RESUMEN
This study introduces further insights from the hit-to-lead optimization process involving a series of benzimidazole derivatives acting as inhibitors of the cruzain enzyme, which targets Trypanosoma cruzi, the causative parasite of Chagas disease. Here, we present the design, synthesis and biological evaluation of 30 new compounds as a third generation of benzimidazole analogues with trypanocidal activity, aiming to enhance our understanding of their pharmacokinetic profiles and establish a structure-metabolism relationships within the series. The design of these new analogues was guided by the analysis of previous pharmacokinetic results, considering identified metabolic sites and biotransformation studies. This optimization resulted in the discovery of two compounds (42e and 49b) exhibiting enhanced metabolic stability, anti-Trypanosoma cruzi activity compared to benznidazole (the reference drug for Chagas disease), as well as being non-cruzain inhibitors, and demonstrating a satisfactory in vitro pharmacokinetic profile. These findings unveil a new subclass of aminobenzimidazole and rigid compounds, which offer potential for further exploration in the quest for discovering novel classes of antichagasic compounds.
RESUMEN
Background: Chagas disease is caused by the parasite Trypanosoma cruzi, and the lack of effective and safe treatments makes identifying new classes of compounds with anti-T. cruzi activity of paramount importance. Methods: Hit-to-lead exploration of a metabolically stable N-imidazoylpiperazine was performed. Results: Compound 2, a piperazine derivative active against T. cruzi, was selected to perform the hit-to-lead exploration, which involved the design, synthesis and biological evaluation of 39 new derivatives. Conclusion: Compounds 6e and 10a were identified as optimized compounds with low micromolar in vitro activity, low cytotoxicity and suitable preliminary absorption, distribution, metabolism and excretion and physicochemical properties. Both compounds reduced parasitemia in mouse models of Chagas disease, providing a promising opportunity for further exploration of new antichagasic compounds.
Asunto(s)
Enfermedad de Chagas , Tripanocidas , Trypanosoma cruzi , Animales , Ratones , Tripanocidas/farmacología , Tripanocidas/química , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Relación Estructura-Actividad , Parasitemia/tratamiento farmacológicoRESUMEN
Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi. Because current treatments present several limitations, including long duration, variable efficacy and serious side effects, there is an urgent need to explore new antitrypanosomal drugs. The present study describes the hit-to-lead optimization of a 2-aminobenzimidazole hit 1 identified through in vitro phenotypic screening of a chemical library against intracellular Trypanosoma cruzi amastigotes, which focused on optimizing potency, selectivity, microsomal stability and lipophilicity. Multiparametric Structure-Activity Relationships were investigated using a set of 277 derivatives. Although the physicochemical and biological properties of the initial hits were improved, a combination of low kinetic solubility and in vitro cytotoxicity against mammalian cells prevented progression of the best compounds to an efficacy study using a mouse model of Chagas disease.
Asunto(s)
Enfermedad de Chagas , Tripanocidas , Trypanosoma cruzi , Animales , Tripanocidas/química , Enfermedad de Chagas/tratamiento farmacológico , Relación Estructura-Actividad , MamíferosRESUMEN
Chagas disease is a major public health problem caused by Trypanosoma cruzi, with an estimated 6-7 million people infected and 70 million at risk of infection. T. brucei gambiense and T. brucei rhodesiense are two subspecies of related parasites that cause human African trypanosomiasis, a neglected tropical disease with also millions of people at risk of infection. Pharmacotherapy for both diseases suffers from low efficacy, side effects, or drug resistance. Recently, we reported a noncovalent competitive inhibitor of cruzain (IC50 26 µM, Ki 3 µM) and TbrCatL (IC50 50 µM), two cysteine proteases considered promising drug targets for trypanosomiasis. Here, we describe the design and synthesis of derivatives of our lead compound. The new thiosemicarbazone derivatives showed potency in the nanomolar concentration range against the two enzymes, but they were later characterized as aggregators. Nevertheless, the thiosemicarbazone derivatives showed promising antiparasitic activities against T. b. brucei (EC50 13-49.7 µM) and T. cruzi (EC50 0.027-0.59 µM) under in vitro conditions. The most active thiosemicarbazone was 200-fold more potent than the current anti-chagasic drug, benznidazole, and showed a selectivity index of 370 versus myoblast cells. We have identified an excellent candidate for further optimization and in vivo studies.
