RESUMEN

This study synthesized and evaluated a series of benzotriazole derivatives denoted 3(a-j) and 6(a-j) for their anti-HIV-1 RT activities compared to the standard drug efavirenz. Notably, compound 3 h, followed closely by 6 h, exhibited significant anti-HIV-1 RT efficacy relative to the standard drug. In vivo oral toxicity studies were conducted for the most active compound 3 h, confirming its nontoxic nature to ascertain the safety profile. By employing molecular docking techniques, we explored the potential interactions between the synthesized compounds (ligands) and a target biomolecule (protein)(PDB ID 1RT2) at the molecular level. We undertook the molecular dynamics study of 3 h, the most active compound, within the active binding pocket of the cocrystallized structure of HIV-1 RT (PDB ID 1RT2). We aimed to learn more about how biomolecular systems behave, interact, and change at the atomic or molecular level over time. Finally, the DFT-derived HOMO and LUMO orbitals, as well as analysis of the molecular electrostatic potential map, aid in discerning the reactivity characteristics of our molecule.

Asunto(s)

Fármacos Anti-VIH , VIH-1 , Simulación del Acoplamiento Molecular , Triazoles , Triazoles/química , Triazoles/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/química , Transcriptasa Inversa del VIH/metabolismo , Humanos , Simulación de Dinámica Molecular , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/toxicidad , Modelos Moleculares , Teoría Funcional de la Densidad , Relación Estructura-Actividad , Alquinos/química , Animales , Ciclopropanos/toxicidad , Benzoxazinas/química , Benzoxazinas/farmacología

RESUMEN

The quest for novel, physiologically active imidazoles remains an exciting topic of research among medicinal chemists. The imidazole ring is a five-membered aromatic heterocycle that is found in both natural and synthesized compounds. Multiple anticancer drug classes are currently available on the market, but concerns including toxicity, limited efficacy and solubility have lowered the overall therapeutic index. Therefore, the hunt for new potential chemotherapeutic agents persists. The development of imidazole as a reliable and safer alternative to anticancer treatment is generating much attention among experts. Tubulin or microtubule polymerization inhibition and changes in the structure and function of DNA, VEGF, topoisomerase, kinases, histone deacetylases and certain other proteins that affect gene expression are among the putative targets.

RESUMEN

Candida albicans infections and their resistance to clinically approved azole drugs are major concerns for human. The azole antifungal drugs inhibit the ergosterol synthesis by targeting lanosterol 14α-demethylase of cytochrome P450 family. The lack of high-resolution structural information of fungal pathogens has been a barrier for the design of modified azole drugs. Thus, a preliminary theoretical molecular dynamic study is carried out to develop and validate a simple homologous model using crystallographic structure of the lanosterol 14α-demethylase of Mycobacterium tuberculosis (PDB ID-1EA1) in which the active site residues are substituted with that of C. albicans (taxid 5476). Further, novel designed pyrazole analogs (SGS1-16) docked on chimeric 1EA1 and revealed that SGS-16 show good binding affinity through non-bonding interaction with the heme, which is different from the leading azole antifungals. The ADME-T results showed these analogs can be further explored in design of more safe and effective antifungal agents.

Asunto(s)

Inhibidores de 14 alfa Desmetilasa/química , Antifúngicos/química , Candida albicans/enzimología , Proteínas Fúngicas/química , Pirazoles/química , Proteínas Recombinantes de Fusión/química , Esterol 14-Desmetilasa/química , Inhibidores de 14 alfa Desmetilasa/síntesis química , Secuencia de Aminoácidos , Antifúngicos/síntesis química , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Candida albicans/química , Candida albicans/genética , Dominio Catalítico , Cristalografía por Rayos X , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Expresión Génica , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/enzimología , Mycobacterium tuberculosis/genética , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Pirazoles/síntesis química , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Alineación de Secuencia , Esterol 14-Desmetilasa/genética , Esterol 14-Desmetilasa/metabolismo , Homología Estructural de Proteína , Termodinámica

