RESUMO
A series of short chain 4-aminoquinoline-imidazole derivatives have been synthesized in one pot two step multicomponent reaction using van leusen standard protocol. The diethylamine function of chloroquine is replaced by substituted imidazole derivatives containing tertiary terminal nitrogen. All the synthesized compounds were screened against the chloroquine sensitive (3D7) and chloroquine resistant (K1) strains of Plasmodium falciparum. Some of the compounds (6, 8, 9 and 17) in the series exhibited comparable activity to CQ against K1 strain of P. falciparum. All the compounds displayed resistance factor between 0.09 and 4.57 as against 51 for CQ. Further, these analogues were found to form a strong complex with hematin and inhibit the ß-hematin formation, therefore these compounds act via heme polymerization target.
Assuntos
Aminoquinolinas/química , Antimaláricos/síntese química , Desenho de Fármacos , Imidazóis/química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Resistência a Medicamentos/efeitos dos fármacos , Hemina/antagonistas & inibidores , Hemina/metabolismo , Imidazóis/síntese química , Imidazóis/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade , Células VeroRESUMO
A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methylpiperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile.
Assuntos
Aminoquinolinas/síntese química , Antimaláricos/síntese química , Malária/tratamento farmacológico , Plasmodium cynomolgi/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Plasmodium yoelii/efeitos dos fármacos , Administração Oral , Aminoquinolinas/farmacologia , Animais , Antimaláricos/farmacologia , Chlorocebus aethiops , Cloroquina/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Heme/antagonistas & inibidores , Heme/metabolismo , Hemina/antagonistas & inibidores , Hemina/biossíntese , Concentração Inibidora 50 , Macaca mulatta , Malária/parasitologia , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Testes de Sensibilidade Parasitária , Plasmodium cynomolgi/crescimento & desenvolvimento , Plasmodium cynomolgi/metabolismo , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/metabolismo , Plasmodium yoelii/crescimento & desenvolvimento , Plasmodium yoelii/metabolismo , Relação Estrutura-Atividade , Células VeroRESUMO
In the present study we have synthesized a new class of 4-aminoquinolines and evaluated against Plasmodium falciparum in vitro (3D7-sensitive strain & K1-resistant strain) and Plasmodium yoelii in vivo (N-67 strain). Among the series, eleven compounds (5, 6, 7, 8, 9, 11, 12, 13, 14, 15 and 21) showed superior antimalarial activity against K1 strain as compared to CQ. In addition, all these analogues showed 100% suppression of parasitemia on day 4 in the in vivo mouse model against N-67 strain when administered orally. Further, biophysical studies suggest that this series of compounds act on heme polymerization target.
Assuntos
Aminoquinolinas/química , Aminoquinolinas/uso terapêutico , Antimaláricos/química , Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Plasmodium yoelii/efeitos dos fármacos , Aminoquinolinas/farmacologia , Animais , Antimaláricos/farmacologia , Chlorocebus aethiops , Descoberta de Drogas , Resistência a Medicamentos , Humanos , Malária Falciparum/tratamento farmacológico , Camundongos , Testes de Sensibilidade Parasitária , Células VeroRESUMO
The present study describes the synthesis of a series of new 4-aminoquinoline-derived thiazolidines and evaluation of their antimalarial activity against a NF-54 strain of Plasmodium falciparum in vitro and N-67 strain of Plasmodium yoelii in vivo. Among the series, two compounds, 2-(4-chloro-phenyl)-thiazolidine-4-carboxylic acid [2-(7-chloro-quinolin-4-ylamino)-ethyl]-amide hydrochloride (14) and 2-(2,6-dichloro-phenyl)-thiazolidine-4-carboxylic acid [2-(7-chloro-quinolin-4-ylamino)-ethyl]-amide hydrochloride (22) exhibited significant suppression of parasitaemia in the in vivo assay. All the analogues were found to form strong complex with haematin and inhibited the ß-haematin formation in vitro. These results suggest that these compounds act on heme polymerization target.
