RESUMEN
OBJECTIVE: To determine prognostic value of bone marrow retention index (RI-bm) and bone marrow-to-liver ratio (BLR) measured on baseline dual-phase 18F-FDG PET/CT in a series of newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) treated homogeneously with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. PATIENTS AND METHODS: This prospective study enrolled 135 patients with newly diagnosed DLBCL. All patients underwent dual-phase 18F-FDG PET/CT. The following PET parameters were calculated for both tumor and bone marrow: maximum standardized uptake value (SUVmax) at both time points (SUVmax early and SUVmax delayed), SUVmax increment (SUVinc), RI, and BLR. Patients were treated with R-CHOP regimen and response at end of treatment was assessed. RESULTS: The final analysis included 98 patients with complete remission. At a median follow-up of 22 months, 57 patients showed no relapse, 74 survived, and 24 died. The 2-year relapse-free survival (RFS) values for patients with higher and lower RI-bm were 20% and 65.1%, respectively (p < 0.001), and for patients with higher and lower BLR were 30.2% and 69.6%, respectively (p < 0.001). The 2-year overall survival (OS) values for patients with higher and lower RI-bm were 60% and 76.3%, respectively (p = 0.023), and for patients with higher and lower BLR were 57.3% and 78.6%, respectively (p = 0.035). Univariate analysis revealed that RI-bm and BLR were independent significant prognostic factors for both RFS and OS (hazard ratio [HR] = 4.02, p < 0.001, and HR = 3.23, p < 0.001, respectively) and (HR = 2.83, p = 0.030 and HR = 2.38, p = 0.041, respectively). CONCLUSION: Baseline RI-bm and BLR were strong independent prognostic factors in DLBCL patients. CLINICAL RELEVANCE STATEMENT: Bone marrow retention index (RI-bm) and bone marrow-to-liver ratio (BLR) could represent suitable and noninvasive positron emission tomography/computed tomography (PET/CT) parameters for predicting pretreatment risk in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. KEY POINTS: ⢠Bone marrow retention index (RI-bm) and bone marrow-to-liver ratio (BLR) are powerful prognostic variables in diffuse large B-cell lymphoma (DLBCL) patients. ⢠High BLR and RI-bm are significantly associated with poor overall survival (OS) and relapse-free survival (RFS). ⢠RI-bm and BLR represent suitable and noninvasive risk indicators in DLBCL patients.
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Fluorodesoxiglucosa F18 , Linfoma de Células B Grandes Difuso , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Pronóstico , Médula Ósea/diagnóstico por imagen , Médula Ósea/patología , Rituximab/uso terapéutico , Radiofármacos/uso terapéutico , Prednisona/uso terapéutico , Vincristina/uso terapéutico , Estudios Prospectivos , Recurrencia Local de Neoplasia/patología , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Doxorrubicina/uso terapéutico , Ciclofosfamida/uso terapéutico , Hígado/patologíaRESUMEN
A series of 1H-indeno[2',1':5,6]dihydropyrido[2,3-d]pyrimidine and 1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine derivatives was prepared and screened for antiparasitic and viral RNase H inhibitory activity. Several compounds showed considerable activity against Toxoplasma gondii parasites and Leishmania major amastigotes, which warrants further investigation. Based on the structural similarities of certain derivatives with common viral RNase H inhibitors, a HIV-1 RNase H assay was used to study the RNase H inhibition by selected test compounds. Docking of active derivatives into the active site of the HIV-1 RNase H enzyme was carried out. The new compound 2a, inactive in the antiparasitic tests, showed distinct HIV-1 RNase H inhibition. Thus, ring substitution determines antiparasitic or HIV-1 RNase H inhibitory activity of this promising compound class.