RESUMEN

BACKGROUND: Pyrazole is one of the excellent structural motifs in medicinal chemistry. Various physiological and therapeutic possibilities have been exploited by incorporating different pharmacophoric groups in the pyrazole moiety. OBJECTIVE: This has opened a new arena of pyrazole analogs that can be developed into medicinal agents such as anti-inflammatory, analgesic, antipyretic, antiviral, antibacterial, anticancer, anticonvulsant, hypoglycemic, carbonic anhydrase inhibitors, mono amino oxidase (MAO) inhibitors, etc. Though, pyrazole analogs have proven their clinical efficacy as different pharmacological agents, a few of them have been withdrawn from the market due to their side effects. Thus, research on potential new drug candidates bearing the pyrazole moiety with lesser side effects has fairly increased over the last few years. CONCLUSION: This review explores diverse pharmacological activities exhibited by pyrazole analogs reported recently, which may be of great help for researchers in the area of drug discovery to understand the current scenario of pyrazole based compounds and to design and develop newer drug candidates with improved efficacy.

Asunto(s)

Pirazoles/uso terapéutico , Analgésicos/química , Analgésicos/uso terapéutico , Antiinfecciosos/uso terapéutico , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Antipiréticos/química , Antipiréticos/uso terapéutico , Humanos , Estructura Molecular , Pirazoles/química , Pirazoles/farmacología

RESUMEN

The aim of this study was to enhance the dissolution and bioavailability of telmisartan (TLM), a poorly water soluble drug by co-milling approach. Physical mixtures of TLM and poly(vinyl alcohol) (PVA) were co-milled in a planetary micro mill in a dry condition by varying process parameters such as drug to polymer weight ratio, ball-to-powder weight ratio, and rotational speed. The co-milled products offered cumulative percentage dissolution of TLM above 75% in 30 min (CG 1 and CG2). These samples were characterized using field emission scanning electron microscopy (FE-SEM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and Raman spectra analysis. Well-dispersed acicular shaped particles of TLM were observed in co-milled products. A mixture of crystalline and amorphous TLM with a particle size less than 1 µm was present in CG1. The particle size of TLM observed in CG2 was less than 2 µm. In addition to crystalline and amorphous form of TLM, defective/disordered crystals of TLM were also present in CG 2. Therefore, CG2 tablets exhibited poor stability. CG 1 tablets were found to be stable under accelerated stability test conditions. The relative bioavailability of TLM of CG 1 containing tablets in comparison with Micardis® was 93.92±12.84% (in rabbits). Thus, co-milling of TLM with PVA proves to be a promising "alkalinizer free green approach" to ensure the dissolution and bioavailability of poorly water soluble TLM.

Asunto(s)

Bencimidazoles/química , Bencimidazoles/farmacocinética , Benzoatos/química , Benzoatos/farmacocinética , Composición de Medicamentos/métodos , Polímeros/química , Cloruro de Polivinilo/química , Animales , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría/métodos , Microscopía Electrónica de Rastreo/métodos , Tamaño de la Partícula , Polvos/química , Conejos , Solubilidad , Comprimidos/química , Comprimidos/farmacocinética , Telmisartán , Difracción de Rayos X/métodos

RESUMEN

Thiazolidines are multifaceted molecules and exhibit varied types of biological activities, and also showed anticonvulsants and antidepressants activity. It is the diversified class of heterocyclic compounds. Thiazolidinediones (TZD) has been shown beneficial action in various CNS diseases. The significant mechanism of TZD-induced neuroprotection useful in prevention of microglial activation and cytokine that is responsible for inflammatory condition and chemokine expression. At the molecular level TZDs were also responsible to prevent the activation of pro-inflammatory transcription factors as well as promoting the anti-oxidant mechanisms in the injured CNS. Important SAR, molecular mechanism and potent biological activities with special references to central nervous system are discussed in this article. Various investigations suggest that this moiety pave the way for design and discovery of new drug candidates.

