Analysis and hit filtering of a very large library of compounds screened against Mycobacterium tuberculosis.

There is an urgent need for new drugs against tuberculosis which annually claims 1.7-1.8 million lives. One approach to identify potential leads is to screen in vitro small molecules against Mycobacterium tuberculosis (Mtb). Until recently there was no central repository to collect information on compounds screened. Consequently, it has been difficult to analyze molecular properties of compounds that inhibit the growth of Mtb in vitro. We have collected data from publically available sources on over 300 000 small molecules deposited in the Collaborative Drug Discovery TB Database. A cheminformatics analysis on these compounds indicates that inhibitors of the growth of Mtb have statistically higher mean logP, rule of 5 alerts, while also having lower HBD count, atom count and lower PSA (ChemAxon descriptors), compared to compounds that are classed as inactive. Additionally, Bayesian models for selecting Mtb active compounds were evaluated with over 100 000 compounds and, they demonstrated 10 fold enrichment over random for the top ranked 600 compounds. This represents a promising approach for finding compounds active against Mtb in whole cells screened under the same in vitro conditions. Various sets of Mtb hit molecules were also examined by various filtering rules used widely in the pharmaceutical industry to identify compounds with potentially reactive moieties. We found differences between the number of compounds flagged by these rules in Mtb datasets, malaria hits, FDA approved drugs and antibiotics. Combining these approaches may enable selection of compounds with increased probability of inhibition of whole cell Mtb activity.

pi Molecular Orbital Crossing a(2)(chi)/b(1)(psi) in 1,10-Phenanthroline Derivatives. Ab Initio Calculations and EPR/ENDOR Studies of the 4,7-Diaza-1,10-phenanthroline Radical Anion and Its M(CO)(4) Complexes (M = Cr, Mo, W).

Ab initio, semiempirical, and HMO perturbation calculations were employed to assess the relative positioning of the closely situated low-lying unoccupied pi MOs a(2)(chi) and b(1)(psi) in 1,10-phenanthroline (phen) and its 3,4,7,8-tetramethyl (tmphen) and four symmetrical diaza derivatives (n,m-dap). Compared to a(2)(chi), the b(1)(psi) pi MO is distinguished by markedly higher MO coefficients at the chelating nitrogen pi centers in 1,10-positions; eventually, a higher Coulomb integral value at those positions will thus always favor the lowering of b(1) beyond a(2). Using the Coulomb integral parameter at the chelating 1,10-nitrogen pi centers as the HMO perturbation variable, the crossing of both energy levels in terms of decreasing preference for the a(2)(chi) over the b(1)(psi) orbital as the lowest unoccupied MO follows the sequence 5,6-dap > 2,9-dap > 4,7-dap > phen > 3,8-dap. The calculations reveal a(2)(chi) as the LUMO in 5,6-dap for all reasonable perturbation parameters, in agreement with previous observations for ruthenium(II) complexes which reveal a discrepancy between the lowest-lying "redox pi orbital" (a(2)) and the "optical pi MO" (b(1)) to which the most intense low-energy MLCT transition occurs. According to the HMO calculations, the situation is more ambiguous for the 4,7-dap analogue, yet EPR/ENDOR studies clearly show that the one-electron-reduced ligand and its tetracarbonylmetal(0) complexes (Cr, Mo, W) have the b(1)(psi) orbital singly occupied. Only ab initio calculations with double-zeta basis and inclusion of d polarization functions reproduced correctly the experimentally observed orbital ordering for tmphen (a(2) < b(1)) and for phen and 4,7-dap (b(1) < a(2)).