Asunto(s)
Enfermedad de Chagas , Tiosemicarbazonas , Tripanocidas , Trypanosoma brucei brucei , Trypanosoma cruzi , Humanos , Tripanocidas/farmacología , Tiosemicarbazonas/farmacología , Inhibidores de Cisteína Proteinasa/farmacología , Relación Estructura-Actividad , Enfermedad de Chagas/tratamiento farmacológicoRESUMEN
Natural products based on imidazole scaffolds have inspired the discovery of a wide variety of bioactive compounds. Herein, a series of imidazoles that act as competitive and potent cruzain inhibitors was investigated using a combination of ligand- and structure-based drug design strategies. Quantitative structure-activity relationships (QSARs) were generated along with the investigation of enzyme-inhibitor molecular interactions. Predictive hologram QSAR (HQSAR, r2pred = 0.80) and AutoQSAR (q2 = 0.90) models were built, and key structural properties that underpin cruzain inhibition were identified. Moreover, comparative molecular field analysis (CoMFA, r2pred = 0.81) and comparative molecular similarity indices analysis (CoMSIA, r2pred = 0.73) revealed 3D molecular features that strongly affect the activity of the inhibitors. These findings were examined along with molecular docking studies and were highly compatible with the intermolecular contacts that take place between cruzain and the inhibitors. The results gathered herein revealed the main factors that determine the activity of the imidazoles studied and provide novel knowledge for the design of improved cruzain inhibitors.
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Cisteína Endopeptidasas/química , Imidazoles/farmacología , Simulación del Acoplamiento Molecular , Inhibidores de Proteasas/química , Proteínas Protozoarias/química , Relación Estructura-Actividad Cuantitativa , Sitios de Unión , Cisteína Endopeptidasas/metabolismo , Diseño de Fármacos , Imidazoles/química , Inhibidores de Proteasas/farmacología , Unión Proteica , Proteínas Protozoarias/antagonistas & inhibidores , Proteínas Protozoarias/metabolismoRESUMEN
Leishmaniasis is a major infectious disease with hundreds of thousands of new cases and over 20,000 deaths each year. The current drugs to treat this life-threatening infection have several drawbacks such as toxicity and long treatment regimens. A library of 1.8 million compounds, from which the hits reported here are publicly available, was screened against Leishmania infantum as part of an optimization program; a compound was found with a 2-aminobenzimidazole functionality presenting moderate potency, low metabolic stability and high lipophilicity. Several rounds of synthesis were performed to incorporate chemical groups capable of reducing lipophilicity and clearance, leading to the identification of compounds that are active against different parasite strains and have improved in vitro properties. As a result of this optimization program, a group of compounds was further tested in anticipation of in vivo evaluation. In vivo tests were carried out with compounds 29 (L. infantum IC50: 4.1 µM) and 39 (L. infantum IC50: 0.5 µM) in an acute L. infantum VL mouse model, which showed problems of poor exposure and lack of efficacy, despite the good in vitro potency.
Asunto(s)
Bencimidazoles/farmacología , Descubrimiento de Drogas , Leishmania infantum/efectos de los fármacos , Leishmaniasis/tratamiento farmacológico , Animales , Antiprotozoarios/farmacología , Bencimidazoles/química , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Microsomas HepáticosRESUMEN
A virtual screening conducted with nearly 4â¯000â¯000 compounds from lead-like and fragment-like subsets enabled the identification of a small-molecule inhibitor (1) of the Trypanosoma cruzi cruzain enzyme, a validated drug target for Chagas disease. Subsequent comprehensive structure-based drug design and structure-activity relationship studies led to the discovery of carbamoyl imidazoles as potent, reversible, and competitive cruzain inhibitors. The most potent carbamoyl imidazole inhibitor (45) exhibited high affinity with a Ki value of 20 nM, presenting both in vitro and in vivo activity against T. cruzi. Furthermore, the most promising compounds reduced parasite burden in vivo and showed no toxicity at a dose of 100 mg/kg. These carbamoyl imidazoles are structurally attractive, nonpeptidic, and easy to prepare and synthetically modify. Finally, these results further advance our understanding of the noncovalent mode of inhibition of this pharmaceutically relevant enzyme, building strong foundations for drug discovery efforts.
