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1.
J Enzyme Inhib Med Chem ; 36(1): 1607-1621, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34281458

RESUMEN

Multitarget directed ligands (MTDLs) are emerging as promising treatment options for Alzheimer's disease (AD). Coumarin derivatives serve as a good starting point for designing MTDLs due to their inherent inhibition of monoamine oxidase (MAO) and cholinesterase enzymes, which are complicit in AD's complex pathophysiology. A preliminary series of 3,7-substituted coumarin derivatives were synthesised and evaluated for enzyme inhibitory activity, cytotoxicity as well as neuroprotective ability. The results indicated that the compounds are weak cholinesterase inhibitors with five compounds demonstrating relatively potent inhibition and selectivity towards MAO-B with IC50 values between 0.014 and 0.498 hx00B5;µM. Significant neuroprotective effects towards MPP+-compromised SH-SY5Y neuroblastoma cells were also observed, with no inherent cytotoxicity at 10 µM for all compounds. The overall results demonstrated that substitution of the phenylethyloxy moiety at the 7-position imparted superior general activity to the derivatives, with the propargylamine substitution at the 3-position, in particular, displaying the best MAO-B selectivity and neuroprotection.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Cumarinas/farmacología , Diseño de Fármacos , Inhibidores de la Monoaminooxidasa/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Alzheimer/metabolismo , Línea Celular Tumoral , Cumarinas/síntesis química , Cumarinas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/química , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Relación Estructura-Actividad
2.
J Enzyme Inhib Med Chem ; 35(1): 1596-1605, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32779503

RESUMEN

A series of multi-target directed edaravone derivatives bearing N-benzyl pyridinium moieties were designed and synthesised. Edaravone is a potent antioxidant with significant neuroprotective effects and N-benzyl pyridinium has previously exhibited positive results as part of a dual-site binding, peripheral anionic site (PAS) and catalytic anionic site (CAS), acetylcholinesterase (AChE) inhibitor. The designed edaravone-N-benzyl pyridinium hybrid compounds were docked within the AChE active site. The results indicated interactions with conserved amino acids (Trp279 in PAS and Trp84 in CAS), suggesting good dual-site inhibitory activity. Significant in vitro AChE inhibitory activities were observed for selected compounds (IC50: 1.2-4.6 µM) with limited butyrylcholinesterase inhibitory activity (IC50's >160 µM), indicating excellent selectivity towards AChE (SI: 46 - >278). The compounds also showed considerable antioxidant ability, similar to edaravone. In silico studies indicated that these compounds should cross the blood-brain barrier, making them promising lead molecules in the development of anti-Alzheimer's agents.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Edaravona/farmacología , Simulación del Acoplamiento Molecular , Fármacos Neuroprotectores/farmacología , Compuestos de Piridinio/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Edaravona/síntesis química , Edaravona/química , Electrophorus , Caballos , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Compuestos de Piridinio/química , Relación Estructura-Actividad
3.
Molecules ; 25(19)2020 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-33027964

RESUMEN

The impact of excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptor overactivation and voltage gated calcium channel (VGCC) depolarization is prominent among the postulated processes involved in the development of neurodegenerative disorders. NGP1-01, a polycyclic amine, has been shown to be neuroprotective through modulation of the NMDA receptor and VGCC, and attenuation of MPP+-induced neurotoxicity. Recently, we reported on the calcium modulating effects of tricycloundecene derivatives, structurally similar to NGP1-01, on the NMDA receptor and VGCC of synaptoneurosomes. In the present study, we investigated novel 4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives for their cytotoxicity, neuroprotective effects via attenuation of MPP+-induced neurotoxicity and calcium influx inhibition abilities through the NMDA receptor and VGCC using neuroblastoma SH-SY5Y cells. All compounds, in general, showed low or no toxicity against neuroblastoma cells at 10-50 µM concentrations. At 10 µM, all compounds significantly attenuated MPP+-induced neurotoxicity as evident by the enhancement in cell viability between 23.05 ± 3.45% to 53.56 ± 9.29%. In comparison to known active compounds, the derivatives demonstrated mono or dual calcium modulating effect on the NMDA receptor and/or VGCC. Molecular docking studies using the NMDA receptor protein structure indicated that the compounds are able to bind in a comparable manner to the crystallographic pose of MK-801 inside the NMDA ion channel. The biological characteristics, together with results from in silico studies, suggest that these compounds could act as neuroprotective agents for the purpose of halting or slowing down the degenerative processes in neuronal cells.