Assuntos
Aminoquinolinas/química , Antimaláricos/síntese química , Antimaláricos/farmacologia , Heme/química , Animais , Antimaláricos/química , Técnicas de Química Sintética , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Hemeproteínas/metabolismo , Malária/tratamento farmacológico , Camundongos , Plasmodium falciparum/efeitos dos fármacos , Polimerização , Tiazolidinas/químicaRESUMO
A new series of quinoline analogs have been synthesized and found active against P. falciparum in vitro and P. yoelli in vivo. Compounds 8, 10 and 11 exhibited superior in vitro activity compared to chloroquine. Selected compounds 8, 10 and 11 exhibited significant suppression of parasitaemia in vivo assay. These analogs form a complex with hematin and inhibit the ß-hematin formation, suggesting that this class of compounds act on a heme polymerization target. Further this study confirms that quinoline ring nitrogen is essential for both transportation of the molecule across the membrane as well as for tight binding to hematin.
Assuntos
Antiprotozoários/farmacologia , Desenho de Fármacos , Plasmodium/efeitos dos fármacos , Tiazolidinas/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tiazolidinas/síntese química , Tiazolidinas/químicaRESUMO
Hepatitis C virus (HCV) NS5B RNA polymerase is crucial for replicating the HCV RNA genome and is an attractive target for developing anti-HCV drugs. A novel series of 2,3-diaryl-1,3-thiazolidin-4-one derivatives were evaluated for their ability to inhibit HCV NS5B. Of this series, compounds 4c, 5b, 5c and 6 emerged as more potent, displaying over 95% inhibition of NS5B RNA polymerase activity in vitro. The two most active compounds 4c and 5c exhibited an IC(50) of 31.9 microM and 32.2 microM, respectively, against HCV NS5B.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Tiazolidinas/síntese química , Tiazolidinas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Técnicas de Química Combinatória , Desenho de Fármacos , Hepatite C/tratamento farmacológico , Concentração Inibidora 50 , Estrutura Molecular , Relação Estrutura-Atividade , Tiazolidinas/química , Replicação Viral/efeitos dos fármacosRESUMO
Malaria is one of the foremost public health problems in developing countries affecting nearly 40% of the global population. Apart from this, the past two decade's emergence of drug resistance has severely limited the choice of available antimalarial drugs. Furthermore, the general trend emerging from the SAR-studies is that chloroquine resistance does not involve any change to the target of this class of drugs but involves compound specific efflux mechanism. Based on this premise a number of groups have developed short chain analogues of 4-aminoquinoline, which are active against CQ-resistant strains of P. falciparum in in vitro studies. However, these derivatives undergo biotransformation (de-alklyation) significantly affecting lipid solubility of the drug. In view of this background information, we thought that it would be interesting to study the effect of additional lipophilicity and cationic charge at the lateral side chain of 4-aminoquinoline. This prompted us to explore the cationic amino acid conjugates namely, lysine and ornithine of 4-aminoquinoline with a view to achieve improved antimalarial activity and to the best of our knowledge such amino acid conjugates have not been hitherto reported in the literature in the case of 4-aminoquinolines. In the present study, a new series of side-chain modified 4-aminoquinolines have been synthesized and found active against both susceptible and multidrug resistant strains of P. falciparum in vitro and P. yoelli in vivo. The seminal finding of the present study is that a new series of compounds having significantly more activity against CQ resistant parasites has been identified.
Assuntos
Aminoquinolinas/farmacologia , Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Aminoquinolinas/síntese química , Animais , Antimaláricos/síntese química , Cloroquina/farmacologia , Resistência a Múltiplos Medicamentos , Concentração Inibidora 50 , Lisina/química , Lisina/farmacologia , Ornitina/química , Ornitina/farmacologia , Testes de Sensibilidade Parasitária , Plasmodium falciparum/crescimento & desenvolvimento , Solubilidade , Relação Estrutura-AtividadeRESUMO
A new series of side-chain modified 4-aminoquinolines have been synthesized and found active against P. falciparum in vitro and P. yoelli in vivo. Compounds 6, 11, 12, and 19 exhibited superior in vitro activity compared to chloroquine. Selected compounds 6, 12, and 19 exhibited significant suppression in the in vivo assay. These analogs form a complex with hematin and inhibit the beta-hematin formation, suggesting that this class of compounds act on a heme polymerization target.