Asunto(s)
Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacología , Diseño de Fármacos , Proteínas Protozoarias/antagonistas & inhibidores , Tripanocidas/química , Tripanocidas/farmacología , Cisteína Endopeptidasas/química , Modelos Moleculares , Conformación Proteica , Proteínas Protozoarias/química , Relación Estructura-Actividad , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/enzimologíaRESUMEN
The studies culminating in the synthesis of two large subunits of tautomycetin are described. The first one, fragment C1-C12 that has an anti-1,3-dimethyl system and a terminal diene unit, was accomplished in 10 linear steps in 7.4% overall yield. The second one, fragment C13-C25 which bears the sensitive anhydride framework and the majority of the stereogenic centers, was prepared in 13 linear steps (longest sequence) in 8% overall yield. Among the key transformations used, a regioselective epoxide opening, a Pd-catalyzed addition of terminal alkyne to acceptor alkyne, a Mukaiyama aldol reaction, a Yamaguchi esterification, and a homemade mild di-esterification can be cited. The chosen strategies allowed good yields, stereoselectivity, reproducibility, and scalability for several important intermediates.
RESUMEN
In this work, using DFT calculations, we investigated the 1,4 and 1,5 asymmetric induction in boron enolate aldol reactions of α-alkoxy and α,ß-bisalkoxy methyl ketones. We evaluated the steric influence of alkyl substituents at the α position and the stereoelectronic influence of the oxygen protecting groups at the α and ß positions. Theoretical calculations revealed the origins of the 1,4 asymmetric induction in terms of the nature of the ß-substituent. The synergistic effect between the α,ß-syn and α,ß-anti-bisalkoxy stereocenters was elucidated. In the presence of the ß-alkoxy center, the reaction proceeds through the Goodman-Paton 1,5-stereoinduction model, experiencing a minor influence of the α-alkoxy center.
RESUMEN
This study analyzed the influence of different retreatment protocols on amount of remaining filling material and amount of new sealer after endodontic retreatment. Forty mandibular molars with curved mesial roots were prepared with ProTaper Universal system, and filled with AH Plus sealer mixed with 0.1% rhodamine B and gutta-percha. After 7 days, the specimens were randomized according to the retreatment protocol (n = 10): ProTaper Retreatment System (PTR); PTR+Orange Oil (PTR+OO); PTR+Passive Ultrasonic Irrigation (PTR+PUI). No retreatment was performed in the control group (CG). After retreatment, the root canals were filled with AH Plus mixed with 0.1% fluorescein and gutta-percha. Samples were evaluated under confocal laser scanning microscopy and analyzed using Image J software. Data were analyzed using Kruskal-Wallis and Dunn tests (p < 0.05). Regarding presence of residual filling, the Kruskal-Wallis test indicated no differences among the different retreatment techniques in the perimeter and the isthmus analyses (p > 0.05); however, PTR+PUI was associated with a lesser amount of residual filling material in the canal area analysis (p < 0.05). In evaluating the new filling, the perimeter analysis showed a lesser amount of new endodontic sealer in the PTR group (p < 0.05). Moreover, the PTR+PUI group presented a significantly greater amount of new endodontic sealer in the canal area analysis (p < 0.05). There was no difference among groups in the isthmus analysis (p > 0.05). It can be concluded that PTR associated to PUI yielded better results in removing root canal filling material from the canal area. However, none of the protocols resulted in root walls completely free of remnants.