Asunto(s)
Bloqueadores de los Canales de Calcio , Canales de Calcio , Simulación del Acoplamiento Molecular , Neuronas , Fármacos Neuroprotectores , Receptores de N-Metil-D-Aspartato , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/química , Canales de Calcio/metabolismo , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Neuronas/química , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismo
4.
Biologicals ; 60: 15-23, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31130314

RESUMEN

Medicines are assigned International Nonproprietary Names (INN) by the World Health Organization (WHO), pursuing the aim to increase patient safety. Following scientific developments in drug discovery and biotechnology, the number of biological medicines is constantly growing and a surge in INN applications for them has been observed. Pharmacologically active biological substances have a complex structure and mechanism of action posing new challenges in selecting names that appropriately reflect such properties. As a consequence, existing nomenclature naming schemes may need to be revised and new ones developed. This review reports on the recently implemented policies for naming fusion proteins, monoclonal antibodies, advanced therapy substances that cover gene and cell therapy, virus-based therapies as well as vaccines and vaccine-like substances. Different approaches, based on the use of a one-word versus a two-word naming scheme, have been developed for different categories of biological substances highlighting a major and still not completely resolved issue, i.e. how to assign a name that is both informative, short and euphonic.


Asunto(s)
Productos Biológicos , Terminología como Asunto , Humanos , Seguridad del Paciente , Organización Mundial de la Salud
6.
Bioorg Med Chem Lett ; 28(8): 1287-1291, 2018 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-29559277

RESUMEN

Previously we have shown that pentacycloundecylamine-chloroquinoline (PCU-CQ) conjugates possess significant chemosensitizing abilities and can circumvent the resistance associated with chloroquine (CQ) resistant plasmodia. In order to further explore structurally related polycyclic compounds as reversed CQ agents we synthesized a series of eight aza-adamantanol (1-4) and adamantane-imine (5-8) CQ conjugates. All conjugates showed limited cytotoxicity against CHO cells (IC50 > 37 µM). Compounds 1, 2 and 5 were highly active (K1 IC50 < 100 nM) exhibiting a 3-4-fold increase in antiplasmodial activity against CQ resistant strain K1 compared to CQ. Reduced cross-resistance (resistance index, RI: 2-4.3) relative to CQ (RI = 38) was also observed for these compounds. Compound 1 which showed an 18-fold enhancement at retaining its activity against the K1 strain compared to CQ is a promising candidate to substitute CQ in P. falciparum resistant malaria.


Asunto(s)
Adamantano/análogos & derivados , Adamantano/farmacología , Aminoquinolinas/farmacología , Antimaláricos/farmacología , Farmacorresistencia Microbiana/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Adamantano/síntesis química , Adamantano/química , Aminoquinolinas/síntesis química , Aminoquinolinas/química , Aminoquinolinas/toxicidad , Animales , Antimaláricos/síntesis química , Antimaláricos/química , Antimaláricos/toxicidad , Células CHO , Cricetulus , Eritrocitos/microbiología , Humanos , Concentración 50 Inhibidora , Estructura Molecular
7.
Molecules ; 23(2)2018 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-29385098

