RESUMO
The serine protease matriptase-2 has attracted much attention as a potential target for the treatment of iron overload diseases. In this study, a series of 27 symmetric, achiral bisbenzamidines was evaluated for inhibitory activity against human matriptase-2, against the closely related enzyme human matriptase, as well as against human thrombin, bovine factor Xa and human trypsin. The conformationally restricted piperazine derivative 19 and the oxamide-derived bisbenzamidine 1 were identified as the most potent inhibitors of this series for matriptase-2 and matriptase, respectively.
Assuntos
Benzamidinas/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Inibidores de Serina Proteinase/farmacologia , Animais , Benzamidinas/síntese química , Benzamidinas/química , Bovinos , Relação Dose-Resposta a Droga , Fator Xa/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Estrutura Molecular , Serina Endopeptidases/metabolismo , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/química , Relação Estrutura-Atividade , Trombina/antagonistas & inibidores , Trombina/metabolismo , Tripsina/metabolismoRESUMO
The anti-protozoal drug pentamidine is active against opportunistic Pneumocystis pneumonia, but in addition has several other biological targets, including the NMDA receptor (NR). Here we describe the inhibitory potencies of 76 pentamidine analogs at 2 binding sites of the NR, the channel binding site labeled with [(3)H]MK-801 and the [(3)H]ifenprodil binding site. Most analogs acted weaker at the ifenprodil than at the channel site. The spermine-sensitivity of NR inhibition by the majority of the compounds was reminiscent of other long-chain dicationic NR blockers. The potency of the parent compound as NR blocker was increased by modifying the heteroatoms in the bridge connecting the 2 benzamidine moieties and also by integrating the bridge into a seven-membered ring. Docking of the 45 most spermine-sensitive bisbenzamidines to a recently described acidic interface between the N-terminal domains of GluN1 and GluN2B mediating polyamine stimulation of the NR revealed the domain contributed by GluN1 as the most relevant target.
Assuntos
Encéfalo/metabolismo , Maleato de Dizocilpina/química , Pentamidina/análogos & derivados , Piperidinas/química , Receptores de N-Metil-D-Aspartato/química , Animais , Sítios de Ligação , Maleato de Dizocilpina/metabolismo , Simulação de Acoplamento Molecular , Pentamidina/síntese química , Pentamidina/metabolismo , Piperazina , Piperazinas/química , Piperazinas/metabolismo , Piperidinas/metabolismo , Estrutura Terciária de Proteína , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Trítio/químicaRESUMO
Increasing the affinity of diamidines for AT-rich regions of DNA has long been an important goal of medicinal chemists who wanted to improve the antiparasitic and antifungal properties of that class of derivatives. In recent years it was demonstrated that diamidines could interfere with many other biomolecular targets including ion channels as well as enzymes and modulate some RNA-protein, DNA-protein, and protein-protein interactions. It is therefore not surprising that diamidines now emerge as novel potential drug candidates for the treatment of various diseases, i.a. neurodegenerative disorders, acidosis-related pathological conditions, hypertension, thrombosis, type 2 diabetes, myotonic dystrophy, and cancers. A summary of the most striking results obtained to date in those domains is presented is this review.
Assuntos
Amidinas/farmacologia , Amidinas/uso terapêutico , Amidinas/química , Animais , DNA/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Enzimas/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Canais Iônicos/antagonistas & inibidores , Distrofia Miotônica/tratamento farmacológico , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Proteínas/antagonistas & inibidores , RNA/antagonistas & inibidores , Trombose/tratamento farmacológicoRESUMO
A facile three step synthesis of a group of N1,N5-bis[4-(5-alkyl-1,2,4-oxadiazol-3-yl)phenyl]glutaramides, N1,N5-bis[4-(1,2,4-oxadiazol-3-yl)phenyl]glutaramide and N1,N5-bis[4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]glutaramide is described. These products are designed to function as masked bis-amidine prodrugs of a promising N1,N5-bis[4-(N'-(carbamimidoyl)phenyl]glutaramide antifungal lead.