Asunto(s)
Materiales de Obturación del Conducto Radicular/química , Materiales de Obturación del Conducto Radicular/uso terapéutico , Tratamiento del Conducto Radicular/métodos , Instrumentos Dentales , Cavidad Pulpar/química , Cavidad Pulpar/efectos de los fármacos , Humanos , Microscopía Confocal , Reproducibilidad de los Resultados , Retratamiento/métodos , Tratamiento del Conducto Radicular/instrumentación , Estadísticas no Paramétricas , Resultado del TratamientoRESUMEN
Phenotypic HTS campaigns with a blood stage malaria assay have been used to discover novel chemotypes for malaria treatment with potential alternative mechanisms of action compared to existing agents. N1-(5-(3-Chloro-4-fluorophenyl)furan-2-yl)-N3,N3-dimethylpropane-1,3-diamine, 1 was identified as a modest inhibitor of P. falciparum NF54 (IC50 = 875 nM) with an apparent long plasma half-life after high dose oral administration to mice, although the compound later showed poor metabolic stability in liver microsomes through ring- and side chain-oxidation and N-dealkylation. We describe here the synthesis of derivatives of 1, exploring the influence of substitution patterns around the aromatic ring, variations on the alkyl chain and modifications in the core heterocycle, in order to probe potency and metabolic stability, where 4k showed a long half-life in rats.
Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Diseño de Fármacos , Furanos/química , Furanos/farmacología , Plasmodium falciparum/efectos de los fármacos , Aminas/química , Animales , Antimaláricos/metabolismo , Estabilidad de Medicamentos , Furanos/metabolismo , Semivida , Humanos , Ratones , Pruebas de Sensibilidad Parasitaria , Ratas , Relación Estructura-ActividadRESUMEN
Elaiophylin is an unusual C2-symmetric antibiotic macrodiolide produced on a bacterial modular polyketide synthase assembly line. To probe the mechanism and selectivity of diolide formation, we sought to reconstitute ring formation in vitro by using a non-natural substrate. Incubation of recombinant elaiophylin thioesterase/cyclase with a synthetic pentaketide analogue of the presumed monomeric polyketide precursor of elaiophylin, specifically its N-acetylcysteamine thioester, produced a novel 16-membered C2-symmetric macrodiolide. A linear dimeric thioester is an intermediate in ring formation, which indicates iterative use of the thioesterase active site in ligation and subsequent cyclization. Furthermore, the elaiophylin thioesterase acts on a mixture of pentaketide and tetraketide thioesters to give both the symmetric decaketide diolide and the novel asymmetric hybrid nonaketide diolide. Such thioesterases have potential as tools for the in vitro construction of novel diolides.
RESUMEN
Leprosy is an ancient infectious disease caused by Mycobacterium leprae. According to comparative genomics studies, this disease originated in Eastern Africa or the Near East and spread with successive human migrations. The Europeans and North Africans introduced leprosy into West Africa and the Americas within the past 500 years. In Brazil, this disease arrived with the colonizers who disembarked at the first colonies, Rio de Janeiro, Salvador and Recife, at the end of the sixteenth century, after which it was spread to the other states. In 1854, the first leprosy cases were identified in State of Amazonas in the north of Brazil. The increasing number of leprosy cases and the need for treatment and disease control led to the creation of places to isolate patients, known as leprosaria. One of them, Colonia Antônio Aleixo was built in Amazonas in 1956 according to the most advanced recommendations for isolation at that time and was deactivated in 1979. The history of the Alfredo da Matta Center (AMC), which was the first leprosy dispensary created in 1955, parallels the history of leprosy in the state. Over the years, the AMC has become one of the best training centers for leprosy, general dermatology and sexually transmitted diseases in Brazil. In addition to being responsible for leprosy control programs in the state, the AMC has carried out training programs on leprosy diagnosis and treatment for health professionals in Manaus and other municipalities of the state, aiming to increase the coverage of leprosy control activities. This paper provides a historical overview of leprosy in State of Amazonas, which is an endemic state in Brazil.