RESUMEN

In order to utilize the neuroprotective properties of polycyclic cage compounds, and explore the NO-donating ability of nitrophenyl groups, an array of compounds was synthesized where the different nitrophenyl groups were appended on oxa and aza-bridged cage derivatives. Biological evaluations of the compounds were done for cytotoxicity, neuroprotective abilities, the inhibition of N-methyl-d-aspartate (NMDA)-mediated Ca2+ influx, the inhibition of voltage-mediated Ca2+ influx, and S-nitrosylation abilities. All of the compounds showed low toxicity. With a few exceptions, most of the compounds displayed good neuroprotection and showed inhibitory activity for NMDA-mediated and voltage-gated calcium influx, ranging from high (>70%) to low (20-39%) inhibition. In the S-nitrosylation assay, the compounds with the nitro moiety as the NO-donating group exhibited low to good nitrosylation potency compared to the positive controls. From the biological evaluation of the tested compounds, it was not possible to obtain a simple correlation that could explain the results across all of the biological study domains. This can be ascribed to the independent processes evaluated in the different assays, which reiterate that neuroprotection is a result of multifactorial biochemical mechanisms and interactions. However, these results signify the important aspects of the pentacylcoundecylamine neuroprotectants across different biological study realms.


Asunto(s)
Señalización del Calcio/efectos de los fármacos , Fármacos Neuroprotectores , Donantes de Óxido Nítrico , Animales , Supervivencia Celular/efectos de los fármacos , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Donantes de Óxido Nítrico/síntesis química , Donantes de Óxido Nítrico/química , Donantes de Óxido Nítrico/farmacología , Células PC12 , Ratas
8.
Molecules ; 23(7)2018 07 10.
Artículo en Inglés | MEDLINE | ID: mdl-29996497

RESUMEN

Dengue fever is a major public health concern in many tropical and sub-tropical regions. The development of agents that are able to inhibit the dengue virus (DENV) is therefore of utmost importance. This study focused on the synthesis of dual acting hybrids comprising structural features of known DENV inhibitors, amantadine (1) and benzsulfonamide derivatives. Hybrid compound 3, N-(adamantan-1-yl)-4-[(adamantan-1-yl)sulfamoyl]benzamide, was synthesized by reacting amantadine (1) with 4-(chlorosulfonyl)benzoic acid (2), after optimization, in a 2:1 ratio under microwave irradiation conditions in a one-pot reaction. Mono-adamantane derivatives 6 and 7 were synthesised via acyl halide formation of benzoic acid (4) and 4-sulfamoyl benzoic acid (5), respectively, followed by conjugation with amantadine (1) through a conventional or microwave irradiation assisted nucleophilic addition/substitution reaction. The use of microwave irradiation lead to significant increases in yields and a reduction in reaction times. Nuclear magnetic resonance, infra-red and mass spectral data confirmed the structures. Compound 3 and 7 showed significant anti-DENV serotype 2 activity (IC50 = 22.2 µM and 42.8 µM) and low cytotoxicity (CC50 < 100 µM). Possible mechanisms of action are also proposed, which are based on the biological results and molecular docking studies.


Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Virus del Dengue/efectos de los fármacos , Microondas , Células A549 , Antivirales/química , Benzamidas/química , Muerte Celular/efectos de los fármacos , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Estándares de Referencia , Proteínas no Estructurales Virales/metabolismo
9.
Molecules ; 22(10)2017 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-28973990

RESUMEN

A medium-throughput screen using Mycobacterium tuberculosis H37Rv was employed to screen an in-house library of structurally diverse compounds for antimycobacterial activity. In this initial screen, eleven 7-substituted coumarin derivatives with confirmed monoamine oxidase-B and cholinesterase inhibitory activities, demonstrated growth inhibition of more than 50% at 50 µM. This prompted further exploration of all the 7-substituted coumarins in our library. Four compounds showed promising MIC99 values of 8.31-29.70 µM and 44.15-57.17 µM on M. tuberculosis H37Rv in independent assays using GAST-Fe and 7H9+OADC media, respectively. These compounds were found to bind to albumin, which may explain the variations in MIC between the two assays. Preliminary data showed that they were able to maintain their activity in fluoroquinolone resistant mycobacteria. Structure-activity relationships indicated that structural modification on position 4 and/or 7 of the coumarin scaffold could direct the selectivity towards either the inhibition of neuronal enzymes or the antimycobacterial effect. Moderate cytotoxicities were observed for these compounds and slight selectivity towards mycobacteria was indicated. Further neuroprotective assays showed significant neuroprotection for selected compounds irrespective of their neuronal enzyme inhibitory properties. These coumarin molecules are thus interesting lead compounds that may provide insight into the design of new antimicrobacterial and neuroprotective agents.