Assuntos
Aminoquinolinas/síntese química , Antimaláricos/síntese química , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Hemeproteínas/antagonistas & inibidores , Hemeproteínas/biossíntese , Camundongos , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Plasmodium yoelii/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A series of 1,3-thiazolidin-4-ones and metathiazanones were synthesized and evaluated as anti-HIV agents. The results of the in vitro assays showed that some of the synthesized compounds were effective inhibitor of reverse transcriptase enzyme of human immunodeficiency virus type-1 (HIV-1) at micromolar concentrations with less cytotoxicity in MT-4 cells as compared to thiazolobenzimidazole (TBZ). Structure-activity relationship studies revealed that the nature of the substituents at the 2 and 3 positions of the thiazolidin-4-one nucleus had a significant impact on the in vitro anti-HIV activity of this class of antiretroviral agents. One of the compounds, 1, inhibited the enzyme at 0.204 microM concentrations with minimal cytotoxicity to MT-4 cells.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Tiazolidinas/química , Tiazolidinas/farmacologia , Fármacos Anti-HIV/química , Linhagem Celular , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tiazolidinas/síntese químicaRESUMO
Iron is crucial for many biochemical reactions involved in the growth and multiplication of the malaria parasite Plasmodium falciparum. There are many reports indicating that the iron chelators have antimalarial activity in vitro, in vivo and in human studies. However, these compounds suffer from a number of serious problems such as limited membrane permeability, short half-life and require long subcutaneous infusions. To circumvent these drawbacks we have designed a new class of iron chelators, wherein EDTA is tethered to 4-aminoquinoline. Here 4-aminoquinoline scaffold is used as a carrier to penetrate biological membrane and facilitate targetting the compounds to acidic food vacuole of the parasite. This study describes the synthesis of novel iron chelators and their in vitro antimalarial activity against P. falciparum strain of NF-54. The calculated LogP values of these compounds suggest the importance of lipophilicity for the antimalarial activity. The EDTA esters are more active than the corresponding acids. The biophysical studies suggest that these compounds may inhibit the parasite growth by iron chelation mechanism.
Assuntos
Aminoquinolinas/síntese química , Aminoquinolinas/farmacologia , Antimaláricos/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Quelantes de Ferro/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/síntese química , Células Cultivadas , Ácido Edético/farmacologia , Humanos , Concentração Inibidora 50 , Quelantes de Ferro/síntese química , Testes de Sensibilidade Microbiana , Modelos QuímicosRESUMO
Ormeloxifene hydrochloride (Centchroman) is once-a-week non-steroidal oral contraceptive agent marketed in India and other countries. In this study, we report a validated isocratic high-performance liquid chromatographic (HPLC) method for chiral separation of D- and L-ormeloxifene hydrochloride. This method is capable of baseline separation of its D- and L-isomers. HPLC separation was achieved on a Lux 5µ cellulose-1 with a mobile phase comprising hexane, isopropanol, methanol and triethylamine (90:10:1:0.5). Validation parameters such as limit of detection, limit of quantitation, linearity, precision, accuracy, specificity and preformulation studies were conducted according to new guidelines of International Conference on Harmonization.
Assuntos
Benzopiranos/química , Cromatografia Líquida de Alta Pressão/métodos , Anticoncepcionais/química , Limite de Detecção , EstereoisomerismoRESUMO
The HIV-1 RT inhibitory activity of 2-(2,6-dihalophenyl)-3-(substituted pyridin-2-yl)-thiazolidin-4-ones has been analyzed with different topological descriptors obtained from DRAGON software. Here, simple topological descriptors (TOPO), Galvez topological charge indices (GVZ) and 2D autocorrelation descriptors (2DAUTO) have been found to yield good predictive models for the activity of these compounds. The correlations obtained from the TOPO class descriptors suggest that less extended or compact saturated structural templates would be better for the activity. The participating GVZ class descriptors suggest that they have same degree of influence on the activity. In 2DAUTO class, the large participation of descriptors of lags seven and three indicate the association of activity information with the seven and three centered structural fragments of these compounds. The physicochemical weighting components of these descriptors suggest homogeneous influence of mass, volume, electronegativity and/ or polarizability on the activity.
