Sci. Pharm., Volume 85, Issue 4 (December 2017) – 4 articles

Point mutations in Plasmodium falciparum dihydrofolate reductase (pfDHFR), especially the double mutant variant (A16V + S108T), led to ineffective inhibiting by cycloguanil (Cyc). Cycloguanil derivatives showed good inhibiting properties against wild-type and mutant pfDHFR with an inhibition constant as low as the nanomolar level. However, there have been no reports on the stereochemistry of the compounds, and this is important because the pure enantiomeric form of a chiral drug can exert desirable, as well as non-desirable responses on the body or both. In this work, three-dimensional structures of Cyc derivatives in R and S configuration were constructed and optimized using Hartree-Fock/6-31G (d,p). Their structures were docked into the binding pocket of wild-type and double mutant (A16V + S108T) pfDHFR, complexed with nicotinamide adenine dinucleotide phosphate (NADPH). Results indicate that both wild-type and mutant pfDHFR are enantioselective towards enantiomeric Cyc derivatives (R and S configuration). Full article

Abstract: Due to the multiplicity of useful applications of metal oxide nanoparticles (ONPs) in medicine are growing exponentially, in this study, Fe₃O₄ (iron oxide) nanoparticles (IONPs) were biosynthesized using Rosemary to evaluate the leishmanicidal efficiency of green synthesized IONPs. This is the first report of the leishmanicidal efficiency of green synthesized IONPs against Leishmania major. The resulting biosynthesized IONPs were characterized by ultraviolet-visible spectroscopy (UV-Vis), X-ray diffraction (XRD), transmission electron microscopy (TEM), and Fourier transform infrared spectroscopy (FTIR). The leishmanicidal activity of IONPS was studied via 3-4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results showed the fabrication of the spherical shape of monodisperse IONPs with a size 4 ± 2 nm. The UV-visible spectrophotometer absorption peak was at 334 nm. The leishmanicidal activity of biogenic iron oxide nanoparticles against Leishmania major (promastigote) was also studied. The IC₅₀ of IONPs was 350 µg/mL. In this report, IONPs were synthesized via a green method. IONPs are mainly spherical and homogeneous, with an average size of about 4 nm, and were synthesized here using an eco-friendly, simple, and inexpensive method. Full article

Small intestinal injury is known to be one of the most commonly appearing pathologies, resulting in the use of medications such as: nonsteroidal anti-inflammatory drugs (NSAIDs), antitumor drugs and angiotensin-converting enzyme (ACE) inhibitors. The principal objective of this study is to evaluate the action of a novel mercaptoacrylic acid derivative able to release H₂S on parameters of NO-synthase system and oxidative stress. Inducing enteropathy, three types of medications were used: indomethacin, an NSAID (35 mg/kg); methotrexate, an antitumor drug (10 mg/kg); and enalapril, an ACE inhibitor (2 mg/kg/day). 2-[(4-chlorophenyl-carbamoyl)-methyl]-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-acrylic acid (2C3DHTA) was introduced based on the background of medication-induced enteropathy (10 mg/kg/day). The survey showed that malondialdehyde (MDA) concentration, myeloperoxidase (MPO) activity, superoxide dismutase (SOD), catalase, and NO-synthases (NOS) were determined in the small intestinal mucosa. The increase in inducible NO-synthase (iNOS) activity was due to indomethacin and methotrexate administration. Constitutive NO-synthase (cNOS) activity was decreased by an ACE-inhibitor. The cytoprotective effect was demonstrated by 2C3DHTA, which returned iNOS activity to its control level and increased cNOS activity. The enterotoxic action of studied medication was accompanied by the development of oxidative stress manifested, activity of MPO was increased. MPO activity and manifestations of oxidative stress were decreased by 2C3DHTA. Effects of 2C3DHTA can be explained by the action of H₂S, released from this compound in the gastrointestinal (GI) system. Full article

Twelve N-substituted-glycinyl triazolyl oxazolidinone derivatives were screened for antimycobacterial activity against susceptible (Mycobacterium tuberculosis (Mtb) H37Rv) and resistant (isoniazid (INH)-resistant Mtb (SRI 1369), rifampin (RMP)-resistant Mtb (SRI 1367), and ofloxacin (OFX)-resistant Mtb (SRI 4000)) Mtb strains. Most of the compounds showed moderate to strong antimycobacterial activity against all strains tested, with minimum inhibitory concentration (MIC) value ranges of 0.5–11.5, 0.056–11.6, 0.11–5.8, and 0.03–11.6 μM, and percent inhibition ranges of 41–79%, 51–72%, 50–75%, and 52–71% against Mtb H37Rv, INH-R, RMP-R, and OFX-R M. tuberculosis, respectively. The 3,5-dinitrobenzoyl and 5-nitrofuroyl derivatives demonstrated strong antimycobacterial activities with the N-(5-nitrofuroyl) derivatives (PH-145 and PH-189) being the most potent, with MIC value range of 0.3–0.6 μM against all strains tested. Compounds were not bactericidal, but showed intracellular (macrophage) antimycobacterial activity. A reliable validated analytical method was developed for a representative compound PH-189 using Waters Acquity ultra High-Performance Liquid Chromatography (UHPLC) system with quaternary Solvent Manager (H-Class). A simple extraction method indicated that PH-189 was stable in human plasma after 90 min at 37 °C with more than 90% successfully recovered. Moreover, stress stability studies were performed and degradants were identified by using UHPLC-ESI-QToF under acidic, basic, and oxidative simulated conditions. Full article