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Ribonucleasa H del Virus de la Inmunodeficiencia Humana , Inhibidores de la Transcriptasa Inversa/farmacología , Ribonucleasa H/metabolismo , Pirimidinas/farmacología , Pirimidinas/química , Antiparasitarios/farmacología , Relación Estructura-ActividadRESUMEN
The regiospecific reduction of 4,6-dinitrobenzimidazole derivatives leading to the corresponding 4-amino-6-nitrobenzimidazoles was studied. The identification of the formed product structures was accomplished by spectroscopic and X-ray diffraction data. The anticancer and antiparasitic activities of the synthesized compounds were examined, and promising activities against Toxoplasma gondii and Leishmania major parasites were discovered for certain 4,6-dinitrobenzimidazoles in addition to moderate anticancer activities of the 4-amino-6-nitrobenzimidazole derivatives against T.â gondii cells. However, the tumor cell experiments revealed a promising sensitivity of p53-negative colon cancer cells to these compounds.
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Leishmania major , Toxoplasma , Antiparasitarios/farmacología , Antiparasitarios/químicaRESUMEN
A series of [RuCl2(p-cymene)(NHC)] complexes were obtained by reacting [RuCl2(p-cymene)]2 with in situ generated Ag-N-heterocyclic carbene (NHC) complexes. The structure of the obtained complexes was determined by the appropriate spectroscopy and elemental analysis. In addition, we evaluated the biological activities of these compounds as antienzymatic, antioxidant, antibacterial, anticancer, and antiparasitic agents. The results revealed that complexes 3b and 3d were the most potent inhibitors against AchE with IC50 values of 2.52 and 5.06 µM mL-1. Additionally, 3d proved very good antimicrobial activity against all examined microorganisms with IZ (inhibition zone) over 25 mm and MIC (minimum inhibitory concentration) < 4 µM. Additionally, the ligand 2a and its corresponding ruthenium (II) complex 3a had good cytotoxic activity against both cancer cells HCT-116 and HepG-2, with IC50 values of (7.76 and 11.76) and (4.12 and 9.21) µM mL-1, respectively. Evaluation of the antiparasitic activity of these complexes against Leishmania major promastigotes and Toxoplasma gondii showed that ruthenium complexes were more potent than the free ligand, with an IC50 values less than 1.5 µM mL-1. However, 3d was found the best one with SI (selectivity index) values greater than 5 so it seems to be the best candidate for antileishmanial drug discovery program, and much future research are recommended for mode of action and in vivo evaluation. In general, Ru-NHC complexes are the most effective against L. major promastigotes.
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Antiinfecciosos , Antineoplásicos , Complejos de Coordinación , Rutenio , Rutenio/farmacología , Rutenio/química , Antioxidantes/farmacología , Ligandos , Antiinfecciosos/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/químicaRESUMEN
Efficient drugs for the treatment of leishmaniasis, which is classified as a neglected tropical disease, are sought for. This review covers potential drug candidates from natural plant, fungus and algae sources, which were described over the last six years. The identification of these natural antileishmanials often based on the knowledge of traditional medicines. Crucial insights into the activities of these natural remedies against Leishmania parasites and against infections caused by these parasites in laboratory animals or patients are provided and compared with selected former active examples published more than six years ago. In addition, immuno-modulatory natural antileishmanials and recent developments on combination therapies including natural products and approved antileishmanials are discussed. The described natural products revealed promising data warranting further efforts on the discovery and development of new antileishmanials based on patterns from nature.