Asunto(s)
Antibacterianos/química , Inhibidores de la Colinesterasa/química , Cumarinas/química , Inhibidores de la Monoaminooxidasa/química , Mycobacterium tuberculosis/efectos de los fármacos , Fármacos Neuroprotectores/química , Animales , Antibacterianos/farmacología , Sitios de Unión , Línea Celular , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Cumarinas/farmacología , Cricetulus , Farmacorresistencia Bacteriana , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Inhibidores de la Monoaminooxidasa/farmacología , Fármacos Neuroprotectores/farmacología , Unión Proteica , Relación Estructura-Actividad
10.
Malar J ; 15: 50, 2016 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-26823078

RESUMEN

BACKGROUND: A large number of natural products have shown in vitro antiplasmodial activities. Early identification and prioritization of these natural products with potential for novel mechanism of action, desirable pharmacokinetics and likelihood for development into drugs is advantageous. Chemo-informatic profiling of these natural products were conducted and compared to currently registered anti-malarial drugs (CRAD). METHODS: Natural products with in vitro antiplasmodial activities (NAA) were compiled from various sources. These natural products were sub-divided into four groups based on inhibitory concentration (IC50). Key molecular descriptors and physicochemical properties were computed for these compounds and analysis of variance used to assess statistical significance amongst the sets of compounds. Molecular similarity analysis, estimation of drug-likeness, in silico pharmacokinetic profiling, and exploration of structure-activity landscape were also carried out on these sets of compounds. RESULTS: A total of 1040 natural products were selected and a total of 13 molecular descriptors were analysed. Significant differences were observed among the sub-groups of NAA and CRAD for at least 11 of the molecular descriptors, including number of hydrogen bond donors and acceptors, molecular weight, polar and hydrophobic surface areas, chiral centres, oxygen and nitrogen atoms, and shape index. The remaining molecular descriptors, including clogP, number of rotatable bonds and number of aromatic rings, did not show any significant difference when comparing the two compound sets. Molecular similarity and chemical space analysis identified natural products that were structurally diverse from CRAD. Prediction of the pharmacokinetic properties and drug-likeness of these natural products identified over 50% with desirable drug-like properties. Nearly 70% of all natural products were identified as potentially promiscuous compounds. Structure-activity landscape analysis highlighted compound pairs that form 'activity cliffs'. In all, prioritization strategies for the NAA were proposed. CONCLUSIONS: Chemo-informatic profiling of NAA and CRAD have produced a wealth of information that may guide decisions and facilitate anti-malarial drug development from natural products. Articulation of the information provided within an interactive data-mining environment led to a prioritized list of NAA.


Asunto(s)
Antimaláricos/química , Productos Biológicos/química , Peso Molecular
11.
Bioorg Med Chem Lett ; 26(4): 1151-5, 2016 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-26832222