RESUMEN

BACKGROUND: Structural modifications of thiazolidinediones at 3rd and 5th position have exhibited significant biological activities. In view of the facts, and based on in silico studies carried out on thiazolidine-2,4-diones as HIV-1- RT inhibitors, a novel series of 2,4-thiazolidinedione analogs have been designed and synthesized. METHODS: Title compounds were prepared by the reported method. Conformations of the structures were assigned on the basis of results of different spectral data. The assay of HIV-1 RT was done as reported by Silprasit et al. Antimicrobial activity was determined by two fold serial dilution method. Docking study was performed for the highest active compounds by using Glide 5.0. RESULTS: The newly synthesized compounds were evaluated for their HIV-1 RT inhibitory activity. Among the synthesized compounds, compound 24 showed significant HIV-1 RT inhibitory activity with 73% of inhibition with an IC50 value of 1.31 µM. Compound 10 showed highest activity against all the bacterial strains.A molecular modeling study was carried out in order to investigate the possible interactions of the highest active compounds 24, 10 and 4 with the non nucleoside inhibitory binding pocket(NNIBP) of RT, active site of GlcN-6-P synthase and cytochrome P450 14-α-sterol demethylase from Candida albicans (Candida P450DM) as the target receptors respectively using the Extra Precision (XP) mode of Glide software. CONCLUSION: A series of novel substituted 2-(5-benzylidene-2,4-dioxothiazolidin-3-yl)-N-(phenyl)propanamides (4-31) have been synthesized and evaluated for their HIV-1 RT inhibitory activity, antibacterial and antifungal activities. Some of the compounds have shown significant activity. Molecular docking studies showed very good interaction.

Asunto(s)

Antibacterianos/farmacología , Fármacos Anti-VIH/farmacología , Antifúngicos/farmacocinética , Diseño de Fármacos , Modelos Moleculares , Inhibidores de la Transcriptasa Inversa/farmacología , Tiazolidinedionas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/metabolismo , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/metabolismo , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/metabolismo , Sitios de Unión , Candida albicans/efectos de los fármacos , Candida albicans/enzimología , Candida albicans/crecimiento & desarrollo , Sistema Enzimático del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Proteínas Fúngicas/antagonistas & inhibidores , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Glutamina-Fructosa-6-Fosfato Transaminasa (Isomerizadora)/antagonistas & inhibidores , Glutamina-Fructosa-6-Fosfato Transaminasa (Isomerizadora)/química , Glutamina-Fructosa-6-Fosfato Transaminasa (Isomerizadora)/metabolismo , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/química , Transcriptasa Inversa del VIH/metabolismo , Cinética , Ligandos , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Simulación del Acoplamiento Molecular , Unión Proteica , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/metabolismo , Relación Estructura-Actividad , Tiazolidinedionas/síntesis química , Tiazolidinedionas/química , Tiazolidinedionas/metabolismo

RESUMEN

Benzimidazoles are the fused heterocyclic ring systems which form an integral part of vitamin B12 and have been luring many researchers all over the world to assess their potential therapeutic significance. They are known for their crucial role in numerous diseases via various mechanisms. Substitution of benzimidazole nucleus is a crucial step in the drug discovery process. Therefore, it is necessary to gather the latest information along with the earlier information to understand the present status of benzimidazole nucleus in drug discovery. In the present review, benzimidazole derivatives with different pharmacological activities are described on the basis of SAR study using structural substitution pattern around the benzimidazole nucleus and aims to review the reported work related to the chemistry and pharmacological activities of benzimidazole derivatives during recent years. The present manuscript to the best of our knowledge is the first compilation on synthesis and medicinal aspects including structure-activity relationships of benzimidazole reported to date.

Asunto(s)

Bencimidazoles/química , Bencimidazoles/farmacología , Descubrimiento de Drogas , Animales , Humanos , Estructura Molecular , Relación Estructura-Actividad

RESUMEN

In the present investigation, the synthesis and antimicrobial evaluation of 1,2,4-triazolo [3,4-b][1,3,4] thiadiazine including different pharmacophores are aimed at. In this study, a series of 6-aryl-3- (3,4 -dialkoxyphenyl)-7H -[1,2,4]triazolo [3,4-b][1,3,4] thiadiazine (7a-7k) was synthesized by condensing 4-amino-5-(3,4-dialkoxyphenyl)-4H-[1,2,4]- triazole-3-thiol (6) with various aromatic carboxylic acids in the presence of phenacyl bromides through one-pot reaction. Eleven fused heterocyclic derivatives were successfully synthesized. The structures of these newly synthesized compounds were characterized by IR, (1)H NMR and mass spectroscopic studies. All the synthesized compounds were screened for their antimicrobial evaluation. Some of the compounds exhibited promising antimicrobial activity. From the present study it may be concluded that synthesized compounds are fruitful in terms of their structural novelty and marked biological activities. These compounds could be further modified to develop potential and safer antifungal agents.