Asunto(s)
Lepra/epidemiología , Lepra/prevención & control , Brasil/epidemiología , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Hospitales de Aislamiento/historia , Humanos , Lepra/historia , Mycobacterium leprae , PrevalenciaRESUMEN
Conglobatin is an unusual C2-symmetrical macrodiolide from the bacterium Streptomyces conglobatus with promising antitumor activity. Insights into the genes and enzymes that govern both the assembly-line production of the conglobatin polyketide and its dimerization are essential to allow rational alterations to be made to the conglobatin structure. We have used a rapid, direct in vitro cloning method to obtain the entire cluster on a 41-kbp fragment, encoding a modular polyketide synthase assembly line. The cloned cluster directs conglobatin biosynthesis in a heterologous host strain. Using a model substrate to mimic the conglobatin monomer, we also show that the conglobatin cyclase/thioesterase acts iteratively, ligating two monomers head-to-tail then re-binding the dimer product and cyclizing it. Incubation of two different monomers with the cyclase produces hybrid dimers and trimers, providing the first evidence that conglobatin analogs may in future become accessible through engineering of the polyketide synthase.
Asunto(s)
Antineoplásicos/metabolismo , Streptomyces/genética , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Clonación Molecular , Escherichia coli/metabolismo , Genes Bacterianos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Familia de Multigenes , Oxazoles/química , Oxazoles/aislamiento & purificación , Oxazoles/metabolismo , Sintasas Poliquetidas/genética , Sintasas Poliquetidas/metabolismo , Streptomyces/química , Streptomyces/metabolismoRESUMEN
Leprosy is an ancient infectious disease caused by Mycobacterium leprae. According to comparative genomics studies, this disease originated in Eastern Africa or the Near East and spread with successive human migrations. The Europeans and North Africans introduced leprosy into West Africa and the Americas within the past 500 years. In Brazil, this disease arrived with the colonizers who disembarked at the first colonies, Rio de Janeiro, Salvador and Recife, at the end of the sixteenth century, after which it was spread to the other states. In 1854, the first leprosy cases were identified in State of Amazonas in the north of Brazil. The increasing number of leprosy cases and the need for treatment and disease control led to the creation of places to isolate patients, known as leprosaria. One of them, Colonia Antônio Aleixo was built in Amazonas in 1956 according to the most advanced recommendations for isolation at that time and was deactivated in 1979. The history of the Alfredo da Matta Center (AMC), which was the first leprosy dispensary created in 1955, parallels the history of leprosy in the state. Over the years, the AMC has become one of the best training centers for leprosy, general dermatology and sexually transmitted diseases in Brazil. In addition to being responsible for leprosy control programs in the state, the AMC has carried out training programs on leprosy diagnosis and treatment for health professionals in Manaus and other municipalities of the state, aiming to increase the coverage of leprosy control activities. This paper provides a historical overview of leprosy in State of Amazonas, which is an endemic state in Brazil.
Asunto(s)
Animales , Masculino , Comportamiento de Nidificación , Características de la Residencia , Conducta Sexual Animal , Territorialidad , Tamaño Corporal , Cíclidos , Repeticiones de Microsatélite/genética , Paternidad , Espermatozoides/fisiologíaRESUMEN
Elaiophylin is an unusual C2 -symmetric antibiotic macrodiolide produced on a bacterial modular polyketide synthase assembly line. To probe the mechanism and selectivity of diolide formation, we sought to reconstitute ring formation inâ vitro by using a non-natural substrate. Incubation of recombinant elaiophylin thioesterase/cyclase with a synthetic pentaketide analogue of the presumed monomeric polyketide precursor of elaiophylin, specifically its N-acetylcysteamine thioester, produced a novel 16-membered C2 -symmetric macrodiolide. A linear dimeric thioester is an intermediate in ring formation, which indicates iterative use of the thioesterase active site in ligation and subsequent cyclization. Furthermore, the elaiophylin thioesterase acts on a mixture of pentaketide and tetraketide thioesters to give both the symmetric decaketide diolide and the novel asymmetric hybrid nonaketide diolide. Such thioesterases have potential as tools for the inâ vitro construction of novel diolides.
