A venue, Madison, Wisconsin 53 706-1396, U. S. A.The radical cation of N , N'-bis-(4-dimethylaminophenyl)pyridazine (3' +) has a near-IR band with a transition energy of 29.7 f 0.5 kcal mol-' (1 kcel= 4.184 W) in acetonitrile. This band is assigned to a Hush-type charge-transfer band, and the transition energy to the Marcus X value for electron transfer. Such a large X is inconsistent with previous estimates of X for intermolecular electron transfer between mono-p-phenylenediamines and their radical cations. It agrees well with estimates of X based on AM1 semi-empirical MO calculations, which gives the enthalpy contribution to XI. at about 21 kcal mol-' for 3'+. It is suggested that the traditional method of estimating Xi. by summing bond displacements weighted by force constants produces values which are significantly too low for systems such as phenylenediamines, where pyramidalization changes are important. The results suggest that X for tetramethyl-pphenylenediamine self-electron transfer (1". +) has been significantly underestimated, and that this prototype organic electron transfer reaction is not as strongly diabatic as was previously concluded.

The interaction of the pyrazole-containing macrocyclic receptors 3,6,9,12,13,16,19,22,25,26-decaazatricyclo-[22.2.1.1(11,14)]-octacosa-1(27),11,14(28),24-tetraene 1[L1], 13,26-dibenzyl-3,6,9,12,13,16,19,22,25,26-decaazatricyclo-[22.2.1.1(1)(1,14)]-octacosa-1(27),11,14(28),24-tetraene 2[L2], 3,9,12,13,16,22,25,26-octaazatricyclo-[22.2.1.1(11,14)]-octacosa-1(27),11,14(28),24-tetraene 3[L3], 6,19-dibenzyl-3,6,9,12,13,16,19,22,25,26-decaazatricyclo-[22.2.1.1(11,)(14)]-octacosa-1(27),11,14(28),24-tetraene 4[L4], 6,19-diphenethyl-3,6,9,12,13,16,19,22,25,26-decaazatricyclo-[22.2.1.1(11,14)]-octacosa-1(27),11,14(28),24-tetraene 5[L5], and 6,19-dioctyl-3,6,9,12,13,16,19,22,25,26-decaazatricyclo-[22.2.1.1(11,14)]-octacosa-1(27),11,14(28),24-tetraene 6[L6] with l-glutamate in aqueous solution has been studied by potentiometric techniques. The synthesis of receptors 3-6[L3-L6] is described for the first time. The potentiometric results show that 4[L4] containing benzyl groups in the central nitrogens of the polyamine side chains is the receptor displaying the larger interaction at pH 7.4 (Keff = 2.04 x 10(4)). The presence of phenethyl 5[L5] or octyl groups 6[L6] instead of benzyl groups 4[L4] in the central nitrogens of the chains produces a drastic decrease in the stability [Keff = 3.51 x 10(2) (5), Keff = 3.64 x 10(2) (6)]. The studies show the relevance of the central polyaminic nitrogen in the interaction with glutamate. 1[L1] and 2[L2] with secondary nitrogens in this position present significantly larger interactions than 3[L3], which lacks an amino group in the center of the chains. The NMR and modeling studies suggest the important contribution of hydrogen bonding and pi-cation interaction to adduct formation.

The in vivo trypanosomicidal activity of the imidazole-based benzo[g]phthalazine derivatives 1-4 and of the new related pyrazole-based compounds 5 and 6 has been studied in both the acute and chronic phases of Chagas disease. As a rule, compounds 1-6 were more active and less toxic than benznidazole in the two stages of the disease, and the monosubstituted derivatives 2, 4, and 6 were more effective than their disubstituted analogs. Feasible mechanisms of action of compounds 1-6 against the parasite have been explored by considering their inhibitory effect on the Fe-SOD enzyme, the nature of the excreted metabolites and the ultrastructural alterations produced. A complementary histopathological analysis has confirmed that the monosubstituted derivatives are less toxic than the reference drug, with the behavior of the imidazole-based compound 4 being especially noteworthy.

All the compounds assayed were active in vitro against the two Leishmania species and were less toxic against mammalian cells than the reference drug, but the monosubstituted compounds were significantly more effective and less toxic than their disubstituted counterparts.

The synthesis and trypanosomatic behavior of a new series of 1,4-bis(alkylamino)benzo[g]phthalazines 1- 4 containing the biologically significant imidazole ring are reported. In vitro antiparasitic activity against Trypanosoma cruzi epimastigotes is remarkable, especially for compound 2, whereas toxicity against Vero cells is very low. Conversion of epimastigotes to metacyclic forms in the presence of the tested compounds causes significant decreases in the amastigote and trypomastigote numbers. Fe-SOD inhibition is noteworthy, whereas effect on human Cu/Zn-SOD is negligible.

A series of new phthalazine derivatives 1-4 containing imidazole rings were prepared. The monoalkylamino substituted derivatives 2 and 4 were more active in vitro against T. cruzi and less toxic against Vero cells than both their disubstituted analogues and the reference drug benznidazole. Compounds 2 and 4 highly inhibited the antioxidant parasite enzyme Fe-SOD, and molecular modeling suggested that they interact with the H-bonding system of the iron atom moiety. In vivo tests on the acute phase of Chagas disease gave parasitemia inhibition values twice those of benznidazole, and a remarkable decrease in the reactivation of parasitemia was found in the chronic phase for immunodeficient mice. Glucose metabolism studies showed that compounds 1-4 did not affect the succinate pathway but originated important changes in the excretion of pyruvate metabolites. The morphological alterations found in epimastigotes treated with 1-4 confirmed extensive cytoplasm damage and a high mortality rate of parasites.

Keywords:Pyrazole macrocycles / Copper and zinc coordination / Acid-base and metal formation equilibria / Polyamine ligands / Paramagnetic NMRThe synthesis of a new macrocyclic receptor (L 4 ) containing two 3,5-dimethylpyrazole units connected by dipropylenetriamine bridges is reported for the first time; pH-metric titrations indicate that L 4 shows six protonation steps in the pH range 2−11. In the absence of metal ions, the pyrazole moieties are not involved in acid-base processes in this pH range.

No abstract