RESUMEN

The infectious disease Malaria is caused by different species of the genus Plasmodium. Resistance to quinoline antimalarial drugs and decreased susceptibility to artemisinin-based combination therapy have increased the need for novel antimalarial agents. Historically, natural products have been used for the treatment of infectious diseases. Identification of natural products and their semi-synthetic derivatives with potent antimalarial activity is an important method for developing novel antimalarial agents. Manzamine alkaloids are a unique group of ß-carboline alkaloids isolated from various species of marine sponge displaying potent antimalarial activity against drug-sensitive and -resistant strains of Plasmodium. In this review, we demonstrate antimalarial potency, cytotoxicity and antimalarial SAR of manzamine alkaloids.

Asunto(s)

Antimaláricos , Carbazoles , Alcaloides Indólicos , Animales , Antimaláricos/química , Antimaláricos/aislamiento & purificación , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Carbazoles/química , Carbazoles/aislamiento & purificación , Carbazoles/farmacología , Carbazoles/uso terapéutico , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/aislamiento & purificación , Alcaloides Indólicos/farmacología , Alcaloides Indólicos/uso terapéutico , Plasmodium/efectos de los fármacos , Relación Estructura-Actividad

RESUMEN

In recent years, heterocyclic compounds, analogs, and derivatives have attracted strong interest due to their useful biological and pharmacological properties. The small and simple triazole nucleus is present in compounds aimed at evaluating new entities that possess anti-microbial, anti-tumor, antitubercular, anti-convulsant, anti-depressant, antimalarial, and anti-inflammatory activities. Triazoles display a broad range of biological activities and are found in many potent, biologically active compounds, such as trazodone (antidepressant drug), rizatriptan (antimigrane drug), hexaconazole (antifungal drug) and alprazolam (hyptonic, sedative and tranquilizer drug). So far, modifications of the triazole ring have proven highly effective with improved potency and lesser toxicity. The present review highlights the recently synthesized triazoles possessing important biological activities.

Asunto(s)

Triazoles/química , Triazoles/farmacología , Animales , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Humanos , Estructura Molecular , Relación Estructura-Actividad , Triazoles/síntesis química

RESUMEN

BACKGROUND: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are one of the key components in highly active anti-retroviral therapy because of their high specificity and less toxicity. NNRTIs inhibit reverse transcriptase enzyme by binding to the allosteric site, which is 10Å away from the active site. Rapid emergence of resistance is the major problem with all anti-HIV agents. Hence, there is continuous need to develop novel anti-HIV agents active against both drug sensitive and resistance strains. RESULTS: All the 16 synthesized 2-(1,3-dioxo-3a,4-dihydro-1H-isoindol-2(3H,7H,7aH)-yl)-N-(substitutedphenyl) acetamide 4(a-p) analogs were characterized by Fourier transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, mass spectroscopy, and elemental analysis. Lipinski rule of five parameters and molecular parameters like solubility, drug likeness, and drug score were derived for designed analogs using online servers like Molinspiration and Osiris property explorer. Synthesized compounds were evaluated for their HIV-1 reverse transcriptase inhibitor activity by HIV-1 RNA-dependent DNA polymerase activity assay at 2 and 20 µM concentrations. CONCLUSIONS: Among the 16 synthesized compounds, 4a, 4b, 4f, 4g, 4k, and 4l showed weak reverse transcriptase inhibitor activity at 20 µM concentration. For the designed compounds, there was no correlation observed between molecular modeling and in vitro studies.

