Amphotericin B (AmB, 1) is the drug of choice for treating the most serious systemic fungal or protozoan infections. Nevertheless, its application is limited by low solubility in aqueous media and serious side effects such as infusion-related reactions, hemolytic toxicity, and nephrotoxicity. Owing to these limitations, it is essential to search for the polyene derivatives with better chemotherapeutic properties. With the objective of obtaining AmB derivatives with lower self-aggregation and improved solubility, we synthesized a series of amides of AmB bearing an additional basic group in the introduced residue. The screening of antifungal activity in vitro revealed that N-(2-aminoethyl)amide of AmB (amphamide, 6) had superior antifungal activity compared to that of the paternal AmB. Preclinical studies in mice confirmed that compound 6 had a much lower acute toxicity and higher antifungal efficacy in the model of mice candidosis sepsis compared with that of AmB (1). Thus, the discovered amphamide is a promising drug candidate for the second generation of polyene antibiotics and is also prospective for in-depth preclinical and clinical evaluation.

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A series of amides of the antifungal antibiotic amphotericin B (AmB) and its conjugates with benzoxaboroles was tested to determine whether they form pores in lipid bilayers and to compare their channel characteristics. The tested derivatives produced pores of larger amplitude and shorter lifetime than those of the parent antibiotic. The pore conductance was related to changes in the partial charge of the hydrogens of the hydroxyl groups in the lactone ring that determined the anion coordination in the channel. Neutralization of one of the polar group charges in the AmB head during chemical modification produced a pronounced effect by diminishing the dwell time of the polyene channel compared to modification of both groups. In this study, compounds that had a modification of one carboxyl or amino group were less effective in initializing phase separation in POPC-membranes compared to derivatives that had modifications of both polar groups as well as the parent antibiotic. The effects were attributed to the restriction of the aggregation process by electrical repulsion between charged derivatives in contrast to neutral compounds. The significant correlation between the ability of derivatives to increase the permeability of model membranes—causing the appearance of single channels in lipid bilayers or inducing calcein leakage from unilamellar vesicles—and the minimal inhibitory concentration indicated that the antifungal effect of the conjugates was due to pore formation in the membranes of target cells.

Tris(1 alkylindol 3 yl)methanes were obtained and oxidized into tris(1 alkylindol 3 yl)methylium salts. The resulting salts are more toxic to cultured tumor cells than to non tumor ones. The cytotoxicity of tris(1 alkylindol 3 yl)methylium salts depends on the length of the substituent at the N atom of the heterocycle, increasing from an N unsubstituted derivative toward N butyl and N pentyl derivatives. A further increase in the length of the N alkyl substituent lowers the cytotoxicity. The cytotoxicity of tris(1 alkylindol 3 yl)methylium salts for tumor cells correlates with their antibacterial and antifungal activity. Tris(1 alkylindol 3 yl)methylium salts produced a cytocide effect on Gram positive microorganisms and the most active compounds, on Gram negative microorganisms as well. Similar patterns of the struc ture-activity relationship of N alkylated tris(indol 3 yl)methylium derivatives, which was ob served for various lines of tumor cells, bacteria, and fungi, suggest the general character of the mechanisms of the death of prokaryotic and eukaryotic cells induced by these compounds.

Intramolecular cyclization reactions of 3,4 bis(indol 3 yl)maleimides 1, 3 (indol 1 yl) 4 (indol 3 yl)maleimides 2, and 3,4 bis(indol 1 yl)maleimides 3 under the action of protic acids were studied in order to estimate the parameters of the interaction between protonated and unprotonated indole moieties. Geometric parameters, charge distributions, energy characteris tics, and information concerning the frontier orbitals of bisindolylmaleimides 1-3 were ob tained from density functional B3LYP/6 31G(d) quantum chemical calculations. Alternative pathways of protonation of bisindolylmaleimides with differently bonded indole and maleimide moieties were studied and pathways of cyclization of corresponding conjugated acids leading to polyannelated compounds were analyzed. All the key intermediates of the cyclization reactions correspond to stationary points on the potential energy surfaces (minima and transition states). Analysis of the potential energy surfaces revealed almost linear dependences of the activation energies of the cyclization reactions under study on the distances between the reaction centers, on the angle of approach of intramolecular electrophile, and on the energy gap (energy differ ence between frontier orbitals). The key role in the cyclization reactions is played by structural similarity between the starting indoleninium cations and the activated complexes of the reac tions under study.Research on the chemical properties and reactivity of 3,4 bisindolylmaleimides is of interest in connection with the fact that some compounds of this series and related indolo[2,3]carbazoles possess valuable biological proper ties. 1,2 Earlier, 3,4 it was shown that intramolecular cy clizations of 3,4 bis(indol 3 yl)maleimides 1, 3 (indol 1 yl) 4 (indol 3 yl)maleimides 2, and 3,4 bis(indol 1 yl)maleimides 3 under the action of protic acids proceed differently and result in different types of compounds. 3,4 Bis(indol 3 yl)maleimides 1 under acid catalysis con ditions and after dehydrogenation form indolo[2,3]carb azole derivatives 4 (Scheme 1). In the absence of oxidant (DDQ) intermediate 5 undergoes isomerization into aminophenylcarbazole 6 (see Scheme 1). Possible mecha nisms of the cyclization and isomerization of system 1 are shown in Scheme 2.Unlike 3,4 bis(indol 3 yl)maleimides 1, 3 (indol 1 yl) 4 (indol 3 yl)maleimides 2 and 3,4 bis(indol 1 yl)maleimides 3 under the action of protic acids undergo 2-4´ or 2-7´ cyclization to give 8b,9 dihydroin dolo [4´,3´:3,4,5]pyrrolo[3´,4´:6,7][1,4]azepino[1,2 a]in dol 1,3(2H,5H ) diones 7 or 9b,10 dihydroindo lo[1´,7´:4,5,6]pyrrolo[3´,4´:2,3][1,4]diazepino[1,7 a]in dol 1,3 diones 8, respectively (Scheme 3). Compounds 7 and 8 under the action of DDQ in toluene were converted to indolo[4´,3´:3,4,5]pyrrolo[3´,4´:6,7]azepino[1,2 a]in dol 1,3(2H,5H ) diones 9 and 1H indolo[1´,7´:4,5,6]pyr rolo[3´,4´:2,3][1,4]diazepino[1,7 a]indol 1,3(2H ) diones 10, respectively. Possible cyclization mecha nisms 3,4 are shown in Scheme 3.Since the cyclization reactions of differently fused bisind...