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Antiprotozoarios/química , Productos Biológicos/química , Hongos/química , Plantas/química , Rhodophyta/química , Antiprotozoarios/aislamiento & purificación , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Sinergismo Farmacológico , Hongos/metabolismo , Humanos , Leishmania/efectos de los fármacos , Leishmaniasis/tratamiento farmacológico , Leishmaniasis/parasitología , Aceites Volátiles/química , Aceites Volátiles/farmacología , Plantas/metabolismo , Rhodophyta/metabolismoRESUMEN
A series of the title curcuminoids with structural variance in the heteroatom of the cycloalkanone and the p-substituents of the phenyl rings were tested for their activities against Leishmania major and Toxoplasma gondii parasites. The majority of them showed high activities against both parasite forms with EC50 values in the sub-micromolar concentration range. Bis(p-pentafluorothio)-substituted 3,5-di[(E)-benzylidene]piperidin-4-one 1b was not just noticeable antiparasitic, but also exhibited a considerable selectivity for L. major promastigotes over normal Vero cells. While derivatives differing only in the p-phenyl substituents being CF3 or SF5 showed similar antiparasitic activities, the cyclic ketone hub was more decisive both for the anti-parasitic activities and the selectivities for the parasites vs. normal cells. QSAR calculations confirmed the observed structure-activity relations and suggested structural variations for a further improvement of the antiparasitic activity. Docking studies based on DFT calculations revealed L. major pteridine reductase 1 as a likely molecular target protein of the title compounds.
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Antiparasitarios/farmacología , Cicloparafinas/farmacología , Diarilheptanoides/farmacología , Leishmania major/efectos de los fármacos , Toxoplasma/efectos de los fármacos , Antiparasitarios/síntesis química , Antiparasitarios/química , Cicloparafinas/química , Diarilheptanoides/síntesis química , Diarilheptanoides/química , Relación Dosis-Respuesta a Droga , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-ActividadRESUMEN
A new 3,4-difluorobenzylidene analog of curcumin, CDF, was recently reported, which demonstrated significantly enhanced bioavailability and inâ vivo anticancer activity compared with curcumin. For highlighting the antiparasitic behavior of CDF, we tested this compound together with its new O-methylated analog MeCDF against Leishmania major and Toxoplasma gondii parasites. Both CDF and MeCDF were tested inâ vitro against L. major and T. gondii. In addition, the inâ vitro cytotoxicity against Vero cells and macrophages was determined and selectivity indices were calculated. The DPPH radical scavenging activity assay was carried out in order to determine the antioxidant activity of the test compounds. Both compounds showed high activities against both parasite forms with EC50 values in the (sub-)micromolar range (0.35 to 0.8â µM for CDF, 0.31 to 1.2â µM for MeCDF). The higher activity of CDF against L. major amastigotes when compared with MeCDF can in parts be attributed to the antioxidant activity of CDF while MeCDF lacking any antioxidant activity was more active than CDF against T.â gondii parasites. In conclusion, CDF and MeCDF are promising antiparasitic drug candidates due to their high activities against L.â major and T.â gondii parasites.
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Antioxidantes/farmacología , Antiparasitarios/farmacología , Curcumina/análogos & derivados , Diarilheptanoides/farmacología , Leishmania major/efectos de los fármacos , Toxoplasma/efectos de los fármacos , Animales , Antioxidantes/química , Antiparasitarios/química , Compuestos de Bifenilo/antagonistas & inhibidores , Chlorocebus aethiops , Curcumina/química , Curcumina/farmacología , Diarilheptanoides/química , Femenino , Halogenación , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Picratos/antagonistas & inhibidores , Células VeroRESUMEN
New pyranonaphthoquinone derivatives were synthesized and investigated for their activity against Trypanosoma brucei, Leishmania major, and Toxoplasma gondii parasites. The pentafluorophenyl derivative was efficacious against T. brucei with single digit micromolar EC50 values and against T. gondii with even sub-micromolar values. The 3-chloro-4,5-dimethoxyphenyl derivative showed an activity against amastigotes of Leishmania major parasites comparable to that of amphotericin B. In addition, antioxidant activities were observed for the bromophenyl derivatives, and their redox behavior was studied by cyclovoltammetry. Anti-parasitic and antioxidative activities of the new naphthoquinone derivatives appear uncorrelated.
