-~ao em Farmacologia e Química Medicinal, Instituto de Cîencias Biom edicas, Universidade Federal do Rio de Janeiro, Cidade Universit aria, Ilha do Fund~ao, Rio de Janeiro, RJ, Brazil Programa de P os-Graduac-~ao em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universit aria, Ilha do Fund~ao, Rio de Janeiro, RJ, Brazil

Synthesis and evaluation of analgesic, antiinflammatory and antiplatelet properties of new 2-pyridylarylhydrazone derivatives†

Abstract This work describes recent results from our research program aiming at the synthesis and pharmacological evaluation of new compounds acting as antiinflammatory, analgesic and platelet antiaggregatory. In this paper the synthesis and the pharmacological profile as analgesic, antiinflammatory and anti-platelet of new functionalized 2-pyridylarylhydrazone derivatives 5a–r are discussed. This class of N-heterocyclic derivatives represents a new series of prototype candidates with analgesic and antiinflammatory properties possessing also an important anti-aggregating activity. The pharmacological results herein disclosed suggest that the antiinflammatory and analgesic activities of these new pyridynehydrazone derivatives observed in the carrageenan pleurisy model and acetic acid writhing test, respectively, is probably due to an interference on the arachidonic acid (AA) metabolism. The most important antiinflammatory derivative 2-(2-formylfurane)pyridylhydrazone 5p presented a 79% inhibition of pleurisy at a dose of 80.1 μmol/kg. We also described the results concerning the mechanism of action of this series of N-heterocyclic derivatives in platelet aggregation which suggest a Ca2+ participation, probably by a complexation scavenger mechanism. Compound 2-(2-formylfurane)pyridylhydrazone 5p was able to complex Ca2+ in in vitro experiments at 100 μM concentration, indicating that this series of compounds can act as Ca2+ scavenger depending on the nature of the aryl moiety present at the imine subunit.

Antiplatelet properties of novel N-substituted-phenyl-1,2,3-triazole-4-acylhydrazone derivatives

This paper describes the design, synthesis and pharmacological evaluation of new N-acylhydrazone (NAH) compounds, belonging to the N-substituted-phenyl-1,2,3-triazole-4-acylhydrazone class (2a-p). Classical heteroaromatic ring bioisosterism strategies were applied to the previously reported N-phenylpyrazolyl-4-acylhydrazone derivative 1, elected as lead-compound due to its important anti-aggregating profile on arachidonic acid induced platelet aggregation (IC(50)=24+/-0.5 micro M), from which emerge this new series 2. These new compounds 2a-p were readily synthesized, characterized and tested on platelet aggregation assays induced by collagen (5 micro g/mL), ADP (5 micro M) and arachidonic acid (100 micro M) in rabbit citrated platelet-rich plasma. Compounds 2b, 2d, and 2h were found to be the most potent, exhibiting a significant antiplatelet activity on arachidonic acid- and collagen-induced platelet aggregation. In addition, these new antiplatelet agents are free of gastric ulcerogenic effect and presented discrete anti-inflammatory and analgesic properties. The N-para-chlorophenyltriazolyl-4-acylhydrazone compound 2h produced the highest inhibitory effect on collagen (IC(50)=21.6+/-0.4 micro M) and arachidonic acid-induced platelet aggregation (IC(50)=2.2+/-0.06 micro M), suggesting that the nature of the substituent on the phenyl ring of the N-heteroaromatic system of NAH moiety may be an important structural requirement for the improvement of antiplatelet activity, in comparison with lead-series 1.

Synthesis and anti-inflammatory activity of phthalimide derivatives, designed as new thalidomide analogues.

This paper describes the synthesis and anti-inflammatory activity of new N-phenyl-phthalimide sulfonamides (3a-e) and the isosters N-phenyl-phthalimide amides (4a-e), designed as hybrids of thalidomide (1) and aryl sulfonamide phosphodiesterase inhibitor (2). In these series, compound 3e (LASSBio 468), having a sulfonyl-thiomorpholine moiety, showed potent inhibitory activity on LPS-induced neutrophil recruitment with ED(50)=2.5mg kg(-1), which was correlated with its inhibitory effect on TNF-alpha level.