Assuntos
Fármacos Anti-HIV/farmacologia , Técnicas de Química Combinatória/métodos , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Piridinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Tiazolidinedionas/farmacologia , Fármacos Anti-HIV/química , Inibidores da Protease de HIV/química , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/fisiologia , Testes de Sensibilidade Microbiana , Piridinas/química , Relação Quantitativa Estrutura-Atividade , Análise de Regressão , Inibidores da Transcriptase Reversa/química , Tiazolidinedionas/químicaRESUMO
Selected 4-thiazolidinone have been synthesized and tested as anti-HIV activity. The results of the in vitro tests showed that one of the compounds, 5, inhibited the enzyme at 0.204 microM concentration with minimal toxicity to MT-4 cell. Furthermore, the QSAR studies indicated the role of PMIZ, Ovality and Total energy content of the compounds in rationalizing the activity.
Assuntos
Fármacos Anti-HIV/farmacologia , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Tiazolidinedionas/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Linhagem Celular , Técnicas de Química Combinatória/métodos , Inibidores da Protease de HIV/síntese química , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/genética , HIV-1/fisiologia , Humanos , Modelos Químicos , Relação Quantitativa Estrutura-Atividade , Inibidores da Transcriptase Reversa/síntese química , Tiazolidinedionas/síntese química , Testes de Toxicidade , Replicação Viral/efeitos dos fármacosRESUMO
During the search for a potent antifungal drug, a cell-permeable metabolite was isolated from a soil isolate taxonomically identified as Penicillium radicum. The strain was found to be a potent antifungal agent. Production conditions of the active compound were optimized and the active compound was isolated, purified, characterized and identified as a phosphoinositide 3-kinase (PI3K) inhibitor, commonly known as wortmannin (Wtmn). This is very first time we are reporting the production of Wtmn from P. radicum. In addition to its previously discovered anticancer properties, the broad spectrum antifungal property of Wtmn was re-confirmed using various fungal strains. Virtual screening was performed through molecular docking studies against potential antifungal targets, and it was found that Wtmn was predicted to impede the actions of these targets more efficiently than known antifungal compounds such as voriconazole and nikkomycin i.e. 1) mevalonate-5-diphosphate decarboxylase (1FI4), responsible for sterol/isoprenoid biosynthesis; 2) exocyst complex component SEC3 (3A58) where Rho- and phosphoinositide-dependent localization is present and 3) Kre2p/Mnt1p a Golgi alpha1,2-mannosyltransferase (1S4N) involved in the biosynthesis of yeast cell wall glycoproteins). We conclude that Wtmn produced from P. radicum is a promising lead compound which could be potentially used as an efficient antifungal drug in the near future after appropriate structural modifications to reduce toxicity and improve stability.
Assuntos
Androstadienos/química , Antifúngicos/química , Penicillium/química , Inibidores de Fosfoinositídeo-3 Quinase , Androstadienos/isolamento & purificação , Androstadienos/farmacologia , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Fungos/efeitos dos fármacos , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Penicillium/classificação , Penicillium/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Filogenia , WortmaninaRESUMO
Interactions of [Cr(salprn)(H(2)O)(2)]ClO(4) with nucleosides and dinucleotides were studied using electrospray ionization mass spectrometry. The nucleosides 2'-deoxycytidine, thymidine, 2'-deoxyadenosine, 2'-deoxyguanosine, cytidine, adenosine and guanosine form 1 : 1 and 2 : 1 adducts with [Cr(salprn)](+), whereas the dinucleotides CpG, GpC, ApT, TpA and TpC form only the 1 : 1 adducts. Collisional activation (CA) spectra of these adducts reveal that Cr(+) attaches to the bases in nucleosides and to both the phosphate and base, especially cytosine and guanine moieties, in the nucleotides. The sugar residues appear to offer no binding sites as elimination of sugar residues is fairly abundant in the CA spectra of the adducts of many of the nucleosides.
