In recent studies some urea derivatives have been identified as potent anti-tuberculosis agents by targeting mycobacterial membrane protein large 3 (MmpL3). However, this compound series as exemplified by AU1235 exhibited poor in vitro pharmacokinetic profile. With AU1235 as the lead, we have identified a novel benzimidazole series as potential anti-tuberculosis agents by using scaffold hopping approach. Among these synthesized compounds, 2-aminobenzimidazole derivative 8b showed the potent anti-tuberculosis activity with the MIC value of 0.03 microg x mL(-1). This compound also showed improved metabolic stability compared to AU1235. Our investigation indicated that benzimidazole derivatives are the promising lead for further optimization as anti-tuberculosis agents.
Antitubercular Agents ; pharmacology ; Benzimidazoles ; chemistry ; pharmacology ; Drug Design ; Humans ; Structure-Activity Relationship ; Tuberculosis ; drug therapy

Benzimidazoles ; pharmacology ; Benzoates ; pharmacology ; Cell Proliferation ; drug effects ; Humans ; Muscle, Smooth, Vascular ; cytology ; Myocytes, Smooth Muscle ; cytology ; drug effects ; Tetrazoles ; pharmacology ; Valine ; analogs & derivatives

OBJECTIVETo study the effects of telmisartan on voltage dependant potassium channel (Kv) expression in lymphocytes from spontaneously hypertensive rat (SHR).

METHODSPeripheral blood was collected from male SHR aged 16 and 4 weeks. Peripheral lymphocytes were separated from heparinized whole blood by standard Ficoll-Hypaque density gradient centrifugation. The whole-cell Kv currents were recorded with patch-clamp technique in the absence and presence of telmisartan(10, 30, 100 µmol/L). Real-time PCR was used to determine Kv1.3 mRNA expression in lymphocytes.

RESULTS(1) The currents density of Kv was higher in lymphocytes from 16 weeks-old SHR [ (119.0 ± 9.6) pA/pF] than from 4 weeks-old SHR [(59.0 ± 7.2) pA/pF, P < 0.05]. (2) Currents density was positively correlated with systolic blood pressure in 16 weeks-old SHR (r = 0.837, P < 0.05). (3) The lymphocytes Kv 1.3 mRNA expression was significantly higher in 16-weeks-old SHR than in 4-weeks-old SHR (P < 0.05). (4) Telmisartan reduced the whole-cell Kv currents in a concentration-dependent manner (10.5 ± 3.4)% at 10 µmol/L, (45.8 ± 3.7)% at 30 µmol/L and (81.6 ± 4.2)% at 100 µmol/L, P < 0.01.

CONCLUSIONSThe lymphocyte Kv channel is upregulated in 16 weeks-old SHR suggesting a role of Kv in the pathophysiology of hypertension. Kv current in lymphocyte could be significantly blocked by telmisartan in a concentration dependent manner.

4-Aminopyridine ; pharmacology ; Animals ; Benzimidazoles ; pharmacology ; Benzoates ; pharmacology ; Lymphocytes ; drug effects ; metabolism ; Male ; Patch-Clamp Techniques ; Potassium Channels, Voltage-Gated ; drug effects ; Rats ; Rats, Inbred SHR ; metabolism

OBJECTIVETo investigate the antimicrobial activity of Pariet, Tekpron, Nexium, respectively, against Helicobacter pylori (H. pylori) in vitro.

METHODSAntimicrobial effects of these medicines were evaluated through detection of MICs for 3 H. pylori strains isolated from different countries.

RESULTSThe MIC(99) contents were 2.25 mg/L, 42.5 mg/L and 360 mg/L, respectively, for the three medicines. The strains under testing exhibited the same susceptibility to each medicine. Nexium did not inhibit the bacteria under the concentration of 3.6 - 36 mg/L with more and bigger H. pylori colonies seen when compared with controls.

CONCLUSIONSThe growth inhibitory activity appeared to be different among the three PPI medicines under investigation, with Rabeprazole the most potential agent of the three. Data suggested that the action of growth inhibition in vitro was resting on the characteristic of the given PPI as well as the supplements of the medicine.

2-Pyridinylmethylsulfinylbenzimidazoles ; Benzimidazoles ; pharmacology ; Enzyme Inhibitors ; pharmacology ; Esomeprazole ; analogs & derivatives ; pharmacology ; Helicobacter pylori ; drug effects ; Lansoprazole ; Microbial Sensitivity Tests ; Proton Pump Inhibitors ; Rabeprazole

OBJECTIVETo study the effect of peroxisome proliferator activated receptor γ (PPAR-γ) agonist on the angiotensin converting enzyme 2 (ACE2) mRNA expression in monocyte-derived macrophages of essential hypertensive patients.