Os produtos naturais e a química medicinal moderna

Natural products have been utilized by humans since ancient times and the relief and cure of their diseases was the first purpose for using natural products in medicine. The history of the oriental and occidental civilizations is very rich in examples of the utilization of natural products in medicine and health care. Chinese traditional medicine is one of the most important examples of how natural products can be efficient in the treatment of diseases, and it points to the importance of scientific research on natural products, concerning the discovery of new active chemical entities. The complexity, chemical diversity and biological properties of natural products always fascinated people, and during the last 200 years, this led to the discovery of important new drugs. In the last 30 years, the development of new bioassay techniques, biotechnology methods, bio-guided phytochemical studies, automated high throughput screening and high performance analytical methods, have introduced new concepts and possibilities of rational drug design and drug discovery. In this context, natural products have played an important and decisive role in the development of modern medicinal chemistry.

Discovery of novel analgesic and anti-inflammatory 3-arylamine-imidazo[1,2-a]pyridine symbiotic prototypes

We describe herein the design, synthesis and pharmacological evaluation of novel 3-arylamine-imidazo[1,2-a]pyridine derivatives structurally designed as novel symbiotic prototypes presenting analgesic and anti-inflammatory properties. The derivatives obtained were submitted to in vivo assays of nociception, hyperalgesia and inflammation, and to in vitro assays of human PGHS-2 inhibition. These assays allowed the identification of compound LASSBio-1135 (3a) as an anti-inflammatory and analgesic symbiotic prototype. This compound inhibited moderately the human PGHS-2 enzyme activity (IC(50)=18.5 microM) and reverted the capsaicin-induced thermal hyperalgesia (100 micromol/kg, po) similarly to p38 MAPK inhibitor SB-203580 (2). Additionally, LASSBio-1135 (3a) presented activity similar to celecoxib (1) regarding the reduction of the carrageenan-induced rat paw edema (33% of inhibition at 100 micromol/kg, po). We also discovered derivatives LASSBio-1140 (3c) and LASSBio-1141 (3e) as analgesic and anti-inflammatory prototypes, which were able to attenuate the capsaicin-induced thermal hyperalgesia (100 micromol/kg, po) and reduce the carrageenan-induced paw edema (ED(50)=11.5 micromol/kg (3.3mg/kg) and 14.5 micromol/kg (4.1mg/kg), respectively), being both more active than celecoxib (1), despite the fact that their effects involve a different mechanism of action. Additionally, derivative LASSBio-1145 (3j) showed remarkable analgesic (ED(50)=22.7 micromol/kg (8.9 mg/kg)) and anti-inflammatory (ED(50)=8.7 micromol/kg (3.4 mg/kg)) profile in vivo (100 micromol/kg; po), in AcOH-induced abdominal constrictions in mice and carrageenan-induced rat paw edema models, respectively, being a novel orally-active anti-inflammatory drug candidate that acts as a selective PGHS-2 inhibitor (IC(50)=2.8 microM).

Synthesis, trypanocidal activity and docking studies of novel quinoxaline-N-acylhydrazones, designed as cruzain inhibitors candidates

In this paper, we report the structural design, synthesis, trypanocidal activity and docking studies of novel quinoxaline-N-acylhydrazone (NAH) derivatives, planned as cruzain inhibitors candidates, a cysteine protease essential for the survival of Trypanosoma cruzi within the host cell. The salicylaldehyde N-acylhydrazones 7a and 8a presented IC(50) values of the same magnitude order than the standard drug nifurtimox (Nfx), when tested in vitro against epimastigote forms of Trypanosoma cruzi (Tulahuen 2 strain) and were non-toxic at the highest assayed doses rendering selectivity indexes (IC(50) (macrophages)/IC(50) (Trypanosoma cruzi)) of >25 for 7a and >20 for 8a, with IC(50) values in macrophages >400 microM.