Kinetic studies on the Hinsberg condensation were performed trying to improve yields and achieve regio‐selectivity in the attainment of benzene‐substituted 3‐methylquinoxalin‐2(1H)‐ones. The course of the reactions between o‐phenylenediamine (o‐PDA) and substituted o‐PDA with pyruvic acid (2a) or ethyl pyruvate (2b) were followed by uv spectrophotometry at different pH values. The formation of 3‐methylquinoxalin‐2(1H)‐one (6a) was improved using sulphuric acid‐water mixtures, in which the reaction proceeded by a different mechanism. 3‐Methyl‐7‐methoxyquinoxalin‐2(1H)‐one (7b) was regioselectively synthesized independently of the pH of the reaction media. Reaction of 2‐amino‐4‐methylamine (1c) with 2a or 2b led to a mixture of 6 and 7‐quinoxalinone isomers, 6c and 7c, while 2‐amino‐4‐nitroaniline (1d) and 2,4‐diaminoaniline (1e) with 2a or 2b did not afford the heterocycle. In every case reactions with 2a were 100–1000 times faster than those with 2b. Mechanisms are proposed trying to account for the experimental results.

The benzothiadiazine dioxide (BTD) derivatives are potent nonnucleoside human cytomegalovirus (HCMV) inhibitors. As part of our comprehensive structure−activity relationship study of these compounds, we have now synthesized N,N- and N,O-dibenzyl derivatives with different para-substituents (alkyl, phenyl, electron-donating, electron-withdrawing) in the phenyl ring of the benzyl moieties. The antiviral activity against HCMV (AD-169 strain) was also experimentally measured showing IC50 values between 2.5 and 50 μM. Comparative molecular field analysis (CoMFA) was employed to generate a model, based upon 32 diverse BTD derivatives, to delineate structural and electrostatic features important for enhanced activity against HCMV. The steric (van der Waals) interactions with the receptor majoritary describes the variation in antiviral activity among the inhibitors. Finally, the CoMFA model was used to design two sets of novel BTD derivatives. Synthesis and subsequent anti-HCMV evaluation of these compounds enabled us to maintain the activity of this new kind of HCMV inhibitors.

We evaluated a number of lipophilic dyes and fluorochromes, including oxazone and thiazone derivatives of oxazine and thiazine dyes, scintillator agents, a carotenoid and a metal-porphyrin complex for visualization of lipid droplets within aldehyde fixed cultured HeLa and BGC-1 cells. Observation under ultraviolet, blue or green exciting light revealed selective fluorescence of lipid droplets, particularly after treatment with aqueous solutions of Nile blue and brilliant cresyl blue oxazones, toluidine blue thiazone, or propylene glycol solutions of canthaxanthin, ethyl-BAO, and ZnTPyP. Mounting in water was required to maintain the fluorescence of lipids; the use of glycerol, Mowiol or Vectashield was not adequate. The effect of dye structure on staining intensity was assessed with the aid of numerical structure parameters modeling lipophilicity (HI and log P), overall size (MW) and the size of the conjugated system (conjugated bond number; CBN). The best stains for lipid droplets were relatively lipophilic (HI > 4.0, log P > 5.0), of small size overall (MW < 370), with small conjugated systems (CBN < 24), and not significantly amphiphilic. The two hydrophobic-hydrophilic parameters (the classic log P and the hydrophobic index, HI; values calculated by molecular modeling software) were highly correlated; however, HI was a more suitable hydrophobicity index for the dyes studied here.

Hypoxic regions of tumours are associated with increased resistance to radiation and chemotherapy. Nevertheless, hypoxia has been used as a tool for specific activation of some antitumour prodrugs, named bioreductive agents. Phenazine dioxides are an example of such bioreductive prodrugs. Our 2D-quantitative structure activity relationship studies established that phenazine dioxides electronic and lipophilic descriptors are related to survival fraction in oxia or in hypoxia. Additionally, statistically significant models, derived by partial least squares, were obtained between survival fraction in oxia and comparative molecular field analysis standard model (r² = 0.755, q² = 0.505 and F = 26.70) or comparative molecular similarity indices analysis-combined steric and electrostatic fields (r² = 0.757, q² = 0.527 and F = 14.93), and survival fraction in hypoxia and comparative molecular field analysis standard model (r² = 0.736, q² = 0.521 and F = 18.63) or comparative molecular similarity indices analysis-hydrogen bond acceptor field (r² = 0.858, q² = 0.737 and F = 27.19). Categorical classification was used for the biological parameter selective cytotoxicity emerging also good models, derived by soft independent modelling of class analogy, with both comparative molecular field analysis standard model (96% of overall classification accuracy) and comparative molecular similarity indices analysis-steric field (92% of overall classification accuracy). 2D- and 3D-quantitative structure-activity relationships models provided important insights into the chemical and structural basis involved in the molecular recognition process of these phenazines as bioreductive agents and should be useful for the design of new structurally related analogues with improved potency.

Monoarylhydrazones of α-Lapachone: Synthesis, Chemical Properties and Antineoplastic Activity. -(RENOU*, S. G.; ASIS, S. E.; ABASOLO, M. I.; BEKERMAN, D. G.; BRUNO, A. M.; Pharmazie 58 (2003) 10, 690-695; Dep. Quim.