Assuntos
Antifúngicos/síntese química , Glutaratos/síntese química , Oxidiazóis/síntese química , Oximas/síntese química , Pró-Fármacos/síntese química , Animais , Antifúngicos/metabolismo , Glutaratos/metabolismo , Microssomos Hepáticos/metabolismo , Oxidiazóis/metabolismo , Oximas/metabolismo , Pró-Fármacos/metabolismo , RatosRESUMO
A small library of 26 2,2'-[alkane-α,ω-diylbis(oxyphenylene)]bis-1H-benzimidazoles has been prepared and evaluated against Giardia intestinalis, Entamoeba histolytica, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum. Among the tested compounds, eight derivatives (17, 19, 20, 24, 27, 30, 32 and 35) exhibited an anti-Plasmodium falciparum activity characterized by IC(50) values in the range of 180-410 nM (0.11-0.21 µg/mL) and selectivity indexes (IC(50) rat skeletal myoblasts L6 cells vs IC(50)P. falciparum K1 strain) varying between 92 and more than 450. Two of the eight novel drug leads, namely compounds 19 and 32, were also active against G. intestinalis and L. donovani with selectivity indexes of 122 and >164 respectively.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Animais , Linhagem Celular , Humanos , Concentração Inibidora 50 , Malária Falciparum/tratamento farmacológico , Testes de Sensibilidade Parasitária , RatosRESUMO
A series of alkanediamide-linked bisbenzamidines was synthesized and tested in vitro against a drug-sensitive strain of Trypanosoma brucei brucei, a drug-resistant strain of Trypanosoma brucei rhodesiense and Pneumocystiscarinii. Bisbenzamidines linked with longer alkanediamide chains were potent inhibitors of both strains of T. brucei. However, bisbenzamidines linked with shorter alkanediamide chains were the most potent compounds against P. carinii. N,N'-Bis[4-(aminoiminomethyl)phenyl] hexanediamide, 4 displayed potent inhibition (IC50=2-3 nM) against T. brucei and P. carinii, and was non-cytotoxic in the A549 human lung carcinoma cell line. The inhibitory bioactivity was significantly reduced when the amidine groups in 4 were moved from the para to the meta positions or replaced with amides.
Assuntos
Amidinas/síntese química , Anilidas/síntese química , Antiprotozoários/síntese química , Benzamidinas/síntese química , Diamida/química , Amidinas/química , Amidinas/farmacologia , Anilidas/química , Anilidas/farmacologia , Animais , Antiprotozoários/química , Antiprotozoários/toxicidade , Benzamidinas/química , Benzamidinas/toxicidade , Linhagem Celular Tumoral , Humanos , Pneumocystis/efeitos dos fármacos , Relação Estrutura-Atividade , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei rhodesiense/efeitos dos fármacosRESUMO
Tafenoquine (an 8-aminoquinoline) was approved by the Food and Drug Administration (FDA) in 2018 for the radical cure of Plasmodium vivax malaria and preventive action against malaria. Despite the fact that the mechanism of action of the drug remains unclear, all studies indicated that a metabolite is responsible for its efficacy. Routes for the preparation of the drug are described.
RESUMO
In 2018, Baricitinib was approved by the Food and Drig Administration (FDA) for the treatment of rheumatoid arthritis. Baricitinib exerts its action by targeting Janus kinases (JAK). In this study, we describe the necessary steps for preparing the drug using two alternative routes.
RESUMO
A small library of 2,2'-[(alpha,omega-alkanediylbis(oxyphenylene)]bis-1H-benzimidazoles has been prepared and screened in vitro against Pneumocystis carinii, Trypanosoma brucei rhodesiense, and Leishmania donovani. Among the six tested compounds two derivatives emerged as promising hits characterized by IC(50) values lower than that determined for pentamidine against L. donovani.
Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Bisbenzimidazol/síntese química , Bisbenzimidazol/farmacologia , Animais , Antiprotozoários/química , Bisbenzimidazol/química , Leishmania donovani/efeitos dos fármacos , Estrutura Molecular , Pneumocystis carinii/efeitos dos fármacos , Relação Estrutura-Atividade , Trypanosoma brucei brucei/efeitos dos fármacosRESUMO
The third International Electronic Conference on Medicinal Chemistry, organized and sponsored by MDPI AG, publisher, and the journal Pharmaceuticals, took place in November 2017 on the SciForum website (www.sciforum.net/conference/ecmc-3). Around 300 authors from 34 different countries participated at the event, which hosted more than 70 presentations, keynotes, videos, and posters. A short description of some works presented during that scientific meeting is disclosed in this report.
