Evaluation of Acute and Sub-Acute Toxicity, Oxidative Stress and Molecular Docking of Two Nitrofuranyl Amides as Promising Anti-Tuberculosis Agents.

Tuberculosis (TB) remains a widespread infectious disease and one of the top 10 causes of death worldwide. Nevertheless, despite significant advances in the development of new drugs against tuberculosis, many therapies and preventive measures do not lead to the expected favorable health results for various reasons. The aim of this study was to evaluate the acute and sub-acute toxicity and oxidative stress of two selected nitrofuranyl amides with high in vitro antimycobacterial activity. In addition, molecular docking studies were performed on both compounds to elucidate the possibilities for further development of new anti-tuberculosis candidates with improved efficacy, selectivity, and pharmacological parameters. Acute toxicity tests showed that no changes were observed in the skin, coat, eyes, mucous membranes, secretions, and vegetative activity in mice. The histological findings include features consistent with normal histological architecture without being associated with concomitant pathological conditions. The observed oxidative stress markers indicated that the studied compounds disturbed the oxidative balance in the mouse liver. Based on the molecular docking, compound DO-190 showed preferable binding energies compared to DO-209 in three out of four targets, while both compounds showed promising protein-ligand interactions. Thus, both studied compounds displayed promising activity with low toxicity and can be considered for further evaluation and/or lead optimization.

Total Testosterone as a Specific Marker of Acute Kidney Injury in Male Patients With Myocardial Infarction.

Aim The aim of the present study was to assess the significance of total testosterone (T) as a marker of acute kidney injury (AKI) in patients with acute myocardial infarction (MI). Patients and methods The study was a retrospective, single-center cohort study that included 55 consecutive male patients diagnosed with acute MI who were admitted to the Cardiology Clinic of Alexandrovska University Hospital (Sofia, Bulgaria) between July 2011 and December 2013. The plasma total T levels, measured at admission, the peak levels of myocardial necrosis markers, high-sensitive C-reactive protein (hsCRP), and the left ventricular ejection fraction (LVEF) were analyzed in relation to the incidence of AKI. Results The occurrence of AKI was positively predicted by reduced EF (OR=0.825; CI=0.724-0.942; P=0.004), advanced age (OR=1.077; CI=1.038-1.151; P=0.029), and low levels of total T (OR=0.837; CI=0.707-0.990; P=0.037). Reduced systolic function (OR=0.861; 95% CI=0.758-0.978; P=0.022 for EF) and marginally age (OR=1.094; 95% CI=1.000-1.197; P=0.051) contributed to the incidence of AKI in a multivariate model. Total T was not an independent factor (OR=0.841; 95% CI=0.669-1.058; P=0.139) for AKI. The total T levels were significantly inversely correlated with the peak of hsCRP (r= -0.153; P=0.009) and showed a tendency to inverse relation with the SYNTAX score (r= -0.235; P=0.083). Conclusion The total T levels are significantly inversely related to the peak of hsCRP and as a tendency to the SYNTAX score in male patients with acute MI. A low level of plasma total T is not an independent marker of AKI in acute MI. Advanced age and low EF are independent factors for AKI discrimination in a small cohort of patients with acute MI.

Molecular Insight into Mycobacterium tuberculosis Resistance to Nitrofuranyl Amides Gained through Metagenomics-like Analysis of Spontaneous Mutants.

We performed synthesis of new nitrofuranyl amides and investigated their anti-TB activity and primary genetic response of mycobacteria through whole-genome sequencing (WGS) of spontaneous resistant mutants. The in vitro activity was assessed on reference strain Mycobacterium tuberculosis H37Rv. The most active compound 11 was used for in vitro selection of spontaneous resistant mutants. The same mutations in six genes were detected in bacterial cultures grown under increased concentrations of 11 (2×, 4×, 8× MIC). The mutant positions were presented as mixed wild type and mutant alleles while increasing the concentration of the compound led to the semi-proportional and significant increase in mutant alleles. The identified genes belong to different categories and pathways. Some of them were previously reported as mediating drug resistance or drug tolerance, and counteracting oxidative and nitrosative stress, in particular: Rv0224c, fbiC, iniA, and Rv1592c. Gene-set interaction analysis revealed a certain weak interaction for gene pairs Rv1592-Rv1639c and Rv1592-Rv0224c. To conclude, this study experimentally demonstrated a multifaceted primary genetic response of M. tuberculosis to the action of nitrofurans. All three 11-treated subcultures independently presented the same six SNPs, which suggests their non-random occurrence and likely causative relationship between compound action and possible resistance mechanism.

Antimicrobial Triterpenoids and Ingol Diterpenes from Propolis of Semi-Arid Region of Morocco.