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Antiprotozoarios/química , Benzopiranos/química , Animales , Antioxidantes , Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Benzopiranos/farmacología , Humanos , Leishmania major/efectos de los fármacos , Naftoquinonas/química , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacosRESUMEN
A series of bis-naphthoquinone derivatives prepared by condensation of aryl aldehydes with lawsone were tested for antiparasitic activities against Toxoplasma gondii and Trypanosoma brucei parasites. Monofluorophenyl derivative 1a, 3,4-difluorophenyl analog 1c and furyl compound 1l exhibited significant activity against T. gondii cells and appear to be new promising drug candidates against this parasite. The 3,4,5-trifluorophenyl derivative 1g and the isovanillyl derivative 1j displayed selective activity against Leishmania major amastigotes.
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Antiparasitarios/química , Naftoquinonas/química , Antiparasitarios/síntesis química , Antiparasitarios/farmacología , Humanos , Leishmania major/efectos de los fármacos , Leishmania major/crecimiento & desarrollo , Estadios del Ciclo de Vida/efectos de los fármacos , Naftoquinonas/síntesis química , Naftoquinonas/farmacología , Relación Estructura-Actividad , Toxoplasma/efectos de los fármacos , Trypanosoma brucei brucei/efectos de los fármacosRESUMEN
A series of cationic gold(I)-carbene complexes with various 4,5-diarylimidazolylidene ligands were either newly prepared or repurposed for testing against protozoal Leishmania major, Toxoplasma gondii, and Trypanosoma brucei parasites. The syntheses of the new complexes 1b and 1c were described. Ferrocene compound 1a showed the highest activities against L. major amastigotes and T. gondii and distinct selectivity for T. gondii cells when compared with the activity against nonmalignant Vero cells. The ferrocene derivatives 1a-c are generally more active against the L. major amastigotes and the T. gondii tachyzoites than the other tested anisyl gold complexes and the approved drugs atovaquone and amphotericin B. Compounds 1a and 1e showed the highest selectivities for L. major amastigotes. Compounds 1d and 1f showed the highest selectivities for L. major promastigotes; 1f was the most active compound against L. major promastigotes of this series of compounds. The 3,4,5-trimethoxyphenyl analog 1b also exhibited a much greater selectivity for T. b. brucei cells when compared with its activity against human HeLa cells.
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Antiprotozoarios/farmacología , Oro/farmacología , Imidazoles/farmacología , Compuestos Orgánicos de Oro/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Relación Dosis-Respuesta a Droga , Oro/química , Imidazoles/química , Leishmania major/efectos de los fármacos , Estructura Molecular , Compuestos Orgánicos de Oro/síntesis química , Compuestos Orgánicos de Oro/química , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Toxoplasma/efectos de los fármacos , Trypanosoma brucei brucei/efectos de los fármacosRESUMEN
A series of new lawsone Mannich bases derived from salicylaldehydes or nitrofurfural were prepared and tested for their activities against Leishmania major, Toxoplasma gondii, and Trypanosoma brucei brucei parasites. The hydrochloride salts 5a and 6a of the Mannich bases 2a and 3a, derived from unsubstituted salicylaldehyde and long-chained alkyl amines, were selectively and strongly active against T. gondii cells and appear to be new promising drug candidates against this parasite. Compound 6a showed an even higher activity against T. gondii than the known lawsone Mannich base 1b. Compound 4a, derived from salicylaldehyde and 2-methylaminopyridine, was also distinctly active against T. gondii cells. The derivatives 3a (salicyl derivative), 3b (3,5-dichloro-2-hydroxyphenyl derivative), and 3d (5-nitrofuranyl derivative) as well as the hydrochlorides 6a and 6b were also efficacious against T. b. brucei cells with compounds 3a and 3b being more selective for T. b. brucei over Vero cells when compared with the known control compound 1b. The derivatives 5a, 5c, 6a, and 6c proved to be up to five times more active than 1b against L. major promastigotes and up to four times more efficacious against L. major amastigotes.
