Racemic methyl 1,4-dihydro-2, 6-dimethyl-5-nitro-4-(benzofurazanyl)pyridine-3-carboxylates (+/-)-10 and (+/-)-11 and their benzofuroxanyl analogues (+/-)-12 and (+/-)-13 were prepared using a modified Hantzsch reaction that involved the condensation of nitroacetone with methyl 3-aminocrotonate and the appropriate aldehydes. The racemic mixtures were resolved into the corresponding enantiomers. Whole-cell voltage-clamp studies on L-type Ca2+ channels expressed in a rat insulinoma cell line (RINm5F) showed that all the dextrorotatory antipodes were effective agonists of L-type Ca2+ currents, while the levorotatory ones were weak Ca2+ entry blockers. The (+)-enantiomer of benzofurazan-5'-yl derivative 11 demonstrated unusual activity in that, in addition to producing a potentiation of L-type currents, it interfered with the voltage-dependent gating of L-type channels by producing a net delay of their activation at low voltages. This compound represents an interesting tool to probe L-type Ca2+ channel structure and function.

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Acridine derivatives are currently delivered to animals as antihelminthics agents (Durchheimer et al., 1980). In addition, acridine derivatives have shown in vitro activity against protozoan-like Trypanosoma cruzi (Ngadi et al., 1993) and Leishmania donovani (Messa-Valle et al., 1996). This work has been undertaken in the context of our studies on acridine derivatives with potential pharmacological properties (Karolak-Wojciechowska et al., 1996; Karolak-Wojciechowska et al., 1998). It was especially important to perform an X-ray analysis on single crystals of 9-(thio-2-methyl-4-nitrophenyl) acridine, (I), to obtain atomic coordinates which could be used as a starting point for further molecular modelling. The molecular geometry of(I) is presented in Fig. 1. The molecule consists of two cyclic moieties, an acridine and a phenyl ring. The rings are joined via a sulfur bridge at C9 (S1-C9 = 1.782 (3) and S1-C1′ = 1.764 (4) Å). The phenyl ring in (I) is nearly perpendicular to the acridine moiety, with a dihedral of 75.01 (7)°. The molecules of (I) stack head-to-tail along the y-axis, with a distance between molecules of about 4.381 Å. All bond distances and angles have typical values.

The chromatographic chiral resolution of racemic methyl 1,4‐dihydro‐2,6‐dimethyl‐5‐nitro‐4‐benzofurazanyl‐3‐carboxylates 1 and 2 and their benzofuroxanyl analogues 3 and 4 were studied on Whelk‐O1, Chiralcel OD‐H, Chiralcel OJ, and Chiralpak AD and AS. These CSPs were selected on the basis of the results of structural searches in Chirbase. Examination of the data and cluster analysis pointed out the influence of benzofurazane–benzofuroxane change versus α–β connection change on retention and enantioselectivity, respectively. The major contribution to the retention change arose from the type of heterocycle, whereas the major contribution to the enantioselectivity change came from the mode of connection (α or β) almost irrespective of the nature of the heterocycle. It resulted in a similarity of behaviour between 1 and 2 on one hand and 3 and 4 on the other as far as capacity factors were concerned, and in a similarity of behaviour between 1 and 3 on the one hand and 2 and 4 on the other as far as enantioselectivities were concerned. Chiralpak AS was selected for semipreparative resolution of the enantiomers. The study of several CSPs allowed us to obtain correlations of structure with retention and enantioselectivity as well as the choice of a semipreparative support to provide the quantities for biological tests. Chirality 11:602–608, 1999. © 1999 Wiley‐Liss, Inc.