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A series of 5-substituted thieno[2,3-b]- and thieno[3,2-b)- and thieno[3,2-b)thiophene-2-sulfonamides was prepared and evaluated for topical ocular hypotensive activity in glaucoma models. The 5-substituents were varied to maximize both inhibitory potency against carbonic anhydrase and water solubility. At the same time, these substituents were varied in order to obtain compounds with the appropriate pKa to minimize pigment binding in the iris. All of these variables were optimized in the best compound, 5-[[(methoxyethyl)[(methoxyethyl)ethyl] amino]methyl]thieno[2,3-b]thiophene-2-sulfonamide hydrochloride (55).

The bacterial mutagenicity (Ames test) and the one-electron reduction potential for several nitropyridines, nitropyrazines and nitropyrimidines were determined. It was found that, although these nitroheterocycles underwent one-electron reduction more easily than metronidazole, they were not mutagenic in the Ames test. Six-membered ring nitroheterocycles, will, in general, exhibit diminished mutagenic potential compared to five-membered ring nitroheterocycles, and it is postulated that this effect is due to differences in the electronic nature and potential chemical reactivity of their respective nitrenium ions.

A series of eight novel nitropyrazines has been prepared by oxidation of sulfoximine intermediates. The partition coefficient, one-electron reduction potential, sensitizer enhancement ratio, and chronic and acute aerobic cytotoxicity have been measured for each. Two representatives of this series were tested in the Ames test and were not found to be mutagenic.

Utilizing intermediate neglect of differential overlap (INDO) and ab initio methodology, trends in the energy differences between the singlet and triplet states for mono- and polycyclic aryl nitrenium ions have been estimated. Calculations reveal an empirical correlation between the energy separation of the singlet and triplet states of the nitrenium ion and the ability of the parent amine to behave as a carcinogen or mutagen. Non-carcinogenic/non-mutagenic arylamines were characterized by nitrenium ions whose singlet states were much less stable than the triplet. Carcinogenic/mutagenic amines were characterized by nitrenium ions whose singlet states were of similar or greater stability than the triplet. By examination of the charge density at key ring atoms of the singlet and triplet species, a rational approach to the stabilization of one species relative to the other has merged and forms the basis for prediction of genotoxicity in closely related structures. The application of this empirical correlation to the prediction of the carcinogenic/ mutagenic potential of arylamines is discussed.