Close insight into the nature of intermolecular interactions in dihydropyrimidine-2(1H)-thione derivatives

The crystal structures of four 1-(R-phenyl)-4,4,6-trimethyl-3,4-dihydropyrimidine-2IJ1H)-thione derivatives [R = 2-chloro (1), 2,3-di-chloro (2), 2,4-di-methyl (3), and 4-methoxy (4)] were determined and analysis of their molecular conformations was carried out. A comparative study of the intermolecular interactions—including eight closely related structures from CSD—was performed and the degree of isostructurality was quantified. The intermolecular interactions were characterized in terms of the periodic system electron density and the topological analysis highlighted the role of N–H⋯S=C hydrogen bonds in the stabilization of the different supramolecular architectures. PIXEL lattice energy calculations revealed that the dispersion component was the major contributor, together with the important role of the Coulombic term to the total energy. The interaction energies for molecular pairs involving N–H⋯S=C hydrogen bonds indicated a dominant contribution to packing stabilization coming from the Coulombic components. Hirshfeld surfaces and fingerprint plots allowed us to visualize different intermolecular contacts and their relative contributions to the total surface for each compound. Analysis of the electrostatic potentials (ESP) correlated well with the computed energies, thus characterizing the strengths of the different interactions.Instituto de Física La PlataCentro de Química Inorgánic

Synthesis and Leishmanicidal Activity of Novel Urea, Thiourea, and Selenourea Derivatives of Diselenides

A novel series of thirty-one N-substituted urea, thiourea, and selenourea derivatives containing diphenyldiselenide entities were synthesized, fully characterized by spectroscopic and analytical methods, and screened for their in vitro leishmanicidal activities. The cytotoxic activity of these derivatives was tested against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Thirteen of the synthesized compounds showed a significant antileishmanial activity, with 50% effective concentration (EC50) values lower than that for the reference drug miltefosine (EC50, 2.84¿¿M). In addition, the derivatives 9, 11, 42, and 47, with EC50 between 1.1 and 1.95¿¿M, also displayed excellent selectivity (selectivity index ranged from 12.4 to 22.7) and were tested against infected macrophages. Compound 11, a derivative with a cyclohexyl chain, exhibited the highest activity against intracellular amastigotes, with EC50 values similar to those observed for the standard drug edelfosine. Structure-activity relationship analyses revealed that N-aliphatic substitution in urea and selenourea is recommended for the leishmanicidal activity of these analogs. Preliminary studies of the mechanism of action for the hit compounds was carried out by measuring their ability to inhibit trypanothione reductase. Even though the obtained results suggest that this enzyme is not the target for most of these derivatives, their activity comparable to that of the standards and lack of toxicity in THP-1 cells highlight the potential of these compounds to be optimized for leishmaniasis treatment.Comunidad de MadridMinisterio de Economía y CompetitividadFoundation for Applied Medical Investigatio

Lanthanides, lanterns, and lone pairs: computational studies of inorganic complexes

Computational work was performed to support several synthetic projects in the Doerrer lab. The new luminescent cerium complexes [K(THF)6][Ce(OC4F9)4(THF)2] (20) and [K(THF)2][Ce(pinF)2(THF)3] (22) were structurally optimized in the gas phase, and their uncommonly blue-shifted absorption spectra were simulated by TD-DFT. Electronic structure analysis elucidated the 4f→5d transitions responsible for the absorption peaks, showing the involvement of the fluorinated alkoxide ligands in the composition of the donor orbitals. The [pinF]2− ligand was also coordinated to Sn(II) and Sn(IV). The structures of the new compounds [K]2[Sn(pinF)2] (31) and [K]2[Sn(pinF)3] (32) were optimized by DFT and their electronic structures examined, revealing a sterically exposed lone pair in the case of 31, and for 32 showing that its unusually twisted six-coordinate geometry (azimuthal angle ~30°) is maintained in the absence of counterions. Metal-metal interactions were investigated in the diamagnetic lantern compounds [PtM(SOCR)4(OH2)] (R = CH3, M = Mg (1), Zn (56); R = C6H5, M = Mg (2), Ca (3), Zn (4)). 195Pt NMR spectra calculated for these lanterns and the precursor ion [Pt(SAc)4]2− (42) demonstrate the electronic effect of coordinating these Lewis acidic metals to the electron-rich Pt(II) center. Canonical and NBO analyses show that the {PtZn} lanterns 41 and 56 possess dative bonds between Pt and Zn, while Ca and Mg feature purely ionic interactions with Pt. A new class of heterobimetallic lantern complexes of the form [PtM(pipCOS)4(py)] (M = Mn (43), Co (44), Ni (45), and Zn (46)) were synthesized. These species exhibit strong absorption in the visible range that was investigated by DFT. Structural and electronic analyses reveal donation from the lone pair on the piperidine N atom into the delocalized ligand system in the ground state, indicating the potential for LMCT to occur upon excitation. A new bidentate ligand, a condensed thioamide, was bound to a Pt(II) center in the complexes [Pt(ctaPhMe)2] (57) and [Pt(ctaPhMe)2]2− (59). DFT analysis of these and the hypothetical ion [Pt(ctaPhMe)2]− (58) showed that reduction occurs on the ligands themselves, with the added electron density concentrated on carbon atoms in the ring, and that the doubly reduced species exists in the high-spin state