RESUMEN

Pentacycloundecylamines (PCUs) and adamantane amines, such as NGP1-01 (1) and amantadine, have shown significant channel blocking activities. They are postulated to act as chemosensitizers and circumvent the resistance of the plasmodia parasite against chloroquine (CQ) by inhibiting the p-glycoprotein efflux pump and enabling the accumulation of CQ inside the parasite digestive vacuole. Twelve polycyclic amines containing either a PCU or adamantane amine moiety conjugated to different aromatic functionalities through various tethered linkers were selected based on their channel blocking abilities and evaluated as potential chemosensitizers. Compounds 2, 4, 5 and 10 showed significant voltage-gated calcium channel (VGCC) blocking ability (IC50=0.27-35 µM) and were able to alter the CQ IC50 in differing degrees (45-81%) in the multidrug resistant Plasmodium falciparum Dd2 isolate. Among them, the PCU-dansyl amine compound (4) displayed the best potential to act as a chemosensitizer against the Dd2 strain at a 1 µM concentration (RMI=0.19) while displaying moderate antiplasmodial activity (Dd2 IC50=6.25 µM) and low in vitro cytotoxicity against a mammalian cell line (CHO, IC50=119 µM). Compounds 2 and 10 also showed some promising chemosensitizing abilities (RMI=0.36 and 0.35 respectively). A direct correlation was found between the VGCC blocking ability of these polycyclic amines and their capacity to act as CQ resistance modulating agents.


Asunto(s)
Aminas/química , Antimaláricos/química , Adamantano/química , Aminas/metabolismo , Aminas/farmacología , Animales , Antimaláricos/metabolismo , Antimaláricos/farmacología , Células CHO , Canales de Calcio/química , Canales de Calcio/metabolismo , Supervivencia Celular/efectos de los fármacos , Cloroquina/farmacología , Cricetinae , Cricetulus , Resistencia a Medicamentos/efectos de los fármacos , Concentración 50 Inhibidora , Plasmodium falciparum/efectos de los fármacos , Unión Proteica , Relación Estructura-Actividad
12.
Arch Pharm (Weinheim) ; 349(4): 252-67, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26892182

RESUMEN

Preclinical studies for neurodegenerative diseases have shown a multi-targeted approach to be successful in the treatment of these complex disorders with several pathoetiological pathways. Polycyclic compounds, such as NGP1-01 (7a), have demonstrated the ability to target multiple mechanisms of the complex etiology and are referred to as multifunctional compounds. These compounds have served as scaffolds with the ability to attenuate Ca(2+) overload and excitotoxicity through several pathways. In this study, our focus was on mitigating Ca(2+) overload through the L-type calcium channels (LTCC). Here, we report the synthesis and biological evaluation of several novel polycyclic compounds. We determined the IC50 values for both the pentacycloundecylamines and the triquinylamines by means of a high-throughput fluorescence calcium flux assay utilizing Fura-2/AM. The potential of these compounds to offer protection against hydrogen peroxide-induced cell death was also evaluated. Overall, 8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6) .0(3,10) .0(5,9) ]undecane (NGP1-01, 7a) had the most favorable pharmacological profile with an IC50 value of 86 µM for LTCC inhibition and significant reduction of hydrogen peroxide-induced cell death. In general, the triquinylamines were more active as LTCC blockers than the oxa-pentacycloundecylamines. The aza-pentacycloundecylamines were potent LTCC inhibitors, with 8-hydroxy-N-phenylethyl-8,11-azapentacyclo[5.4.0.0(2,6) .0(3,10) .0(5,9) ]undecane (8b) also able to offer significant protection in the cell viability assays.


Asunto(s)
Aminas/química , Bloqueadores de los Canales de Calcio/química , Canales de Calcio Tipo L/metabolismo , Calcio/metabolismo , Hidrocarburos Alicíclicos/química , Quinonas/química , Aminas/síntesis química , Aminas/farmacología , Animales , Apoptosis/efectos de los fármacos , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/farmacología , Supervivencia Celular/efectos de los fármacos , Hidrocarburos Alicíclicos/síntesis química , Hidrocarburos Alicíclicos/farmacología , Peróxido de Hidrógeno/farmacología , L-Lactato Deshidrogenasa/metabolismo , Células PC12 , Quinonas/síntesis química , Quinonas/farmacología , Ratas , Relación Estructura-Actividad
13.
Molecules ; 21(1): 104, 2016 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-26784165