METHODSTotally 57 essential hypertensive patients were randomly divided into three groups: conventional treatment group (n=18), telmisartan group (n=19), and benazepril group (n=20); 20 patients with normal blood pressure were also selected as the control group. Monocyte-derived macrophages were isolated from blood samples of patients in all four groups. The expression of ACE2 mRNA in monocyte-derived macrophages was detected by RT-PCR before treatment and 4 and 12 weeks after treatment.

RESULTSFour and 12 weeks after treatment, the systolic pressure and diastolic pressure of telmisartan group and benazepril group were significantly lower than that of the conventional treatment group (all P<0.01), and the systolic pressure and diastolic pressure of telmisartan group were significantly lower than that of the benazepril group(both P<0.01) .The expression of ACE2 mRNA in monocyte-derived macrophages were significantly lower in essential hypertensive patients than that in control group (P<0.01). After having been treated for 4 weeks and 12 weeks, the expression of ACE2 mRNA in monocyte-derived macrophages of hypertensive patients in telmisartan and benazepril groups were significantly higher than that in conventional treatment group (all P<0.01), and the expression of ACE2 mRNA in telmisartan group was significantly higher than that in benazepril group (both P<0.01).

CONCLUSIONPPAR-γ agonist could increase the ACE2 mRNA expression in monocyte-derived macrophages of essential hypertensive patients.

Aged ; Benzazepines ; pharmacology ; Benzimidazoles ; pharmacology ; Benzoates ; pharmacology ; Female ; Humans ; Hypertension ; drug therapy ; enzymology ; Macrophages ; enzymology ; Male ; Middle Aged ; PPAR gamma ; agonists ; Peptidyl-Dipeptidase A ; genetics ; metabolism ; RNA, Messenger ; genetics

The importance of insulin-like growth factor 1 receptor (IGF-1R) signaling in malignant behaviour of tumour cells is well established. Inhibiting the activity of IGF-1R may result in striking apoptosis in malignant cells growing. IGF-1R antibodies which are currently in phase I and II clinical trials and several IGF-IR TKIs have preclinically been characterized. This review describes recent developments of small molecule tyrosine kinase inhibitors.
Animals ; Apoptosis ; drug effects ; Benzimidazoles ; pharmacology ; Catechin ; analogs & derivatives ; pharmacology ; Cell Line, Tumor ; Humans ; Neoplasms ; pathology ; Piperazines ; pharmacology ; Protein Kinase Inhibitors ; pharmacology ; Pyridones ; pharmacology ; Pyrimidines ; pharmacology ; Pyrroles ; pharmacology ; Receptor, IGF Type 1 ; antagonists & inhibitors ; chemistry ; metabolism ; Signal Transduction

OBJECTIVETo explore the effects of carbendazim on the testicular development and spermatogenic function of male rats and its action mechanism.

METHODSForty clean-grade impubic male Wistar rats were equally randomized into a low-dose, a medium-dose, a high-dose and a control group, treated respectively with carbendazim at 20, 100 and 200 mg/kg (bw) and Tween-80 solution, all by oral gavage once a day for 80 days. After treatment, the rats were weighed, their testes and epididymides immediately excised, their morphological changes observed and the weights of the right testis and epididymis obtained. Sperm motility and counts in the left cauda epididymis were determined. Histopathological changes, cell apoptosis and the expression of Bcl-2/Bax in the testis were detected by HE staining, TUNEL and immunohistochemical SABC method.

RESULTSThe medium- and high-dose groups showed obviously atrophic testes and epididymides, marked histopathological abnormality of the testis, reduced weight of the right testis and epididymis, and decreased sperm motility and counts in the left cauda epididymis (P < 0.01). With the increasing dose of carbendazim, the apoptosis rate and Bax expression were significantly raised, while the expression of Bcl-2 significantly decreased (P < 0.05, P < 0.01).

CONCLUSIONCarbendazim affects the testicular development and spermatogenic function of male rats, and the mechanism may involve cell apoptosis induced by down-regulation of Bcl-2 and up-regulation of Bax.

Animals ; Apoptosis ; drug effects ; Benzimidazoles ; pharmacology ; Carbamates ; pharmacology ; Down-Regulation ; Male ; Rats ; Rats, Wistar ; Spermatogenesis ; drug effects ; Testis ; drug effects ; growth & development ; bcl-2-Associated X Protein ; metabolism

OBJECTIVETo observe the effects of telmisartan on Kv1.3 and Kv1.5 potassium channels expressed in Xenopus oocytes.

