Antimalarial Pyrido[1,2-a]benzimidazoles: Lead Optimization, Parasite Life Cycle Stage Profile, Mechanistic Evaluation, Killing Kinetics, and in Vivo Oral Efficacy in a Mouse Model.

Further structure-activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials have led to the identification of potent, metabolically stable compounds with improved in vivo oral efficacy in the P. berghei mouse model and additional activity against parasite liver and gametocyte stages, making them potential candidates for preclinical development. Inhibition of hemozoin formation possibly contributes to the mechanism of action.

Photoelectron spectroscopy and DFT calculations of easily ionized quadruply bonded Mo2(4+) compounds and their bicyclic guanidinate precursors.

A series of five bicyclic guanidinate compounds containing various combinations of five- and six-membered rings and substituted alkyl groups have been shown by photoelectron spectroscopy to be easily ionized, with the one having two six-membered rings and four ethyl groups being the most easily ionized. The corresponding anions are capable of forming paddlewheel compounds having quadruply bonded Mo2(4+) units which are also easy to ionize. The most easily ionized compound is the ethyl-substituted Mo2(TEhpp)4 complex which has a broad first ionization band centered around 4.27 +/- 0.03 eV and an ionization onset at the very low energy of 3.93 +/- 0.03 eV. Even the compound with ligands containing two five-membered rings, which favors a long Mo-Mo separation because of the large ligand bite, has an ionization energy (4.78 eV) that is less than those of well-known organometallic reducing agents such as (eta5-C9Me7)2Co and (eta5-C5Me5)2Cr.

Increasing the solubility of strong reducing agents containing Mo(2)(4+) units and alkyl-substituted guanidinate ligands.

Six very soluble paddlewheel compounds containing Mo2n+ units, n = 4, 5, 6, and two alkyl-substituted bicyclic guanidinate ligands have been synthesized. The quadruply bonded complexes with n = 4, Mo2(TMhpp)4 and Mo2(TEhpp)4, (TMhpp = the anion of 3,3,9,9-tetramethyl-1,5,7-triazabicyclo[4.4.0]dec-4-ene and TEhpp = the anion of 3,3,9,9-tetraethyl-1,5,7-triazabicyclo[4.4.0]dec-4-ene) are easily oxidized. The electrode potentials in THF are -1.08 and -1.17 V vs. Ag/AgCl, respectively, for the Mo(2)(5+/4+) couple. These potentials are in accord with the low ionization potentials for the quadruply bonded compounds. Because of the high solubility of the Mo(2)(4+) compounds in most common organic solvents they are attractive candidates for use as strong reducing agents in homogeneous systems.

Homologues of the easily ionized compound Mo2(hpp)4 containing smaller bicyclic guanidinates.

Two bicyclic guanidinate ligands consisting of 5,5-membered (tbo) and 5,6-membered (tbn) rings have been used for the preparation of dimolybdenum compounds, such as Mo2(tbo)4 and Mo2(tbo)4Cl, and species containing Mo2(tbn)4(n+) with n = 0-2. The compounds with quadruply bonded Mo2(4+) species are strong reducing agents and have potentials of about -1 V (vs Ag/AgCl) for the Mo2(5+/4+) process. The structure of the THF solvate of Mo2(tbo)4 shows the longest Mo-Mo bond distance, 2.1453(4) A, for a quadruply bonded species, and this is due to a large divergent angle induced by the geometry of the ligand. This distance increases to 2.2305(8) A upon oxidation by CH2Cl2 to Mo2(tbo)4Cl. For the 5,6-membered-ring ligand tbn, even though the divergent angle is large compared to formamidinate ligands, it is not as large as that in tbo, and the Mo-Mo distance in Mo2(tbn)4, 2.082(1) A, is in the normal range for paddlewheel Mo2(4+) compounds. This distance increases to 2.2233(8) A upon oxidation by O2 in CH2Cl2, which forms Mo2(tbn)4Cl2 x CH2Cl2.

Strong reducing agents containing dimolybdenum Mo2(4+) units and their oxidized cations with Mo2(5+/6+) cores stabilized by bicyclic guanidinate anions with a seven-membered ring.