RESUMO
A series of 32 piperazine-linked bisbenzamidines (and related analogues) were analysed for their in vitro and in vivo trypanocidal activity against a drug-sensitive strain of Trypanosoma brucei brucei and a drug-resistant strain of Trypanosoma brucei rhodesiense. The compounds showed similar potencies against both strains. The most potent compounds were bisbenzamidines substituted at the amidinium nitrogens with a linear pentyl group (8, inhibitory concentration for 50% (IC(50))=1.7-3.0 nM) or cyclic octyl group (17, IC(50)=2.3-4.6 nM). Replacement of the diamidine groups with diamidoxime groups resulted in a prodrug (22) that was effective orally against T. b. brucei-infected mice. Three compounds (7, 11 and 15) provided 100% cure when administered parenterally. The results indicate that the nature of the substituents at the amidinium nitrogens of bisbenzamidines strongly influence their trypanocidal activity.
Assuntos
Benzamidinas/farmacologia , Piperazinas/farmacologia , Pró-Fármacos/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Administração Oral , Animais , Benzamidinas/síntese química , Benzamidinas/química , Benzamidinas/uso terapêutico , Resistência a Medicamentos , Humanos , Camundongos , Testes de Sensibilidade Parasitária , Piperazina , Piperazinas/síntese química , Piperazinas/química , Piperazinas/uso terapêutico , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/uso terapêutico , Ratos , Tripanossomicidas/síntese química , Tripanossomicidas/química , Tripanossomicidas/uso terapêutico , Tripanossomíase Africana/mortalidade , Tripanossomíase Africana/parasitologiaRESUMO
The second International Electronic Conference on Medicinal Chemistry, organized and sponsored by the publisher MDPI AG and the Journal Pharmaceuticals, took place in November 2016 on the SciForum website (www.sciforum.net/conference/ecmc-12). More than 150 authors from 22 countries participated in the event. Selected works presented during the scientific meeting are disclosed in this report.
RESUMO
A bisoxyphenylene-bisbenzimidazole series with increasing aliphatic chain length (CH2 to C10 H20 ) containing a meta- (m) or para (p)-benzimidazole linkage to the phenylene ring was tested for ability to inhibit the growth of metronidazole-susceptible (C1) and metronidazole-refractory (085) Trichomonas vaginalis isolates under aerobic and anaerobic conditions. Compound 3m, 2,2'-[α,ω-propanediylbis(oxy-1,3-phenylene)]bis-1H-benzimidazole, displayed a 5.5-fold lower minimum inhibitory concentration (MIC) toward T. vaginalis isolate 085 than metronidazole under aerobic growth conditions, (26 µm compared to 145 µm). A dose of 25 mg/kg per day for four days of compound 3m cured a subcutaneous mouse model infection using T. vaginalis isolates 286 (metronidazole susceptible) and 085 (metronidazole refractory). Compound 3m was weakly reduced by pyruvate:ferredoxin oxidoreductase, but unlike metronidazole was not dependent upon added ferredoxin. It is concluded from structure-activity relationships that there was no obvious trend based on the length of the central aliphatic chain, or the steric position of the bisbenzimidazole enabling prediction of biological activity. The compounds generally fulfill Lipinski's rile of five, indicating their potential as drug leads.
Assuntos
Antiprotozoários/química , Antiprotozoários/uso terapêutico , Bisbenzimidazol/análogos & derivados , Bisbenzimidazol/uso terapêutico , Resistência a Medicamentos , Vaginite por Trichomonas/tratamento farmacológico , Trichomonas vaginalis/efeitos dos fármacos , Animais , Antiprotozoários/farmacologia , Bisbenzimidazol/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Metronidazol/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Trichomonas vaginalis/crescimento & desenvolvimentoRESUMO
A library of 52 pentamidine congeners in which the flexible pentyldioxy linker in pentamidine was replaced with various restricted linkers was tested for in-vitro activity against two Plasmodium falciparum strains and Leishmania donovani. The tested compounds were generally more effective against P. falciparum than L. donovani. The most active compounds against the chloroquine-sensitive (D6, Sierra Leone) and -resistant (W2, Indochina) strains of P. falciparum were bisbenzamidines linked with a 1,4-piperazinediyl or 1, 4-homopiperazinediyl moiety, with IC50 values (50% inhibitory concentration, inhibiting parasite growth by 50% in relation to drug-free control) as low as 7 nM based on the parasite lactate dehydrogenase assay. Seven piperazine-linked bisbenzamidines substituted at the amidinium nitrogens with a linear alkyl group of 3-6 carbons (22, 25, 27, 31) or cycloalkyl group of 4, 6 or 7 carbons (26, 32, 34) were more potent (IC50<40 nM) than chloroquine or pentamidine as anti-plasmodial agents. The most active anti-leishmanial agents were 4,4'-[1,4-phenylenebis(methyleneoxy)]bisbenzenecarboximidamide (2, IC50 approximately 0.290 microM) and 1,4-bis[4-(1H-benzimidazol-2-yl)phenyl] piperazine (44, IC50 approximately 0.410 microM), which were 10- and 7-fold more potent than pentamidine (IC50 approximately 2.90 microM). Several of the more active anti-plasmodial agents (e.g. 2, 31, 33, 36-38) were also potent anti-leishmanial agents, indicating broad antiprotozoal properties. However, a number of analogues that showed potent anti-plasmodial activity (1, 18, 21, 22, 25-28, 32, 43, 45) were not significantly active against the Leishmania parasite. This indicates differential modes of anti-plasmodial and anti-leishmanial actions for this class of compounds. These compounds provide important structure-activity relationship data for the design of improved chemotherapeutic agents against parasitic infections.
Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Pentamidina/análogos & derivados , Pentamidina/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Conformação Molecular , Pentamidina/síntese química , Relação Estrutura-Atividade , Células VeroRESUMO
A series of 15 alkanediamide-linked bisbenzamidines and related analogs was synthesized and tested in vitro against two Trypanosoma brucei (T.b.) subspecies: T.b. brucei and T.b. rhodesiense, Trypanosoma cruzi, Leishmania donovani and two Plasmodium falciparum subspecies: a chloroquine-sensitive strain (NF54) and a chloroquine-resistant strain (K1). The in vitro cytotoxicity was determined against rat myoblast cells (L6). Seven compounds (5, 6, 10, 11, 12, 14, 15) showed high potency against both strains of T. brucei and P. falciparum with the inhibitory concentrations for 50% (IC50) in the nanomolar range (IC50 = 1-96 nM). None of the tested derivatives was significantly active against T. cruzi or L. donovani. Three of the more potent compounds (5, 6, 11) were evaluated in vivo in mice infected with the drug-sensitive (Lab 110 EATRO and KETRI 2002) or drug-resistant (KETRI 2538 and KETRI 1992) clinical isolates of T. brucei. Compounds 5 and 6 were highly effective in curing mice infected with the drug-sensitive strains, including a drug-resistant strain KETRI 2538, but were ineffective against KETRI 1992. Thermal melting of DNA and molecular modeling studies indicate AT-rich DNA sequences as possible binding sites for these compounds. Several of the tested compounds are suitable leads for the development of improved antiparasitic agents.
RESUMO
Conformationally restricted bisbenzamidines and related congeners have been synthesized and evaluated for activity against two Plasmodium falciparum strains. The most active compounds, bisbenzamidines linked by a 1,4-piperazinediyl core, had IC(50) values between 3 and 18 nM against both chloroquine-susceptible and -resistant parasites and IC(50) values for cytotoxicity greater than 5 microM, using the A549 human lung epithelial cell line. DNA binding affinity, as estimated by DeltaT(m), did not correlate with either antiparasite effects or cytotoxicity. Each of the active bisbenzamidines interfered with the formation of hemozoin in cell-free systems.
Assuntos
Antimaláricos/síntese química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Linhagem Celular Tumoral , Sistema Livre de Células , Cloroquina/farmacologia , Resistência a Medicamentos , Hemina/metabolismo , Humanos , Conformação Molecular , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A series of 13 1,4-diarylpiperazines has been prepared, evaluated for antileishmanial activity and their binding affinity to DNA was measured. Among these compounds, 1,4-bis[4-(1H-benzimidazol-2-yl)phenyl]piperazine (14) emerged as the most active compound with an IC(50) value of 0.41 microM which is about sevenfold more potent than pentamidine.