Asunto(s)
Antibacterianos/biosíntesis , Macrólidos/metabolismo , Sintasas Poliquetidas/metabolismo , Tioléster Hidrolasas/metabolismo , Acilación , Antibacterianos/química , Ciclización , Macrólidos/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Tioléster Hidrolasas/genéticaRESUMEN
Hybrid bioisoster derivatives from N-acylhydrazones and furoxan groups were designed with the objective of obtaining at least a dual mechanism of action: cruzain inhibition and nitric oxide (NO) releasing activity. Fifteen designed compounds were synthesized varying the substitution in N-acylhydrazone and in furoxan group as well. They had its anti-Trypanosoma cruzi activity in amastigotes forms, NO releasing potential and inhibitory cruzain activity evaluated. The two most active compounds (6, 14) both in the parasite amastigotes and in the enzyme contain the nitro group in para position of the aromatic ring. The permeability screening in Caco-2 cell and cytotoxicity assay in human cells were performed for those most active compounds and both showed to be less cytotoxic than the reference drug, benznidazole. Compound 6 was the most promising, since besides activity it showed good permeability and selectivity index, higher than the reference drug. Thereby the compound 6 was considered as a possible candidate for additional studies.
Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Hidrazonas/farmacología , Oxadiazoles/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Células CACO-2 , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Hidrazonas/síntesis química , Hidrazonas/química , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/químicaRESUMEN
The absolute configuration of small crystallizable molecules can be determined with anomalous X-ray diffraction as shown by Bijvoet in 1951. For the majority of compounds that can neither be crystallized nor easily be converted into crystallizable derivatives, stereocontrolled organic synthesis is still required to establish their absolute configuration. In this contribution, a new fundamental methodology for resolving the absolute configuration will be presented that does not require crystallization. With residual dipolar coupling enhanced NMR spectroscopy, ensembles of a limited number of structures are created reflecting the correct conformations and relative configuration. Subsequently, from these ensembles, optical rotation dispersion (ORD) spectra are predicted by DFT calculations and compared to experimental results. The combination of these two steps reveals the absolute configuration of a flexible molecule in solution, which is a big challenge to chiroptical methods and DFT in the absence of NMR spectroscopy. Here the absolute stereochemistry of the product of a new Michael addition, synthesized via a niobium(V) chiral enolate, will be elucidated by using the new methodology.
Asunto(s)
Espectroscopía de Resonancia Magnética/métodos , Modelos Químicos , Niobio/química , Estructura Molecular , Niobio/análisis , Dispersión Óptica Rotatoria , Soluciones , EstereoisomerismoRESUMEN
Reactions of the model acylium ion (CH3)2N-C(+)=O with acyclic, exocyclic, and spiro acetals of the general formula R(1)O-CR(3)R(4)-OR(2) were systematically evaluated via pentaquadrupole mass spectrometry. Characteristic intrinsic reactivities were observed for each of these classes of acetals. The two most common reactions observed were hydride and alkoxy anion [R(1)O(-) and R(2)O(-)] abstraction. Other specific reactions were also observed: (a) a secondary polar [4(+) + 2] cycloaddition for acetals bearing alpha,beta-unsaturated R(3) or R(4) substituents and (b) OH(-) abstraction for exocyclic and spiro acetals. These structurally diagnostic reactions, in conjunction with others observed previously for cyclic acetals, are shown to reveal the class of the acetal molecule and its ring type and substituents and to permit their recognition and distinction from other classes of isomeric molecules.
RESUMEN
A new application of TOPological Sub-structural MOlecular DEsign (TOPS-MODE) was carried out in anti-inflammatory compounds using computer-aided molecular design. Two series of compounds, one containing anti-inflammatory and the other containing nonanti-inflammatory compounds were processed by a k-means cluster analysis in order to design the training and prediction sets. A linear classification function to discriminate the anti-inflammatory from the inactive compounds was developed. The model correctly and clearly classified 88% of active and 91% of inactive compounds in the training set. More specifically, the model showed a good global classification of 90%, that is, (399 cases out of 441). While in the prediction set, they showed an overall predictability of 88% and 84% for active and inactive compounds, being the global percentage of good classification of 85%. Furthermore this paper describes a fragment analysis in order to determine the contribution of several fragments towards anti-inflammatory property, also the present of halogens in the selected fragments were analyzed. It seems that the present TOPS-MODE based QSAR is the first alternate general 'in silico' technique to experimentation in anti-inflammatory discovery.