METHODSKv1.3 and Kv1.5 potassium channel currents expressed in Xenopus oocytes were recorded and observed in the absence and presence of telmisartan using standard two-microelectrode voltage clamp techniques.

RESULTSTelmisartan resulted in a concentration- and voltage-dependent inhibition effect on Kv1.3 channel current (IC(50) 2.05 micromol/L)and on Kv1.5 channel current (IC(50) 2.37 micromol/L).

CONCLUSIONSTelmisartan blocks open-state Kv1.3 channel which could be one of the mechanisms related to its immunomodulatory and anti-atherosclerosis effect. Telmisartan also blocks open-state Kv1.5 channel which might partly account for its effect on reducing the incidence of atrial fibrillation.

Animals ; Benzimidazoles ; pharmacology ; Benzoates ; pharmacology ; In Vitro Techniques ; Kv1.3 Potassium Channel ; drug effects ; Kv1.5 Potassium Channel ; drug effects ; Oocytes ; drug effects ; metabolism ; Patch-Clamp Techniques ; Xenopus

OBJECTIVETo observe the inhibitory effect of mizolastine on substance P(SP)-induced production of leukotriene B(4) (LTB(4)) and interleukin 5 (IL-5) in mouse skin.

METHODSMice were fed with different doses of mizolastine or other control drugs, 30 min after administration animals were injected intradermally with SP on the back. The treated skin samples were taken and competitive enzyme-link immunoassay (ELISA) method was applied to detect LTB (4) and IL-5 in the skin samples.

RESULTThe LTB(4) and IL-5 levels in 10 mg/kg mizolastine group were (1.23 +/-0.29)pg/ml and (34.28 +/-11.00)pg/ml, respectively, which were lower than those in saline control group [(5.52+/-1.88)pg/ml and (179.62 +/-46.25)pg/ml respectively] or loratadine group [(3.89+/-1.27)pg/ml and (127.74 +/-43.27)pg/ml respectively]. No significant difference was found between 10 mg/kg mizolastine group and dexamethasone group (P=0.161 and P=0.508).

CONCLUSIONMizolastine might inhibit the production of LTB(4) and IL-5 induced by substance P in mouse skin, suggesting that anti-inflammatory effect and the blockade of histamine H1 receptors might be involved in its anti-pruritic mechanisms.

Animals ; Benzimidazoles ; pharmacology ; Female ; Histamine H1 Antagonists ; pharmacology ; Interleukin-5 ; biosynthesis ; Leukotriene B4 ; biosynthesis ; Male ; Mice ; Mice, Inbred BALB C ; Skin ; metabolism ; Substance P ; antagonists & inhibitors

The effects of several antihypertensive drugs on bone mineral density (BMD) and micro-architectural changes in ovariectomized (OVX) mice were investigated. Eight-week-old female C57/BL6 mice were used for this study. Three days after ovariectomy, mice were treated intraperitoneally with nifedipine (15 mg/kg), telmisartan (5 mg/kg), enalapril (20 mg/kg), propranolol (1 mg/kg) or hydrochlorothiazide (12.5 mg/kg) for 35 consecutive days. Uterine atrophy of all mice was confirmed to evaluate estrogen deficiency state. BMD and micro-architectural analyses were performed on tibial proximal ends by micro-computed tomography (micro-CT). When OVX mice with uterine atrophy were compared with mice without atrophy, BMD decreased (P < 0.001). There were significant differences in BMD loss between different antihypertensive drugs (P = 0.005). Enalapril and propranolol increased BMD loss in mice with atrophied uteri compared with control mice. By contrast, thiazide increased BMD in mice with uterine atrophy compared with vehicle-treated mice (P = 0.048). Thiazide (P = 0.032) and telmisartan (P = 0.051) reduced bone loss and bone fraction in mice with uterine atrophy compared with the control. Thiazide affects BMD in OVX mice positively. The reduction in bone loss by thiazide and telmisartan suggest that these drugs may benefit menopausal women with hypertension and osteoporosis.
Animals ; Antihypertensive Agents/*pharmacology ; Atrophy ; Benzimidazoles/pharmacology ; Benzoates/pharmacology ; Bone Density/*drug effects ; Enalapril/pharmacology ; Female ; Mice ; Mice, Inbred C57BL ; Ovariectomy ; Propranolol/pharmacology ; Thiazides/pharmacology ; Tibia/radiography ; Tomography, X-Ray Computed ; Uterus/anatomy & histology/pathology