Assuntos
Antiprotozoários/síntese química , Divisão Celular/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Piperazinas/síntese química , Animais , Antiprotozoários/farmacologia , Sítios de Ligação , DNA/química , DNA/metabolismo , Concentração Inibidora 50 , Testes de Sensibilidade Parasitária , Piperazinas/farmacologia , Relação Estrutura-AtividadeRESUMO
The continuously increasing use of trimethoprim as a common antibiotic for medical use and for prophylactic application in terrestrial and aquatic animal farming has increased its prevalence in the environment. This has been accompanied by increased drug resistance, generally in the form of alterations in the drug target, dihydrofolate reductase (DHFR). The most highly resistant variants of DHFR are known as type II DHFR, among which R67 DHFR is the most broadly studied variant. We report the first attempt at designing specific inhibitors to this emerging drug target by fragment-based design. The detection of inhibition in R67 DHFR was accompanied by parallel monitoring of the human DHFR, as an assessment of compound selectivity. By those means, small aromatic molecules of 150-250 g/mol (fragments) inhibiting R67 DHFR selectively in the low millimolar range were identified. More complex, symmetrical bis-benzimidazoles and a bis-carboxyphenyl were then assayed as fragment-based leads, which procured selective inhibition of the target in the low micromolar range (K(i) = 2-4 µM). The putative mode of inhibition is discussed according to molecular modeling supported by in vitro tests.
Assuntos
Antibacterianos/química , Proteínas de Bactérias/antagonistas & inibidores , Benzimidazóis/química , Farmacorresistência Bacteriana , Antagonistas do Ácido Fólico/química , Tetra-Hidrofolato Desidrogenase/química , Trimetoprima/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/farmacologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Domínio Catalítico , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios Enzimáticos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Antagonistas do Ácido Fólico/síntese química , Antagonistas do Ácido Fólico/farmacologia , Humanos , Cinética , Camundongos , Modelos Moleculares , Ligação Proteica , Proteínas Recombinantes/química , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/metabolismoRESUMO
Bisbenzamidines, such as pentamidine isethionate, are aromatic dicationic compounds that are active against Pneumocystis and other microbes but are oftentimes toxic to the host. To identify potential anti-Pneumocystis agents, we synthesized bisbenzamidine derivatives in which the parent compound pentamidine was modified by a 1,4-piperazinediyl, alkanediamide, or 1,3-phenylenediamide moiety as the central linker. Several of the compounds were more active against P. carinii and less toxic than pentamidine in cytotoxicity assays. For this study, we evaluated nine bisbenzamidine derivatives representing a range of in vitro activities, from highly active to inactive, for the treatment of pneumocystosis in an immunosuppressed mouse model. Six of these in vitro-active compounds, 01, 02, 04, 06, 100, and 101, exhibited marked efficacies against infection at a dose of 10 mg/kg of body weight, and four compounds, 01, 04, 100, and 101, showed significant increases in survival versus that of untreated infected control mice. Compound 100 was highly efficacious against the infection at 20 mg/kg and 40 mg/kg, with > 1,000-fold reductions in burden, and resulted in improved survival curves versus those for pentamidine-treated mice (at the same doses). All six bisbenzamidine compounds that exhibited high in vitro activity significantly decreased the infection in vivo; two compounds, 12 and 102, with marked to moderate in vitro activities had slight or no activity in vivo, while compound 31 was inactive in vitro and was also inactive in vivo. Thus, the selection of highly active compounds from in vitro cytotoxicity assays was predictive of activity in the mouse model of Pneumocystis pneumonia. We conclude that a number of these bisbenzamidine compounds, especially compound 100, may show promise as new anti-Pneumocystis drugs.
Assuntos
Antifúngicos/química , Antifúngicos/uso terapêutico , Benzamidinas/química , Benzamidinas/uso terapêutico , Pentamidina/química , Piperazinas/química , Pneumonia por Pneumocystis/tratamento farmacológico , Alcanos/química , Animais , Antifúngicos/síntese química , Antifúngicos/toxicidade , Benzamidinas/síntese química , Benzamidinas/toxicidade , Modelos Animais de Doenças , Humanos , Hospedeiro Imunocomprometido , Masculino , Camundongos , Camundongos Endogâmicos C3H , Pentamidina/uso terapêutico , Piperazina , Pneumocystis carinii/efeitos dos fármacos , Pneumonia por Pneumocystis/microbiologia , Pneumonia por Pneumocystis/mortalidadeRESUMO
Infrared and colorimetry data suggest that bisbenzamidines connected by various rigid or flexible linkers are able to interact with heme in cell-free systems. At pH 5.0 the inhibition of formation of beta-hematin could be ascertained by infrared spectroscopy whereas at pH 7.0 the interaction yielded insoluble complexes for which a sandwich-type structure of stoichiometry 2:1, heme-drug, is tentatively proposed.