Assuntos
Compostos de Cromo/química , Fosfatos de Dinucleosídeos/química , Nucleosídeos/química , Nucleotídeos/química , Compostos Organometálicos/química , Espectrometria de Massas/métodos , Modelos Moleculares , Conformação Molecular , Conformação de Ácido Nucleico , Bases de Schiff , Espectrometria de Massa de Íon Secundário/métodosRESUMO
Non-covalent interactions between met- and leu-enkephalins and their antisense peptides were studied by electrospray ionization mass spectrometry. Mixtures of sense and antisense peptides gave both the corresponding homodimers and heterodimers. The relative abundance ratios of the heterodimer to that of the homodimer of the sense peptide and the relative stability constants of the heterodimers were compared with the corresponding values from mixtures of the sense peptides and a control peptide. The results show that there is a preferential interaction between the sense and antisense peptides compared with that between the sense and control peptides.
Assuntos
Elementos Antissenso (Genética)/química , Encefalinas/química , Peptídeos/química , Encefalina Leucina/química , Encefalina Metionina/química , Espectrometria de MassasRESUMO
In general nucleoside analogues were found to possess in vitro amoebicidal property against trophozoites of Entamoeba histolytica. The acid-labile nature of these compounds completely destroyed their ability to cure caecal amoebiasis of rats. However the therapeutic efficacy of one of these compounds yielded most promising results, with 10% cures when it was administered as enteric coated formulation.
Assuntos
Amebicidas/farmacologia , Desoxirribonucleosídeos/farmacologia , Animais , Doenças do Ceco/tratamento farmacológico , Doenças do Ceco/parasitologia , Avaliação Pré-Clínica de Medicamentos , Entamoeba histolytica/efeitos dos fármacos , Entamebíase/tratamento farmacológico , Feminino , Masculino , Ratos , Comprimidos com Revestimento EntéricoRESUMO
Conformational properties of 2',5'-linked 3'-deoxyribonucleotides have been compared with their natural isomer using CD spectroscopy. It is inferred from the salt induced titration curves that the 2',5'-linked-3'deoxyribonucleotides have rigid phosphodiester backbone.
Assuntos
DNA/química , Conformação de Ácido Nucleico , Oligonucleotídeos/química , Fosfatos/química , Tionucleotídeos/química , Sequência de Bases , Dicroísmo Circular , Modelos Químicos , Dados de Sequência Molecular , Conformação Proteica , Proteínas Recombinantes de Fusão/metabolismo , Temperatura , Termodinâmica , Raios UltravioletaRESUMO
Inhibition of DPP-IV enzyme has taken centre stage as a validated drug target for type 2 diabetes therapy and as a result of research efforts done towards developing effective DPP-IV inhibitors, the first clinical candidate of this class came in focus in 1998. Thus, from 1998 to 2013, these 16-years have witnessed heightened research activities in the discovery and development of clinically relevant inhibitors of DPP-IV as antidiabetic agents. The effective DPP-IV inhibitors have played a key role in this endeavour and as result there are eight approved gliptins in the clinical usage while others are in different stages of clinical trials. A wide variety of DPP-IV inhibitors were synthesized and evaluated; and were classified into several categories based on their core structural features. In this article, classification of all the clinically relevant DPP-IV inhibitors based on selectivity, clinical efficacy and safety profiles is reviewed in terms of generations. This review also encompasses clinical phase wise discussion, developmental progress, chemistry and binding modes of all clinical DPP-IV inhibitors. In addition, major challenges facing the future design and development of safe clinical DPP-IV inhibitor are also briefly mentioned.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Peptidomiméticos/química , Peptidomiméticos/metabolismo , Ligação ProteicaRESUMO
A number of thiazolidin-4-one and thiazinan-4-one derivatives were prepared by three component condensation in one pot reaction method. These compounds were evaluated for anti-hyperglycemic activity by in vitro and in vivo assay systems. The compounds with thiazolidin-4-one and thiazinan-4-one moieties exhibited significant anti-hyperglycemic activity. A few compounds (3a, 3b, 4a and 4b) have exhibited both anti-hyperglycemic and anti-dyslipidemic activities. Among them the thiazinan-4-one derivative 4a showed maximal (45%) improvement in oral glucose tolerance test in db/db mice at 30 mg/kg oral dose.