Pharmacogenetics of efficiency and tolerance of the peroral antidiabetic drug metformin

Elektroniskā versija nesatur pielikumusMetformīns ir pirmās izvēles medikaments jaundiagnosticētu 2.tipa cukura diabēta (T2DM) pacientu ārstēšanā. Mēs identificējām asociāciju starp metformīna blakusparādībām un 2 ģenētiskiem variantiem (rs628031 and rs36056065) Organisko Katjonu transportierī 1 (OCT1/SLC22A1). Polimorfismiem rs3119309, rs2481030 un rs7757336, lokalizētiem Organisko Katjonu transportieru 2 un 3 (OCT2/SLC22A2 un OCT3/SLC22A3) starpgēnu reģionā, tika noteikta būtiska asociācija ar metformīna īstermiņa terapijas efektivitāti. Divi no šiem variantiem tika analizēti replikācijas pētījumā ar 126 T2DM pacientiem no Slovākijas un farmakokinētikas pētījumā ar 15 veseliem brīvprātīgajiem. Visbeidzot, 33 ģenētiskas variācijas tika izpētītas ATM, STK11 un T2DM kandidātgēnos, bet tikai dažas no tām bija nomināli asociētas ar metformīna īstermiņa terapijas efektivitāti. Atslēgas vārdi: OCTs, metformīns, farmakoģenētika, blakusparādības, efektivitāte.Metformin is the first-line medication used in treatment of newly-diagnosticed Type 2 diabetes mellitus (T2DM). We show an association between metformin side-effects and two genetic variants (rs628031 and rs36056065) in Organic Cation Transporter 1 (OCT1/SLC22A1). Polymorphisms rs3119309, rs2481030 un rs7757336 in intergenic region between Organic Cation Transporter 2 and 3 (OCT2/SLC22A2 and OCT3/ SLC22A3) were found to be associated with short-term efficiency of metformin therapy. Two of these variants were analysed in replication study in 126 T2DM patients from Slovakia and in pharmacokinetic study with 15 healthy participants. At last, 33 genetic variants in ATM, STK11 and list of T2DM susceptibility genes were investigated, but only few showed a nominal association with short-term efficiency of metformin monotherapy. Keywords: OCTs, metformin, pharmacogenetics, side-effects, efficiency

Pharmacogenetics of efficiency and tolerance of the peroral antidiabetic drug metformin

Elektroniskā versija nesatur pielikumusMetformīns ir pirmās izvēles medikaments jaundiagnosticētu 2.tipa cukura diabēta (T2DM) pacientu ārstēšanā. Mēs identificējām asociāciju starp metformīna blakusparādībām un 2 ģenētiskiem variantiem (rs628031 and rs36056065) Organisko Katjonu transportierī 1 (OCT1/SLC22A1). Polimorfismiem rs3119309, rs2481030 un rs7757336, lokalizētiem Organisko Katjonu transportieru 2 un 3 (OCT2/SLC22A2 un OCT3/SLC22A3) starpgēnu reģionā, tika noteikta būtiska asociācija ar metformīna īstermiņa terapijas efektivitāti. Divi no šiem variantiem tika analizēti replikācijas pētījumā ar 126 T2DM pacientiem no Slovākijas un farmakokinētikas pētījumā ar 15 veseliem brīvprātīgajiem. Visbeidzot, 33 ģenētiskas variācijas tika izpētītas ATM, STK11 un T2DM kandidātgēnos, bet tikai dažas no tām bija nomināli asociētas ar metformīna īstermiņa terapijas efektivitāti. Atslēgas vārdi: OCTs, metformīns, farmakoģenētika, blakusparādības, efektivitāte.Metformin is the first-line medication used in treatment of newly-diagnosticed Type 2 diabetes mellitus (T2DM). We show an association between metformin side-effects and two genetic variants (rs628031 and rs36056065) in Organic Cation Transporter 1 (OCT1/SLC22A1). Polymorphisms rs3119309, rs2481030 un rs7757336 in intergenic region between Organic Cation Transporter 2 and 3 (OCT2/SLC22A2 and OCT3/ SLC22A3) were found to be associated with short-term efficiency of metformin therapy. Two of these variants were analysed in replication study in 126 T2DM patients from Slovakia and in pharmacokinetic study with 15 healthy participants. At last, 33 genetic variants in ATM, STK11 and list of T2DM susceptibility genes were investigated, but only few showed a nominal association with short-term efficiency of metformin monotherapy. Keywords: OCTs, metformin, pharmacogenetics, side-effects, efficiency