RESUMEN

In light of current resistance to antimalarial drugs, there is a need to discover new classes of antimalarial agents with unique mechanisms of action. Identification of unique scaffolds from natural products with in vitro antiplasmodial activities may be the starting point for such new classes of antimalarial agents. We therefore conducted scaffold diversity and comparison analysis of natural products with in vitro antiplasmodial activities (NAA), currently registered antimalarial drugs (CRAD) and malaria screen data from Medicine for Malaria Ventures (MMV). The scaffold diversity analyses on the three datasets were performed using scaffold counts and cumulative scaffold frequency plots. Scaffolds from the NAA were compared to those from CRAD and MMV. A Scaffold Tree was also generated for each of the datasets and the scaffold diversity of NAA was found to be higher than that of MMV. Among the NAA compounds, we identified unique scaffolds that were not contained in any of the other compound datasets. These scaffolds from NAA also possess desirable drug-like properties making them ideal starting points for antimalarial drug design considerations. The Scaffold Tree showed the preponderance of ring systems in NAA and identified virtual scaffolds, which may be potential bioactive compounds.


Asunto(s)
Antimaláricos/química , Productos Biológicos/química , Diseño de Fármacos , Bibliotecas de Moléculas Pequeñas/química , Antimaláricos/farmacología , Bases de Datos de Compuestos Químicos , Descubrimiento de Drogas , Humanos , Malaria/tratamiento farmacológico , Plasmodium/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad , Interfaz Usuario-Computador
14.
Bioorg Med Chem Lett ; 24(23): 5516-9, 2014 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-25451997

RESUMEN

The control of malaria has been complicated by increased resistance of the malaria parasite to existing antimalarials such as chloroquine (CQ). Herein, we report the ability of NGP1-01, the prototype pentacycloundecylamine (PCU), to reverse CQ resistance (>50%) and act as a chemosensitizer. Based on this finding we set out to synthesize a small series of novel agents comprising of a PCU moiety as the reversal agent conjugated to a CQ-like aminoquinoline (AM) molecule and evaluate the potential of these PCU-AM derivatives as reversed CQ agents. PCU-AM derivatives 1-3 showed anti-plasmodial IC50 values in the ranges of 3.74-17.6 nM and 27.6-253.5 nM against CQ-sensitive (D10) and CQ-resistant strains (Dd2) of Plasmodium falciparum, respectively. Compound 1 presented with the best antiplasmodial activity at low nM concentrations against both strains and was found to be 5 fold more active against the resistant strain than CQ. Compound 1 can be considered as a lead compound to develop reversed CQ agents with improved pharmacodynamic and pharmacokinetic properties.


Asunto(s)
Aminas/química , Antimaláricos/farmacología , Cloroquina/farmacología , Malaria/tratamiento farmacológico , Aminas/metabolismo , Humanos , Estructura Molecular
15.
Mini Rev Med Chem ; 24(13): 1277-1292, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38275027

RESUMEN

Neurodegenerative disorders pose a significant challenge to global healthcare systems due to their progressive nature and the resulting loss of neuronal cells and functions. Excitotoxicity, characterized by calcium overload, plays a critical role in the pathophysiology of these disorders. In this review article, we explore the involvement of calcium dysregulation in neurodegeneration and neurodegenerative disorders. A promising therapeutic strategy to counter calcium dysregulation involves the use of calcium modulators, particularly polycyclic cage compounds. These compounds, structurally related to amantadine and memantine, exhibit neuroprotective properties by attenuating calcium influx into neuronal cells. Notably, the pentacycloundecylamine NGP1-01, a cage-like structure, has shown efficacy in inhibiting both N-methyl-D-aspartate (NMDA) receptors and voltage- gated calcium channels (VGCCs), making it a potential candidate for neuroprotection against excitotoxic-induced neurodegenerative disorders. The structure-activity relationship of polycyclic cage compounds is discussed in detail, highlighting their calcium-inhibitory activities. Various closed, open, and rearranged cage compounds have demonstrated inhibitory effects on calcium influx through NMDA receptors and VGCCs. Additionally, these compounds have exhibited neuroprotective properties, including free radical scavenging, attenuation of neurotoxicities, and reduction of neuroinflammation. Although the calcium modulatory activities of polycyclic cage compounds have been extensively studied, apart from amantadine and memantine, none have undergone clinical trials. Further in vitro and in vivo studies and subsequent clinical trials are required to establish the efficacy and safety of these compounds. The development of polycyclic cages as potential multifunctional agents for treating complex neurodegenerative diseases holds great promise.


