QSAR analysis of five generations of cephalosporins to establish the structural basis of activity against methicillin-resistant and methicillin-sensitive Staphylococcus aureus.

Solving the worldwide problem of growing bacterial drug resistance will require a short-run and medium-term strategy. Structure-activity relationship (SAR) and quantitative SAR (QSAR) analyses have recently been utilized to reveal the molecular basis of the antibacterial activity and antibacterial spectrum of penicillins, the use of which is no longer solely empirical. Likewise, a more rational drug design can be achieved with cephalosporins, the largest group of ß-lactam antibiotics. The current contribution aimed to establish the molecular and physicochemical basis of the antibacterial activity of five generations of cephalosporins on methicillin-sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). With SAR and QSAR analyses, the molecular portions that provide essential and additional antibacterial activity were identified. The substitutions with greater volume and polarity on the R2 side chain of the cephem nucleus increase potency on MSSA. The best effect is produced by substitutions with polar nitrogen atoms at the alpha-carbon (Cα). Substitutions with greater volume and polarity on the R1 side chain further enhance antibacterial activity. In contrast, the effect against MRSA seems to be independent of any substitution on R2 or at the Cα, while depending on the accessory portions with greater volume and polarity on R1.

Apocynin combined with drugs as coadjuvant could be employed to prevent and/or treat the chronic kidney disease.

A worldwide public health problem is chronic kidney disease (CKD) presenting alarming epidemiological data. It currently affects about 10% of the adult population worldwide and has a high mortality rate. It is now known that oxidative stress represents one of the most important mechanisms in its pathophysiology, from the early stages to the terminal phase. Oxidation increases inflammation and reduces the capacity of NO• to relax vascular smooth muscle, in part by decreasing bioavailability of tetrahydrobiopterin (BH4), leading to endothelial dysfunction and high blood pressure, and due to the limited effectiveness of existing treatments, new drugs are needed to prevent and/or treat these mechanisms. The aim of this study was to test apocynin in a 5/6 nephrectomy mouse model of CKD to investigate whether its known antioxidant effect can improve the disease outcome. This effect results from the inhibition of NADPH oxidase and consequently a reduced production of the superoxide anion ([Formula: see text]). Animals were divided into five groups: sham, 5/6 nephrectomy only, and 5/6 nephrectomy followed by treatment with captopril, losartan or apocynin. The parameters evaluated were blood pressure and markers of oxidative stress ([Formula: see text]) and endothelial function (BH4). There were significantly lower levels of [Formula: see text] and a greater availability of serum BH4 in the apocynin-treated animals versus the control group and the two other drug treatments. The present findings suggest that apocynin in conjunction with a coadjuvant for modulating blood pressure may be useful for controlling the progression of CRF.

Voltage-Dependent Sodium Channel Blocker Anticonvulsants: An Approach to the Structure-Activity Relationship.

BACKGROUND: Anticonvulsants are drugs used in the treatment of seizures; their pharmacology includes promoters of brain inhibition and inhibitors of brain activity. Of the latter, voltagedependent sodium channel blockers (VGSCB) are the most widely used in therapeutics. OBJECTIVE: The study aimed at proposing the structural requirements of VGSC blockers through a quantitative structure-activity relationship analysis of drugs with proven activity. METHODS: IC50 values of anticonvulsant drugs on VGSCs were considered under similar experimental conditions; some physicochemical properties of the molecules that were correlated with their biological activity were determined in silico. RESULTS: Relationships were observed between the dipole moment, pKa, EHOMO, and MR with the biological activity, which infers that between greater polarity and basicity of the drugs, their activity as blockers will increase. Subsequently, the structural subclassification of the drugs was carried out, based on the urea derivation, the groups of which were: Group 1 (direct and bioisostere derivatives) and Group 2 (homologue and vinylogue derivatives of urea). CONCLUSION: The biological activity depends on the polarity, basicity, and electronic density of the drugs. The derivation of urea is essential, which is present in its original substituted form or a bioisosteric form. Urea can be in the form of a homologue or a vinylogue at the ends of the molecule. Aromatic substitution to the urea portion is necessary.

Diabetic Retinopathy: Important Biochemical Alterations and the Main Treatment Strategies.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by impaired glucose homeostasis, insulin resistance and hyperglycemia. Among its serious multisystemic complications is diabetic retinopathy (DR), which develops slowly and often insidiously. This disorder-the most common cause of vision loss in working-age adults-is characterized by functional and morphological changes in the retina. It results from the exacerbation of ischemic and inflammatory conditions prompted by alterations in the blood vessels, such as the development of leukostasis, thickening of the basement membrane, retinal neovascularization and fibrovascular tissue formation at the vitreoretinal interface. The pathogenic alterations are usually triggered at the biochemical level, involving a greater activity in 4 pathways: the polyol pathway, the hexosamine pathway, the formation of advanced glycation end-products and the activation of protein kinase C isoforms. When acting together, these pathways give rise to increased levels of reactive oxygen species and decreased levels of endogenous antioxidant agents, thus generating oxidative stress. All current therapies are aimed at the later stages of DR, and their application implies side effects. One possible strategy for preventing the complications of DM is to counteract the elevated superoxide production stemming from a high level of blood glucose. Accordingly, some treatments are under study for their capacity to reduce vascular leakage and avoid retinal ischemia, retinal neovascularization and macular edema. The present review summarizes the biochemical aspects of DR and the main approaches for treating it.