The chemical composition and antimicrobial activity of propolis from a semi-arid region of Morocco were investigated. Fifteen compounds, including triterpenoids (1, 2, 7-12), macrocyclic diterpenes of ingol type (3-6) and aromatic derivatives (13-15), were isolated by various chromatographic methods. Their structures were elucidated by a combination of spectroscopic and chiroptical methods. Compounds 1 and 3 are new natural compounds, and 2, 4-6, and 9-11 are newly isolated from propolis. Moreover, the full nuclear magnetic resonance (NMR) assignments of three of the known compounds (2, 4 and 5) were reported for the first time. Most of the compounds tested, especially the diterpenes 3, 4, and 6, exhibited very good activity against different strains of bacteria and fungi. Compound 3 showed the strongest activity with minimum inhibitory concentrations (MICs) in the range of 4-64 µg/mL. The combination of isolated triterpenoids and ingol diterpenes was found to be characteristic for Euphorbia spp., and Euphorbia officinarum subsp. echinus could be suggested as a probable and new plant source of propolis.

In Vivo Toxicity, Redox-Modulating Capacity and Intestinal Permeability of Novel Aroylhydrazone Derivatives as Anti-Tuberculosis Agents.

The emergence and spread of Mycobacterium tuberculosis strains resistant to many or all anti-tuberculosis (TB) drugs require the development of new compounds both efficient and with minimal side effects. Structure-activity-toxicity relationships of such novel, structurally diverse compounds must be thoroughly elucidated before further development. Here, we present the aroylhydrazone compounds (3a and 3b) regarding their: (i) acute and subacute toxicity in mice; (ii) redox-modulating in vivo and in vitro capacity; (iii) pathomorphology in the liver, kidney, and small intestine tissue specimens; and (iv) intestinal permeability. The acute toxicity test showed that the two investigated compounds exhibited low toxicity by oral and intraperitoneal administration. Changes in behavior, food amount, and water intake were not observed during 14 days of the oral administration at two doses of 1/10 and 1/20 of the LD50. The histological examination of the different tissue specimens did not show toxic changes. The in vitro antioxidant assays confirmed the ex vivo results. High gastrointestinal tract permeability at all tested pH values were demonstrated for both compounds. To conclude, both compounds 3a and 3b are highly permeable with low toxicity and can be considered for further evaluation and/or lead optimization.

Effects of statins on endothelial function in patients with coronary artery disease.

BACKGROUND: Flow-mediated dilatation (FMD) of the brachial artery is a method capable of detecting endothelium dysfunction. Statins are generally consent drugs for reducing cardiovascular morbidity and mortality and are shown to improve the systemic endothelial function. HYPOTHESIS: The aim of our study was to assess the endothelial function using FMD of the brachial artery in patients with different degrees of coronary artery stenosis with respect to their treatment with statins. METHODS: We evaluated the FMD of 221 patients with coronary arteriography performed, of whom 99 (44.8%) were receiving statins and 122 (55.2%) were not receiving statins. RESULTS: We did not find a statistically significant difference in the FMD values between the patients with and without a statin treatment: 5.57 +/- 5.68 and 4.69 +/- 4.48, respectively, P = .581. In the subgroup of patients without angiographically visible coronary artery stenoses or with stenoses <20% (86 patients), patients undergoing statin treatment had a significantly better endothelial function compared to patients without such a treatment: FMD 9.24 +/- 6.87 and 6.50 +/- 4.51, respectively, P = .047. CONCLUSIONS: FMD could not distinguish between the patients who were treated with statin and those not treated with statins with the same demographic, clinical, and angiographic characteristics. The only exception was in the group of patients with a minor coronary disease. Statin treatment had a more pronounced effect in the earlier stages of coronary atherosclerosis.

Endothelial function in patients with and without diabetes mellitus with different degrees of coronary artery stenosis.

PURPOSE: To evaluate endothelial function using flow-mediated dilatation (FMD) of the brachial artery in patients with and without diabetes mellitus (DM) with different degrees of coronary artery stenosis. METHOD: We investigated 293 patients, 69 (23.6%) of whom had DM. FMD and coronary arteriography were performed. RESULTS: Patients with DM had a significantly lower FMD (mean +/- SD, 3.7 +/- 3.8%) compared with patients without DM (mean +/- SD, 5.2 +/- 5.3%) (p < 0.05). When the results were broken down by the severity of coronary artery disease (CAD) (no significant coronary artery stenosis, 1-vessel disease, 2-vessel disease, and 3-vessel disease) the only statistically significant difference between diabetics and nondiabetics was found in patients without significant coronary stenosis (mean FMD +/- SD: 5.2 +/- 4.4% in diabetics, 7.6 +/- 5.4% in nondiabetics [p < 0.05]). CONCLUSION: In CAD patients, the presence of DM was associated with endothelial dysfunction. The difference in the FMD was clearly expressed between patients with and without DM in the subgroup without significant coronary stenosis, and was no longer present with advanced coronary atherosclerosis.