Asunto(s)
Calcio , Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Calcio/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Animales , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/química , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Canales de Calcio/metabolismo
16.
Bioorg Med Chem Lett ; 23(6): 1707-11, 2013 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-23414839

RESUMEN

Pentacycloundecylamine (PCU) derived compounds have been shown to be promising lead structures for the development of novel drug candidates aimed at a variety of neurodegenerative and psychiatric diseases. Here we show for the first time a 3D quantitative structure-activity relationship (3D-QSAR) for a series of aza-PCU-derived compounds with activity at the sigma-1 (σ1) receptor. A comparative molecular field analysis (CoMFA) model was developed with a partial least squares cross validated (q(2)) regression value of 0.6, and a non-cross validated r(2) of 0.9. The CoMFA model was effective at predicting the sigma-1 activities of a test set with an r(2) >0.7. We also describe here the docking of the PCU-derived compounds into a homology model of the sigma-1 (σ1) receptor, which was developed to gain insight into binding of these cage compounds to the receptor. Based on docking studies we evaluated in a [(3)H]pentazocine binding assay an oxa-PCU, NGP1-01 (IC50=1.78µM) and its phenethyl derivative (IC50=1.54µM). Results from these studies can be used to develop new compounds with specific affinity for the sigma-1(σ1) receptor.


Asunto(s)
Aminas/química , Relación Estructura-Actividad Cuantitativa , Receptores sigma/química , Aminas/metabolismo , Compuestos Aza/química , Sitios de Unión , Cinética , Simulación del Acoplamiento Molecular , Unión Proteica , Estructura Terciaria de Proteína , Receptores sigma/metabolismo , Receptor Sigma-1
17.
Tuberculosis (Edinb) ; 141: 102350, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37244249

RESUMEN

A series of molecules containing bulky lipophilic scaffolds was screened for activity against Mycobacterium tuberculosis and a number of compounds with antimycobacterial activity were identified. The most active compound, (2E)-N-(adamantan-1-yl)-3-phenylprop-2-enamide (C1), has a low micromolar minimum inhibitory concentration, low cytotoxicity (therapeutic index = 32.26), low mutation frequency and is active against intracellular Mycobacterium tuberculosis. Whole genome sequencing of mutants resistant to C1 showed a mutation in mmpL3 which may point to the involvement of MmpL3 in the antimycobacterial activity of the compound. In silico mutagenesis and molecular modelling studies were performed to better understand the binding of C1 within MmpL3 and the role that the specific mutation may play in the interaction at protein level. These analyses revealed that the mutation increases the energy required for binding of C1 within the protein translocation channel of MmpL3. The mutation also decreases the solvation energy of the protein, suggesting that the mutant protein might be more solvent-accessible, thereby restricting its interaction with other molecules. The results reported here describe a new molecule that may interact with the MmpL3 protein, providing insights into the effect of mutations on protein-ligand interactions and enhancing our understanding of this essential protein as a priority drug target.


