Medicinal Chemistry

The current manuscript describes a high throughput assay designed to identify organic compounds with potential inhibitory effects on sickle hemoglobin polymerization. The assay is fast, economic and reproducible. In just 20-minutes, a test compound can be screened for anti-polymerization activity at five different concentrations; each in quadruple; using as little as 10 mg of purified sickle hemoglobin. The assay was conducted in high phosphate buffer concentration (1.5M), a concentration that allows sickle hemoglobin to polymerize at a very low concentration of 50.0 μM. The new assay was validated by evaluating the inhibitory effects of the amino acid phenylalanine, a standard control used in all gelation assays, and hydroxyl urea, the only FDA approved drug to treat sickle cell anemia. Phenylalanine showed a reproducible and concentration-dependent delay of sickle hemoglobin polymerization at a concentration range of 25-75mM. Hydroxyurea; although its action is thought to be through promoting fetal hemoglobin formation, was found to have direct inhibitory effects on sickle hemoglobin polymerization but at a high concentration range of 64-500mM. The assay was applied for random screening of several organic compounds and 2-thio-salicylic acid was identified to be a powerful inhibitor for polymerization at much lower concentration range of 0.1-1.6 mM.

In the last 30 years oligonucleotides i.e., relatively short polymers (usually 12-24 units long) based on DNA structure, have found a widespread use in biochemical studies and as biochemical probes and chemotherapeutic agents for the downregulation of genetic expression or for exon skipping. Here we present a short review of studies from our laboratories on the synthesis and applications of different kind of conjugates to address some of these techniques. Preparation of conjugates with small alkyl groups, intercalators, fluorescent oligothiophenes, and lipophilic bile-acids will be discussed.

Previously we reported the capacity of the bio-inspired Fe(III) complexes, Fe2PO and Fe2PC, to mimic the activity of superoxide dismutase and peroxidase enzymes, as well as their capacity to reduce the cytotoxicity generated by superoxide radicals in human peripheral blood mononuclear cells, under stress conditions. Based on those findings, we decided to evaluate the cytotoxicity, antioxidant and redox state modulation capacity of Fe2PO and Fe2PC complexes, pondering them as drug candidates against free radicals unbalance disorders. Fe2PO and Fe2PC deactivated the ABTS synthetic radical with an IC50 value of 38.4 ± 0.9 μM and 28.9 ± 0.2 μM, respectively, while against the DPPH radical, the IC50 value was over the higher concentration tested (>200 μM) for both complexes. As desirable for any drug candidate, none of the metallic complexes (at 25, 50 and 100 μM) induced cytotoxicity on M12.C3.F6 cells (a murine B-cell lymphoma model), but differences in the redox state modulation were observed on the basis of fluorescence detection of a 2′,7′-dichlorofluorescin probe by flow cytometry. Cells under normal conditions and preincubated with Fe2PO and Fe2PC complexes slightly augmented the reactive oxygen species concentration, meanwhile, cells under stress condition preincubated with H2O2 and metallic complexes, showed a higher augmentation in the reactive oxygen species concentration, in comparison to the controls. Finally, a cellular internalisation assay was performed, showing that Fe2PO and Fe2PC exert those effects from the outside of the cells. All these results suggest the ability of Fe2PO and Fe2PC complexes to selectively increase the reactive oxygen species concentration in cells with a free radical unbalance, without inducing mortality in cells under normal conditions.

DATPMs were synthesized by the acid-catalysed Baeyer condensation of 4-substituted benzaldehydes and aniline in good yields. The materials were purified by column chromatography and characterized by FTIR, 1H-13CNMR and elemental analysis. The optimized ligands were docked with the IKKα, (PDB code: 3BRT) using the MOE-Dock module and are found to obey Lipinski’s Ro5 cut-off limits. The computational results revealed that the DATPMs, like other derivatives of TPM, could be potential anticancer drugs. Moderate protein kinase inhibitory activity was exhibited by samples 2 and 3 by displaying inhibition bald zone of 10 and 9 mm respectively against the Streptomyces 85E strain.

The present paper focuses on the synthesis of silver nanoparticles using with different leaf extract concentrations of Vitex negundo. The biosynthesized nanoparticles were characterized by UV-vis absorption spectrophotometry, fourier transform infrared spectroscopy, X-ray diffraction, field emission scanning electron microscopy, energy dispersive X-ray, atomic force microscopy, transmission electron microscopy, photoluminescence and zeta potential techniques. The formation of silver nanoparticles was confirmed by the surface plasmon resonance absorption peak at 423 nm in UV-vis absorption spectra of the synthesized silver nanoparticles. The fourier transform infrared spectroscopy indicates flavonoids as a potential reduced agents. Field emission scanning electron microscopy shows the synthesized silver nanoparticles are in spherical shape. Energy dispersive X-ray spectroscopy shows the strong peak belongs to silver, and it confirms the formation of Ag NPs. X-ray diffraction spectra of synthesized silver nanoparticles exhibit they are in face centered cubic crystalline structure. The photoluminescence spectra of synthesized silver nanoparticles show their emission peak at 489-481 nm and the emission intensity is proportional to the different concentrations of leaf extract. The spherical shaped silver nanoparticles are observed by atomic force microscopy technique. The zeta potential value is observed at -13.5 mV, which shows the synthesized silver nanoparticles are incipient instability. The antimicrobial activity of the synthesized nanoparticles is studied using the disc diffusion method, which indicates that both Gram positive and Gram negative microorganisms have been affected by the silver nanoparticles. The observed antibacterial activity could be find important applications in medicine, biology and industry.

Despite enormous efforts have been made in the search for new drugs, diabetes mellitus (DM) still remains the cause of mortality worldwide. A series of chalcone based aryloxyethylamines were synthesized and evaluated for their anti-hyperglycemic activity in SLM and STZ rat models. The majority of the compounds exhibited temperate to good activity ranging from 18.0% to 39.8% in SLM and 14.6% to 31.5% in STZ models, respectively. The most potent compound 31 exhibited glucose lowering of 27.0% in SLM and 31.5% in STZ models. A definite structure–activity relationship was observed while varying the nature and position of the different amines in ring-A of chalcone.