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Antiparasitarios/farmacología , Leishmania major/efectos de los fármacos , Naftoquinonas/farmacología , Toxoplasma/efectos de los fármacos , Trypanosoma brucei brucei/efectos de los fármacos , Antiparasitarios/síntesis química , Antiparasitarios/química , Relación Dosis-Respuesta a Droga , Bases de Mannich/síntesis química , Bases de Mannich/química , Bases de Mannich/farmacología , Estructura Molecular , Naftoquinonas/síntesis química , Naftoquinonas/química , Pruebas de Sensibilidad Parasitaria , Relación Estructura-ActividadRESUMEN
A total of 202 patients with clomiphene citrate (CC) -resistant polycystic ovary syndrome (PCOS) were randomly allocated into two arms of induction of ovulation; the first group (n = 102) received CC 100 mg and metformin 500 mg while the second group (n = 100) received letrozole 2.5 mg with ovulation rate, clinical pregnancy rate, adverse effects, and acceptability were assessed. Patients in the letrozole arm experienced higher rate of ovulation (82% versus 43.1%, p < .001), more dominant follicles (p < .05), better endometrial thickness (p < .001), higher clinical pregnancy rate (36% versus 9.8%, p < .001), higher multiple pregnancy rate (p < .05), lesser adverse effects (p < .05) and higher acceptability (p < .001) compared to patients in the CC and metformin arm. In conclusion; letrozole is better and more acceptable than combined CC and metformin for inducing ovulation in patients with CC-resistant PCOS with higher clinical pregnancy rate and unexpectedly higher multiple pregnancy rate.
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Clomifeno/administración & dosificación , Fármacos para la Fertilidad Femenina/administración & dosificación , Metformina/administración & dosificación , Nitrilos/administración & dosificación , Inducción de la Ovulación/métodos , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Triazoles/administración & dosificación , Adulto , Clomifeno/uso terapéutico , Femenino , Fármacos para la Fertilidad Femenina/uso terapéutico , Humanos , Letrozol , Metformina/uso terapéutico , Nitrilos/uso terapéutico , Ovulación/efectos de los fármacos , Embarazo , Índice de Embarazo , Resultado del Tratamiento , Triazoles/uso terapéutico , Adulto JovenRESUMEN
STUDY OBJECTIVE: To compare the impact of ultrasound-guided transvaginal ovarian needle drilling (TND) versus laparoscopic ovarian drilling (LOD) on ovarian reserve and pregnancy rate in patients with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). DESIGN: A randomized clinical trial (Canadian Task Force classification I). SETTING: A university hospital. PATIENTS: Of 644 patients who presented at an infertility clinic, 246 with CC-resistant PCOS were randomized for treatment. INTERVENTIONS: Patients were randomly allocated to ultrasound-guided TND (n = 124) and LOD (n = 122). MEASUREMENTS AND MAIN RESULTS: Ovarian reserve parameters (serum antimüllerian hormone [AMH] and antral follicle count [AFC]) and pregnancy rate at 3 and 6 months were evaluated. At 3 months, patients in the LOD group experienced a significantly lower AMH (p < .001) and a higher ovulation rate (p < .05) with comparable AFC and pregnancy rate to patients in the TND group (p > .05) and a significant decrease in AMH and AFC within each individual group when compared with baseline (p < .001). At 6 months, patients in the LOD group experienced a significantly lower AMH (p < .001), lower AFC (p < .001), higher ovulation rate (p < .001) and higher pregnancy rate (p < .001) when compared with patients in the TND group. This effect started to diminish between the fourth and sixth month with an increase of AMH and AFC compared with baseline values (p < .05). CONCLUSIONS: Although TND is simple, safe, and less invasive than LOD, its effect on ovarian reserve appears to be transient and diminishes at 6 months. Multicenter studies are warranted to confirm efficacy as a second-line treatment in patients with CC-resistant PCOS.