The syntheses of two analogues of the bicyclic guanidinate ligand hpp (hpp = the anion of the guanidine-type compound 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2a]pyrimidine) which contain two fused rings are reported. Each compound contains one seven-membered ring while the other is either a five (Htbd) or a six (Htbu) membered ring. In THF/Bu4NPF6, the dimolybdenum compounds Mo2(tbd)4 and Mo2(tbu)4 are easily oxidized and they have signals in the differential pulse voltammograms at -1.059 and -1.009 V (vs. Ag/AgCl), respectively and for the Mo2(5+/6+) couples and in the same order -0.242 and -0.312 V for the Mo2(6+/5+) couples. The two compounds produce the corresponding Mo2(bicyclic guanidinate)4Cl compounds immediately upon dissolution in CH2Cl2 and these easily form species with Mo2(6+) cores. In Mo2(tbd)4Cl there are two crystallographically independent molecules with Mo-Mo distances of 2.1711(7) and 2.1690(7) A. The distance between metal atoms increases to 2.206(1) A upon oxidation to Mo2(tbd)4Cl2 which has a triply bonded Mo2(6+) core. For the diamagnetic compound Mo2(tbu)4 this distance is 2.0677(9) A and it increases to 2.133(2) A upon reduction of the bond order from 4 to 3.5 in the paramagnetic compound Mo2(tbu)4Cl.

Paramagnetism at ambient temperature, diamagnetism at low temperature in a Ru2(6+) core: structural evidence for zero-field splitting.

Variable temperature magnetic studies of the Ru(2)(6+) guanidinate compounds Ru(2)(hpp)(4)Cl(2) (1) and Ru(2)(hpp)(4)(CF(3)SO(3))(2) (2) show that they are paramagnetic with two unpaired electrons at room temperature and that they appear essentially diamagnetic at 2 K. In neither compound do the Ru-Ru distances vary by more than 0.008(1) A from 27 to 296 K. This argues strongly that the ground state electronic configuration remains constant over this temperature range and that the decrease in magnetism as the temperature is lowered must be attributable to zero-field splitting of the (3)A(2g) ground state arising from the electronic configuration sigma(2)pi(4)delta(2)pi(2). The Ru-Ru distance in 1 is about 0.04-0.05 A longer than that in 2 which indicates that the Ru(2)(hpp)(4)(2+) core is quite sensitive to the nature of the axial ligands. The electronic spectra show three absorption bands for each compound.

The extraordinary ability of guanidinate derivatives to stabilize higher oxidation numbers in dimetal units by modification of redox potentials: structures of Mo(2)(5+) and Mo(2)(6+) compounds.

Full characterization of the first homologous series of dimolybdenum paddlewheel compounds having electronic configurations of the types sigma(2)pi(4)delta(x), x = 2, 1, 0, and Mo-Mo bond orders of 4, 3.5, and 3, respectively, has been accomplished with the guanidinate-type ligand hpp (hpp = the anion of 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine). Essentially quantitative oxidation of Mo(2)(hpp)(4), 1, by CH(2)Cl(2) gives Mo(2)(hpp)(4)Cl, 2. The halide in 2 can be replaced by reaction with TlBF(4) to produce Mo(2)(hpp)(4)(BF(4)), 3. Further oxidation of 2 by AgBF(4) produces Mo(2)(hpp)(4)ClBF(4), 4. The change from bond order 4 (in 1) to 3.5 in Mo(2)(hpp)(4)Cl is accompanied by an increase in the Mo-Mo bond length of 0.061 to 2.1280(4) A. A further increase of 0.044 A in the Mo-Mo distance to 2.172(1) A is observed as the bond order decreases to 3 in 4. At the same time, the Mo-N distances decrease smoothly as the oxidation state of the Mo atoms increases. Electrochemical studies have shown two chemically reversible processes at very negative potentials, E(1)(1/2)= -0.444 V and E(2)(1/2)= -1.271 V versus Ag/AgCl. These correspond to the processes Mo(2)(6+/5+) and Mo(2)(5+/4+), respectively. The latter potential is displaced by over 1.5 V relative to those of the Mo(2)(formamidinate)(4) compounds and the first one has never been observed in such complexes. Thus, in surprising contrast to previously observed behavior of the dimolybdenum unit, when it is surrounded by the very basic guanidinate ligand hpp, there is an extraordinary stabilization of the higher oxidation numbers of the molybdenum atoms.

Closed-shell molecules that ionize more readily than cesium.

We report a class of molecules with extremely low ionization enthalpies, one member of which has been determined to have a gas-phase ionization energy (onset, 3.51 electron volts) lower than that of the cesium atom (which has the lowest gas-phase ionization energy of the elements) or of any other known closed-shell molecule or neutral transient species reported. The molecules are dimetal complexes with the general formula M2(hpp)4 (where M is Cr, Mo, or W, and hpp is the anion of 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine), structurally characterized in the solid state, spectroscopically characterized in the gas phase, and modeled with theoretical computations. The low-energy ionization of each molecule corresponds to the removal of an electron from the delta bonding orbital of the quadruple metal-metal bond, and a strong interaction of this orbital with a filled orbital on the hpp ligands largely accounts for the low ionization energies.