Asunto(s)
Mycobacterium tuberculosis , Antituberculosos/farmacología , Antituberculosos/metabolismo , Proteínas de Transporte de Membrana/genética , Amidas/metabolismo , Amidas/farmacología , Pruebas de Sensibilidad Microbiana , Proteínas Bacterianas/metabolismo
18.
Bioorg Med Chem ; 20(2): 809-18, 2012 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-22197671

RESUMEN

Neurodegenerative disorders are frequently associated with increased oxidative damage to the brain as a result of free radicals produced by cellular respiration. The onset and progression of neurodegeneration may therefore be curbed by exogenous hydrogen-donating antioxidant moieties such as the naturally occurring flavonoids. A series of 2-phenylquinolin-4(1H)-ones was synthesised and displayed moderate to high antioxidant activity when compared to structurally related flavones and quinolines. Activity of the hydroxy-2-phenylquinolin-4(1H)-ones (8-10) was established in reducing ferrous ions and diminishing hydrogen peroxide and hydroxyl radical production, in the FRAP (1.41-97.71% Trolox equivalents), ORAC (9.18-15.27 µM Trolox equivalents at 0.00 1mM) and TBARS (0.05-0.72 nmol MDA/mg tissue) assays, respectively. The results indicated that the additional hydrogen donating groups on the synthesised 2-phenylquinolin-4(1H)-one series increased antioxidant activity.


Asunto(s)
4-Quinolonas/química , Antioxidantes/química , Flavonas/química , 4-Quinolonas/síntesis química , Antioxidantes/síntesis química , Humanos , Peróxido de Hidrógeno/química , Radical Hidroxilo/química , Enfermedades Neurodegenerativas/metabolismo
19.
Mini Rev Med Chem ; 22(2): 387-407, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-33605858

RESUMEN

The treatment and management of tuberculosis (TB) is a major global concern. Approved drugs for the treatment of TB, to date, have displayed various modes of action which can be grouped into radical releasing and non-radical releasing anti-TB agents. Radical releasing agents are of special interest because they diffuse directly into the mycobacterium cell wall, interact with the host cell DNA, causing DNA strand breakages and fatal destabilization of the DNA helix inhibiting nucleic acid synthase. As a therapeutic agent with the aforementioned activity, nitroimidazoles and most especially bicyclic nitroimidazoles are currently in clinical use for the treatment of tuberculosis. However, the approved drugs, pretomanid (PR) and delamanid (DE) are limited in their nitric oxide radical (NO•) releasing abilities to cause effective bactericidity. It is believed that their bactericidal activity can be improved by harnessing alternative strategies to increase NO• release. The last decade has witnessed the strategic inclusion of NO-donors into native drugs to improve their activities and/or reverse resistance. The rationale behind this strategy is the targeting of NO• release at specific therapeutic sites. This review, therefore, aims to highlight various radical releasing agents that may be effective in the treatment of TB. The review also investigates various structural modifications to PR and DE and suggests alternative strategies to improve NO•release as well as some applications where NO-donor hybrid drugs have been used with good therapeutic effect.


Asunto(s)
Mycobacterium tuberculosis , Nitroimidazoles , Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Pared Celular , Humanos , Nitroimidazoles/farmacología , Nitroimidazoles/uso terapéutico , Tuberculosis/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico
20.
MAbs ; 14(1): 2075078, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35584276

RESUMEN

Appropriate nomenclature for all pharmaceutical substances is important for clinical development, licensing, prescribing, pharmacovigilance, and identification of counterfeits. Nonproprietary names that are unique and globally recognized for all pharmaceutical substances are assigned by the International Nonproprietary Names (INN) Programme of the World Health Organization (WHO). In 1991, the INN Programme implemented the first nomenclature scheme for monoclonal antibodies. To accompany biotechnological development, this nomenclature scheme has evolved over the years; however, since the scheme was introduced, all pharmacological substances that contained an immunoglobulin variable domain were coined with the stem -mab. To date, there are 879 INN with the stem -mab. Owing to this high number of names ending in -mab, devising new and distinguishable INN has become a challenge. The WHO INN Expert Group therefore decided to revise the system to ease this situation. The revised system was approved and adopted by the WHO at the 73rd INN Consultation held in October 2021, and the radical decision was made to discontinue the use of the well-known stem -mab in naming new antibody-based drugs and going forward, to replace it with four new stems: -tug, -bart, -mig, and -ment.


Asunto(s)
Anticuerpos Monoclonales , Preparaciones Farmacéuticas , Organización Mundial de la Salud
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