Medicinal Chemistry - Volume 10, Issue 3, 2014

Resveratrol is a bioactive polyphenol found in many vegetables. It is well known for its multiple pharmacological activities, such as anti-inflammatory, antioxidant, antimicrobial, anticancer, neuroprotective and cardioprotective effects. In vitro evidence of resveratrol efficacy is widespread, however, many concerns regarding its effectiveness in vivo arise from its poor stability in vitro and bioavailability following oral ingestion. This review focuses on the in vitro stability, with special focus on the photochemical stability of resveratrol, and on the therapeutic perspectives of this molecule due to its low bioavailability.

Staphylococcus epidermidis, a commensal microorganism at the human skin and mucosae, is nowadays considered an important opportunistic pathogen related to nosocomial infections on indwelling medical devices due biofilm formation. Bacterial biofilms are the worst aspect in the treatment of infections and now efforts have been made in the search for new molecular entities to overcome this situation. In this work, a compound isolated from marine associated fungi was capable to interfere with the adherence and biofilm formation of S. epidermidis. This compound, identified as mevalonolactone, showed significant inhibition of S. epidermidis ATCC 35984 biofilm formation, without antibacterial activity, evaluated by crystal violet assay, turbidimetric assay and scanning electron microscopy. When assayed against 12 clinical isolates of S. epidermidis, this compound exhibited both biofilm inhibition and antimicrobial activity, but no activity against gram-negative bacteria was observed. Therefore, when this constitutive molecule is added in the antibiofilm and antibacterial assays, it might act as an important agent against this pathogen, contributing to the arsenal of antibiofilm compounds.

Epidermal growth factor receptors belong to the ErbB family of receptor tyrosine kinases (TKs) involved in the proliferation of normal and malignant cells. EGFR has attracted considerable attention as a target for cancer therapy. The findings reported herein are believed to provide some novel insights into the design of effective drugs for the therapeutic treatment of EGFR-related cancers. In particular, it is shown using sophisticated computational tools in a systematic way that the affinity of a wide spectrum of thiazolo[4,5-d]pyrimidine analogs can be carefully tuned up by seeking the desired goal in the structural modifications of EGFR, such as single point mutations of the critical EGFR residues in the active site. It is also demonstrated that a large number of the small ligand molecules can be efficiently divided into subgroups of the structurally similar ligands and that every such a subgroup has its unique inhibitory activity signature. The protein engineering approach, as quite reproducible, is proposed to be a viable partner to experiment in addressing a variety of issues, including investigation of clinically important mutations, development of drug resistance, identification of the most promising anti-cancer drug candidates, etc.

Thioetherhydroxyethylsulfonamide derivatives were synthesized and evaluated for their in vitro antibacterial activity against Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853) and Staphylococcus aureus (ATCC 25923). Results have shown that compounds 8c and 9e display potent activity (MIC = 0.125 µg/mL) against E. coli when compared with the standard drug sulfamethoxazole (SMZ, MIC < 0.5 µg/mL) for this same strain. All the new compounds were fully identified and characterized by NMR (1H and 13C) and X-ray crystallography (for compound 8c). This class of compounds can be considered as a good starting point for the development of new lead molecules in the fight against multi-drug bacterial resistance.

Melanoma is the fatal form of skin cancer. Herein, a three-dimensional quantitative structure-activity relationship study on a series of 105 colchicine binding site-targeted 2-arylthiazolidine-4-carboxylic acid amides (ATCAA) derivatives as melanoma antagonists was conducted. The optimal CoMSIA model yields a Q2 of 0.556, R2ncv of 0.833 and R2pred of 0.757, while the CoMFA yields a Q2 of 0.569, R2ncv of 0.812 and R2pred of 0.589. In addition, molecular docking was also carried out. The study results demonstrated that: (1) Bulky substituents in Rings C and D significantly increase the biological activity of compounds while decrease the activity at Rings A and B; (2) Electropositive groups at Rings A and B as well as electronegative groups at Ring C help to increase the activity; (3) HB donor favors Rings A and D while HB acceptor favors Rings B and C. Besides, a statistical analysis of the key amino acids as well as the ones forming HB with various antagonists of the colchicine binding site was conducted based on 34 essays and found HB to be the key interaction that MTAs have with the colchicine binding site and that Ala 250, Asn 258, Thr 179, Lys 254 and Lys 352 are vital in the composition of the site and the formation of HB. The results of this study provide useful information on designing antagonists with improved activity and insight on the composition of the colchicine binding site.