Synthesis and Evaluation of a Novel Series of β-Diketones and Related Compounds as Anticancer Agents

Abstractβ-Diketones are 1,3-dicarbonyl compounds containing two carbonyl compounds separated by a methylene carbon. This functional diketo group is found in natural sources and can be synthesised in the laboratory. They serve as a synthetic intermediate to medicinally important compounds such as flavonoids. The aim of this thesis is focused on the synthesis and cytotoxic evaluation of novel series of β-diketones bearing different substituents. 30 novel β-diketones and 19 benzoyl thiourea analogues have been synthesised, characterised, and tested for activity on 6 different cancer cell lines. All the β-diketones synthesised appeared as the enolic tautomer, with chemical shifts ranging between 16.25 ppm – 17.15 ppm. The synthesised compounds were tested on lung adenocarcinoma (A549), human bone osteosarcoma cells (U2OS) and three different human myeloid leukaemia cells: K-562, MOLT-4 and CCRF-CEM. An MTT-assay was carried out on the compounds to enable determine their activity. Among the cell lines tested with both series of β-diketones (BDKT) and benzoylthiourea (BTU), the A204 cells have shown greater sensitivity at a lower IC50s at micromolar range than the remaining cell lines. Unlike the other cell lines, the IC50 values of the BDKT series ranged from 3.61 µM to 23.82 µM. 31, 32 and 34 and 30 have the best activity with IC50s 3.61 µM, 3.63 µM and 3.78 µM and 3.87 respectively. Whereas A204 compounds treated BTU series showed lower IC50 values ranging from 3.39 µM to 9.36 µM, suggesting greater activity than the BDKT series. The most active compounds (with lower IC50 values < 4 µM) among the BTU series include 55 (3.39 µM), 56 (3.65 µM), 61 (3.75 µM) 60 (3.76 µM), and 53 (3.97). Molecular docking result analysis of the active compounds: 31, 32 and 34 from the BDKT series have revealed that the presence of halogen groups in the molecules is contributing to its activity. Also, of significant activity in 31,32 and 33 is the bonding interaction with cys241 amino acid residue located in the tubulin binding site. This interaction site is common for most microtubule inhibitors such as colchicine, combretastatin-A4 and curcumins

Síntesis, estudios espectroscópicos, estructurales y conformacionales de nuevas especies de tioureas y guanidinas

En este trabajo de Tesis Doctoral se presentan el estudio de las propiedades vibracionales, estructurales y supramoleculares de una serie de compuestos nuevos pertenecientes a las familias químicas de las tioureas de acilo, amidas y guanidinas de acilo. Los compuestos seleccionados están relacionados desde el punto de vista de la naturaleza de sus sustituyentes, con el objetivo de poder establecer similitudes y entender tendencias en las propiedades fisicoquímicas y estructurales estudiadas. En particular, se presenta una serie de compuestos del tipo tioureas de acilo R1C(O)NHC(S)NH-R2, sustituidos en la posición R1 por grupos adamantilo, noradamantilo y bencilo; mientras que se eligieron sustituyentes R2 de cadenas alifáticas con grupos ricos en electrones [R2 = -C(CH2OH)3, -CH2CH2OCH3, -CH2CH2OH] o aromáticos con presencia de átomos atrayentes de electrones como bromo (Br) y flúor (F) [R2 = -2,4,6-trifluorofenil, -2,4,5-trifluorofenil y -2-Br-4,6-difluorofenil]. En la familia de las guanidinas de acilo ( R1C(O)NHC(N-R3)NH-R2) los sustituyentes R3 corresponden también a los sustituyentes aromáticos.Facultad de Ciencias Exacta