RESUMEN

OBJECTIVES: The effect of microwave (MW) irradiation and conventional heating (CH) on solid dispersion (SD) of poorly water-soluble glipizide (GPZ) and polyethylene glycol 4000 (PEG 4000) were studied in detail. METHODS: The chemical stability of GPZ on exposure to MW irradiation and CH was confirmed by high-performance liquid chromatography, Fourier transform infra red spectroscopy, proton nuclear magnetic resonance and mass spectroscopy studies. Comparative bioavailability studies were performed in rabbits using glipizide sustained-release tablets prepared using MW irradiation (MW-SD) or CH (CH-SD), with Glytop 2.5 mg SR as a reference. KEY FINDINGS: The MW-assisted melt mixing showed higher efficiency than CH in obtaining a homogeneous mixture having glass transparency. The polymorphic transformation of GPZ in each case was further confirmed by powder X-ray diffraction study. The solubility of GPZ in phosphate buffer pH 6.8 was greater for MW-SD (72.250 ± 0.154 µg/ml) than CH-SD (46 ± 0.201 µg/ml). The MW-SD matrix tablet (2.5 mg) displayed retarded drug release (releasing 99.320 ± 4.992% drug in 12 h). In-vivo pharmacokinetic study in rabbits revealed that the relative bioavailability of GPZ from MW-SD tablets improved greatly (153.73 ± 9.713%). CONCLUSIONS: MW-induced SD technology could be a better alternative to CH-SD for the enhanced solubility and bioavailability of GPZ.

Asunto(s)

Glipizida/química , Glipizida/farmacocinética , Microondas , Comprimidos/química , Tecnología Farmacéutica/métodos , Animales , Disponibilidad Biológica , Preparaciones de Acción Retardada , Estabilidad de Medicamentos , Vidrio/química , Calefacción/métodos , Concentración de Iones de Hidrógeno , Polietilenglicoles/química , Conejos , Solubilidad , Comprimidos/farmacocinética , Agua/química

RESUMEN

Alogliptin (codenamed SYR-322) is a recently approved anti-diabetic drug in Japan, which has been under clinical development phase III in USA and Europe. Alogliptin has been developed by Takeda under the brand name "Nesina". Alogliptin is a highly selective ( > 10,000-time selectivity, potent, reversible and durable serine protease dipeptidyl peptidase IV enzyme is compared to DPP-8 and DPP-9) inhibitor, which has been developed as an alternative second-line to metformin in place of a sulphonylurea. Alogliptin has been observed to increase and prolong the action of incretin hormone by inhibiting the DPP-IV enzyme activity. Alogliptin has been observed to well absorb and show low plasma protein binding, which displays slow-binding properties to DPP-IV enzyme. The X-ray crystallography studies have been revealed that Alogliptin binds to DPP-IV active site by non-covalently and provides sustained reduction of plasma DPP-IV activity as well as lowering of blood glucose, in drug-naive patients with T2DM and inadequate glycemic control, once daily oral dosing regimen with varying levels of doses ranging from 25-800 mg. Alogliptin is approved as monotherapy and in combination with alpha-glucosidase & thiazolidinediones. The 26 week clinical study of Alogliptin revealed that Alogliptin doesn't increase the weight and well tolerated. In the present review, we have tried to cover biology of DPP-IV, molecular chemistry, chemical characterization, crystal polymorphic information, interaction studies, commercial synthesis, current patent status, adverse effects and clinical status of Alogliptin giving emphasis on the medicinal chemistry aspect.

Asunto(s)

Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Piperidinas/farmacología , Uracilo/análogos & derivados , Animales , Ensayos Clínicos como Asunto , Dipeptidil Peptidasa 4/química , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Humanos , Modelos Moleculares , Piperidinas/efectos adversos , Piperidinas/química , Piperidinas/farmacocinética , Uracilo/efectos adversos , Uracilo/química , Uracilo/farmacocinética , Uracilo/farmacología

RESUMEN

A series of 1-(2-methyl-4-nitro-imidazol-1-yl)-3-arylaminopropan-2-ones (2a-e), 2-methyl-5-nitro-1-{2-[arylmethoxy]ethyl}-1H-imidazoles (5a-d), and N-(3-hydroxyphenyl)-2-(substituted imidazol-1-yl)alkanamides (8a-e) were synthesized with the aim to develop novel imidazole analogs with broad-spectrum chemotherapeutic properties. Title compounds were evaluated for their anti-HIV and antibacterial activities.