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Síndrome del Ovario Poliquístico/cirugía , Adulto , Femenino , Humanos , Laparoscopía , Reserva Ovárica , Embarazo , Índice de Embarazo , Resultado del Tratamiento , Ultrasonografía IntervencionalRESUMEN
BACKGROUND: Cellulitis of the leg is a common bacterial infection of the skin and underlying tissue. We compared prophylactic low-dose penicillin with placebo for the prevention of recurrent cellulitis. METHODS: We conducted a double-blind, randomized, controlled trial involving patients with two or more episodes of cellulitis of the leg who were recruited in 28 hospitals in the United Kingdom and Ireland. Randomization was performed according to a computer-generated code, and study medications (penicillin [250 mg twice a day] or placebo for 12 months) were dispensed by a central pharmacy. The primary outcome was the time to a first recurrence. Participants were followed for up to 3 years. Because the risk of recurrence was not constant over the 3-year period, the primary hypothesis was tested during prophylaxis only. RESULTS: A total of 274 patients were recruited. Baseline characteristics were similar in the two groups. The median time to a first recurrence of cellulitis was 626 days in the penicillin group and 532 days in the placebo group. During the prophylaxis phase, 30 of 136 participants in the penicillin group (22%) had a recurrence, as compared with 51 of 138 participants in the placebo group (37%) (hazard ratio, 0.55; 95% confidence interval [CI], 0.35 to 0.86; P=0.01), yielding a number needed to treat to prevent one recurrent cellulitis episode of 5 (95% CI, 4 to 9). During the no-intervention follow-up period, there was no difference between groups in the rate of a first recurrence (27% in both groups). Overall, participants in the penicillin group had fewer repeat episodes than those in the placebo group (119 vs. 164, P=0.02 for trend). There was no significant between-group difference in the number of participants with adverse events (37 in the penicillin group and 48 in the placebo group, P=0.50). CONCLUSIONS: In patients with recurrent cellulitis of the leg, penicillin was effective in preventing subsequent attacks during prophylaxis, but the protective effect diminished progressively once drug therapy was stopped. (Funded by Action Medical Research; PATCH I Controlled-Trials.com number, ISRCTN34716921.).
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Antibacterianos/uso terapéutico , Celulitis (Flemón)/tratamiento farmacológico , Penicilinas/uso terapéutico , Anciano , Antibacterianos/efectos adversos , Celulitis (Flemón)/prevención & control , Método Doble Ciego , Femenino , Estudios de Seguimiento , Costos de la Atención en Salud , Servicios de Salud/economía , Servicios de Salud/estadística & datos numéricos , Humanos , Pierna , Masculino , Persona de Mediana Edad , Penicilinas/efectos adversos , Prevención SecundariaRESUMEN
OBJECTIVE: To assess the utility of 18F-PSMA-1007 PET/MRI in initial staging of intermediate- to high-risk prostate cancer (HRPCa). METHODS: A total of 46 patients with pathologically verified intermediate and/or HRPCa who underwent 18F-PSMA-1007 PET/MRI with dedicated pelvic high-resolution multiparametric MRI (mpMRI) were included. RESULTS: PET/MRI showed 100% sensitivity (SN), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), and accuracy in detecting seminal vesicle (SV) and rectal invasion, versus 87.5%, 100%, 100% 93.8%, 95.7% and 50%, 100%,100%, 95.5%, and 95.7% for mpMRI respectively. However, PET/MRI had poor SN (40% and 0%) but high SP (94.4% and 100%) in detection of UB and neurovascular bundle (NV) invasion compared to 100% SN and SP for mpMRI. PET/MRI demonstrated stronger TNM staging agreement with the gold standard than mpMRI-WBMRI. It demonstrated concordance with T, N, and M stages in 40, 41, and 36 patients (k 0.84, 0.60, and 0.68, respectively) versus 29, 33, and 31 patients (k 0.54, 0.22, and 0.50) with accurate over all staging of 38/46 patients versus 30/46 patients (K 0.52 versus 0.22). CONCLUSION: 18F-PSMA-1007 PET/MRI is a promising imaging modality with high diagnostic accuracy in staging intermediate- and HRPCa; it improves local tumour evaluation and provides precise TNM staging. ADVANCES IN KNOWLEDGE: 18F-PSMA-1007 PET/MRI could have high diagnostic accuracy as shown in the current study for staging HRPCa patients that is crucial for treatment selection. We think that our study will contribute to the body of knowledge and improve the literature surrounding the clinical uses of integrated 18F-PSMA-1007 PET/MRI.