Vanadium is known to exhibit several bioactivities and shows potential as a pharmaceutical drug. The current studies were conducted with the goal of synthesizing a new generation of oxovanadium(IV) complexes, investigating their effects on cancer cell proliferation and their immunomodulatory properties, and predicting possible structure activity relationships. The elucidation of the structures of the synthesized complexes was achieved using elemental analysis, conductivity measurements, magnetic property measurements, and IR and electronic spectroscopies. These studies suggest that the synthesized complexes have a binuclear structure. All of the complexes were evaluated on different cancer cell lines, including HeLa, PC-3, and C33A, and on the normal 3T3 fibroblast cells. Some of the compounds exhibited prominent inhibitory activities on the cervical cancer cell lines and the prostate cancer PC-3 cells. The immunomodulatory activity of the vanadium compounds was evaluated on human phagocytes for ROS (reactive oxygen species) production using luminol- and lucigenin-based chemiluminescence assays. No potent effect was exerted by the majority of the tested compounds on whole blood oxidative burst activity. A study of human T-cells proliferation in vitro on vanadium complexes was also conducted. The majority of the compounds were observed to exhibit potent inhibitory effects. The superoxide, nitric oxide and DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging properties were also determined.

Chalcones are a group of plant-derived polyphenolic compounds possessing a wide variety of biological activities. The aim of this study was to synthesize 2,6-dihydroxy-4-isopentenyloxychalcone (1), a chalcone found in plants belonging to the genera Helichrysum, Pleiotaxix and Metalasia, and evaluate its antimicrobial effects against major oral pathogens as well as its anti-inflammatory properties. Compound 1 was synthesized using a simple two-step procedure. Among the seven pathogens tested, Porphyromonas gingivalis and Prevotella intermedia were the most susceptible to inhibition by 1. This chalcone also attenuated the secretion of interleukin-8 and chemokine (C-C motif) ligand 5 (CCL5) by lipopolysaccharide (LPS)-stimulated oral epithelial cells as well as the secretion of matrix metalloproteinase 2 (MMP-2) by LPS-stimulated gingival fibroblasts. In conclusion, our study showed that 1 exerts a dual effect by acting on both oral pathogens and the host inflammatory response and thus represents a molecule of interest for periodontal infections.

Systematic mono-deoxylation of the four hydroxyl groups in the glucose moiety in dapagliflozin led to the discovery of 6-deoxydapagliflozin 1 as a more active sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor (IC50 = 0.67 nM against human SGLT2 (hSGLT2) vs 1.16 nM for dapagliflozin). It exhibited more potent blood glucose inhibitory activity in rat oral glucose tolerance test and induced more urinary glucose in rat urinary glucose excretion test than its parent compound dapagliflozin.

A series of substituted pyridinylpyrazole (or isoxazole) derivatives were synthesized and evaluated for their anti-inflammatory (AI) activity using formalin-induced paw edema bioassays. Their inhibitory activities of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) were also determined. The analgesic activity of the same compounds was evaluated using rat-tail withdrawal technique. Their antipyretic activity was also evaluated. The results revealed that compounds 4a,b, 6a, 8a, 14c and 15a exhibited significant AI and analgesic activities. Compounds 5a, 6a and 8a displayed good antipyretic activity. Compounds 14c and 15a showed good COX-2 inhibitory activity and weak inhibition of COX-1. Additionally, the most active compounds were shown to have a large safety margin (ALD50 >300-400 mg / Kg) and minimal ulcerogenic potentialities when administered orally at a dose of 300 mg/Kg. Docking studies for 14c and 15a with COX-2 showed good binding profile. Antimicrobial evaluation proved that most of the compounds exhibited distinctive activity against the gram negative bacteria, P. aeruginosa and E coli.