Asunto(s)

Antibacterianos/química , Antibacterianos/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Imidazoles/química , Imidazoles/farmacología , Antibacterianos/metabolismo , Fármacos Anti-VIH/metabolismo , Sitios de Unión , Simulación por Computador , Diseño de Fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/química , Transcriptasa Inversa del VIH/metabolismo , VIH-1/enzimología , Imidazoles/metabolismo , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Molecular , Nitroimidazoles/química , Nitroimidazoles/metabolismo , Nitroimidazoles/farmacología , Unión Proteica , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/metabolismo , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-Actividad , Temperatura de Transición

RESUMEN

A series of 1-substituted imidazoles 1a-d and 2a-d were synthesized and screened for antispasmodic and antidiarrheal activities. Antispasmodic activity was tested at various concentrations on isolated tissue preparations; concentration-response curves were plotted and compared with atropine. All compounds were found to inhibit contraction of the guinea pig ileum. Castor oil-induced diarrhea model in rats was used for evaluation of antidiarrheal activity. Parameters such as intestinal transit and volume of intestinal fluid were measured for antidiarrheal activity at 40 mg kg-1 dose and compared with the standard drug loperamide at 6 mg kg-1 dose. Defecation frequency in the test group was found to be significantly lower (p < 0.01) compared to the control group and comparable with that of the standard. The present study reveals that the compounds exert antidiarrheal activity through possible inhibition of intestinal movement and reduction of capillary permeability in the abdominal cavity.

Asunto(s)

Antidiarreicos/química , Antidiarreicos/uso terapéutico , Diseño de Fármacos , Imidazoles/química , Imidazoles/uso terapéutico , Parasimpatolíticos/química , Parasimpatolíticos/uso terapéutico , Animales , Antidiarreicos/farmacología , Antagonistas Colinérgicos/química , Antagonistas Colinérgicos/farmacología , Antagonistas Colinérgicos/uso terapéutico , Diarrea/inducido químicamente , Diarrea/tratamiento farmacológico , Cobayas , Íleon/efectos de los fármacos , Imidazoles/farmacología , Espectroscopía de Resonancia Magnética , Masculino , Estructura Molecular , Relajación Muscular/efectos de los fármacos , Parasimpatolíticos/farmacología , Distribución Aleatoria , Ratas , Ratas Wistar , Espectroscopía Infrarroja por Transformada de Fourier , Relación Estructura-Actividad , Temperatura de Transición

RESUMEN

A new series of 3-(benzylideneamino)-2-phenylquinazoline-4(3H)-ones were prepared through Schiff base formation of 3-amino-2-phenyl quinazoline-4(3)H-one with various substituted carbonyl compounds. Their chemical structures were elucidated by spectral studies. Cytotoxicity and antiviral activity were evaluated against herpes simplex virus-1 (KOS), herpes simplex virus-2 (G), vaccinia virus, vesicular stomatitis virus, herpes simplex virus-1 TK- KOS ACVr, para influenza-3 virus, reovirus-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus, feline corona virus (FIPV), feline herpes virus, respiratory syncytial virus, influenza A H1N1 subtype, influenza A H3N2 subtype, and influenza B virus. Compound 2a showed better antiviral activity against the entire tested virus.

Asunto(s)

Antivirales/síntesis química , Antivirales/farmacología , Quinazolinas/síntesis química , Quinazolinas/farmacología , Bases de Schiff/química , Antivirales/química , Línea Celular , Evaluación Preclínica de Medicamentos , Humanos , Espectroscopía de Resonancia Magnética , Quinazolinas/química , Espectrofotometría Infrarroja

RESUMEN

There is still an urgent need to develop nonnucleoside reverse transcriptase (RT) inhibitors (NNRTI) with a high-genetic barrier to resistance that facilitate patient adherence and allow durable suppression of HIV-1 replication. In this study, we describe the synthesis of a novel series of N-aminoimidazole (NAIM) analogs. Each of the NAIM analogs display potent activity against wild-type recombinant purified HIV-1 RT as well as RTs containing the K103N or Y181C resistance mutations. The analogs, however, do not exhibit significant antiviral activity in cell culture and were, in general, cytotoxic. Nevertheless, these data suggest that the NAIM backbone may provide a suitable scaffold from which inhibitors active against NNRTI-resistant HIV-1 could be developed.