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Niacinamida/análogos & derivados , Oligopéptidos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata , Masculino , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/patología , Radioisótopos de Galio , Tomografía de Emisión de Positrones , Imagen por Resonancia Magnética , Estadificación de NeoplasiasRESUMEN
A series of fourteen pyrimido[1,2-a]benzimidazole compounds was prepared by straightforward heterocyclic chemistry and oxidation methods. The new pyrimidobenzimidazole derivative 2a with a 3-fluorophenyl substituent was identified as a new antiparasitic compound showing excellent activities against Leishmania major parasites. 2a was highly active against L. major promastigotes and amastigotes with EC50 values in the nanomolar concentration range. Compound 3b was less active than 2a against L. major, but more active against Toxoplasma gondii with considerable selectivity. Hence, two promising and selective antiparasitic drug candidates 2a and 3b for the treatment of two parasitic diseases were identified, which can be prepared by green chemistry methods using simple one-pot reactions and oxidation procedures, respectively.
RESUMEN
The aim of this study was devoted into molecular docking calculations to discover the potential antileishmania and antitoxoplasma activities of newly synthesized compounds obtained by applying a practical and simple method under microwave irradiation. All these compounds were tested in vitro for their biological activity against Leishmania major promastigotes, amastigotes, and Toxoplasma gondii tachyzoites. Compounds 2a, 5a, and 5e were the most active against both L. major promastigotes and amastigotes, with IC50 values of less than 0.4 µM mL-1. Compounds 2c, 2e, 2h, and 5d had a strong antitoxoplasma activity of less than 2.1 µM mL-1 against T. gondii. We can conclude that aromatic methyleneisoindolinones are potently active against both L. major and T. gondii. Further studies for mode of action evaluation are recommended. Compounds 5c and 5b are the best drug candidates for antileishmania and antitoxoplasma due to their SI values being over 13. The docking studies of compounds 2a-h and 5a-e against pteridine reductase 1 and T. gondii enoyl acyl carrier protein reductase reveal that compound 5e may be an effective antileishmanial and antitoxoplasma drug discovery initiative.
RESUMEN
A series of synthetic N-acylpyrrolidone and -piperidone derivatives of the natural alkaloid piperlongumine were prepared and tested for their activities against Leishmania major and Toxoplasma gondii parasites. Replacement of one of the aryl meta-methoxy groups by halogens such as chlorine, bromine and iodine led to distinctly increased antiparasitic activities. For instance, the new bromo- and iodo-substituted compounds 3 b/c and 4 b/c showed strong activity against L.â major promastigotes (IC50 =4.5-5.8â µM). Their activities against L.â major amastigotes were moderate. In addition, the new compounds 3 b, 3 c, and 4 a-c exhibited high activity against T.â gondii parasites (IC50 =2.0-3.5â µM) with considerable selectivities when taking their effects on non-malignant Vero cells into account. Notable antitrypanosomal activity against Trypanosoma brucei was also found for 4 b. Antifungal activity against Madurella mycetomatis was observed for compound 4 c at higher doses. Quantitative structure-activity relationship (QSAR) studies were carried out, and docking calculations of test compounds bound to tubulin revealed binding differences between the 2-pyrrolidone and 2-piperidone derivatives. Microtubules-destabilizing effects were observed for 4 b in T.â b.â brucei cells.
Asunto(s)
Antifúngicos , Antiparasitarios , Animales , Chlorocebus aethiops , Antiparasitarios/farmacología , Antiparasitarios/química , Antifúngicos/farmacología , Relación Estructura-Actividad , Halógenos , Células VeroRESUMEN
Leishmaniasis, a neglected tropical parasitic disease (NTPD), is caused by various Leishmania species. It transmits through the bites of the sandfly. The parasite is evolving resistance to commonly prescribed antileishmanial drugs; thus, there is an urgent need to discover novel antileishmanial drugs to combat drug-resistant leishmaniasis. Thymoquinone (2-isopropyl-5-methyl-1,4-benzoquinone; TQ), a primary pharmacologically active ingredient of Nigella sativa (black seed) essential oil, has been reported to possess significant antiparasitic activity. Therefore, the present study was designed to investigate the in vitro and in silico antileishmanial activity of TQ against various infectious stages of Leishmania major (L. major), i.e., promastigotes and amastigotes, and its cytotoxicity against mice macrophages. In silico molecular dockings of TQ were also performed with multiple selected target proteins of L. major, and the most preferred antileishmanial drug target protein was subjected to in silico molecular dynamics (MD) simulation. The in vitro antileishmanial activity of TQ revealed that the half-maximal effective concentration (EC50), half-maximal cytotoxic concentration (CC50), and selectivity index (SI) values for promastigotes are 2.62 ± 0.12 µM, 29.54 ± 0.07 µM, and 11.27, while for the amastigotes, they are 17.52 ± 0.15 µM, 29.54 ± 0.07 µM, and 1.69, respectively. The molecular docking studies revealed that squalene monooxygenase is the most preferred antileishmanial drug target protein for TQ, whereas triosephosphate isomerase is the least preferred. The MD simulation revealed that TQ remained stable in the binding pocket throughout the simulation. Additionally, the binding energy calculations using Molecular Mechanics Generalized-Born Surface Area (MMGBSA) indicated that TQ is a moderate binder. Thus, the current study shows that TQ is a promising antileishmanial drug candidate that could be used to treat existing drug-resistant leishmaniasis.
RESUMEN
Leishmaniasis, a Neglected Tropical Parasitic Disease (NTPD), is induced by several Leishmania species and is disseminated through sandfly (Lutzomyia longipalpis) bites. The parasite has developed resistance to currently prescribed antileishmanial drugs, and it has become pertinent to the search for new antileishmanial agents. The current study aimed to investigate the in vitro and in silico antileishmanial activity of two newly sourced actinomycins, X2 and D, produced by the novel Streptomyces smyrnaeus strain UKAQ_23. The antileishmanial activity conducted on promastigotes and amastigotes of Leishmania major showed actinomycin X2 having half-maximal effective concentrations (EC50), at 2.10 ± 0.10 µg/mL and 0.10 ± 0.0 µg/mL, and selectivity index (SI) values of 0.048 and 1, respectively, while the actinomycin D exhibited EC50 at 1.90 ± 0.10 µg/mL and 0.10 ± 0.0 µg/mL, and SI values of 0.052 and 1. The molecular docking studies demonstrated squalene synthase as the most favorable antileishmanial target protein for both the actinomycins X2 and D, while the xanthine phosphoribosyltransferase was the least favorable target protein. The molecular dynamics simulations confirmed that both the actinomycins remained stable in the binding pocket during the simulations. Furthermore, the MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) binding energy calculations established that the actinomycin X2 is a better binder than the actinomycin D. In conclusion, both actinomycins X2 and D from Streptomyces smyrnaeus strain UKAQ_23 are promising antileishmanial drug candidates and have strong potential to be used for treating the currently drug-resistant leishmaniasis.