Novel tacrine/acridine anticholinesterase inhibitors with piperazine and thiourea linkers.

A new series of substituted tacrine/acridine and tacrine/tacrine dimers with aliphatic or alkylene-thiourea linkers was synthesized and the potential of these compounds as novel human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE) inhibitors with nanomolar inhibition activity was evaluated. The most potent AChE inhibitor was found to be homodimeric tacrine derivative 14a, which demonstrated an IC50 value of 2 nM; this value indicates an activity rate which is 250-times higher than that of tacrine 1 and 7500-times higher than 7-MEOTA 15, the compounds which were used as standards in the study. IC50 values of derivatives 1, 9, 10, 14b and 15 were compared with the dissociation constants of the enzyme-inhibitor complex, Ki1, and the enzyme-substrate-inhibitor complex, Ki2, for. A dual binding site is presumed for the synthesized compounds which possess two tacrines or tacrine and acridine as terminal moieties show evidence of dual site binding. DFT calculations of theoretical desolvation free energies, ΔΔGtheor, and docking studies elucidate these suggestions in more detail.

4-(9,10-Dihydroacridin-9-ylidene)thiosemicarbazide and its five-membered thiazole and six-membered thiazine derivatives.

Two methyl derivatives, five-membered methyl 2-{2-[2-(9,10-dihydroacridin-9-ylidene)-1-methylhydrazinyl]-4-oxo-4,5-dihydro-1,3-thiazol-5-ylidene}acetate, C(20)H(16)N(4)O(3)S, (I), and six-membered 2-[2-(9,10-dihydroacridin-9-ylidene)-1-methylhydrazinyl]-4H-1,3-thiazin-4-one, C(18)H(14)N(4)OS, (II), were prepared by the reaction of the N-methyl derivative of 4-(9,10-dihydroacridin-9-ylidene)thiosemicarbazide, C(14)H(12)N(4)S, (III), with dimethyl acetylenedicarboxylate and methyl propiolate, respectively. The crystal structures of (I), (II) and (III) are molecular and can be considered in two parts: (i) the nearly planar acridine moiety and (ii) the singular heterocyclic ring portion [thiazolidine for (I) and thiazine for (II)] including the linking amine and imine N atoms and the methyl C atom, or the full side chain in the case of (III). The structures of (I) and (II) are stabilized by N-H...O hydrogen bonds and different pi-pi interactions between acridine moieties and thiazolidine and thiazine rings, respectively.

Spectroscopic, structural and theoretical studies of novel, potentially cytotoxic 4-acridonecarboxamide imines.

Ten novel, potentially intercalating 4-acridonecarboxamide azomethines and ketimines have been prepared by the condensation reaction of 9-oxo-9,10-dihydroacridine-4-carboxylic acid hydrazide with various aldehydes and ketones. The structures of the compounds were characterized spectroscopically by NMR ((1)H, (13)C, (15)N nuclei and 2D experiments), UV-vis, IR and fluorescence methods and by quantum chemical calculations using DFT at the B3LYP/6-311+G(d,p) level of theory and semiempirical ZINDO and AM1 methods. NMR chemical shift variations for C-4' were assessed due to changes in the polarizability of the imine C(4')=N(3') bond rather than direct inductive effects arising from the C-4' substituents. In concert with this was the reversed order observed for the N-3' chemical shifts with DFT-calculated atomic charges confirming the bond polarization. Both intra- and intermolecular hydrogen bonds between the acridone NH hydrogen and the amidic carbonyl oxygen were found to exist by FT-IR spectroscopy. Quantum chemical calculations were used to evaluate the configurational, tautomeric, conformational and hydrogen bonding states of the molecules as well as predict the NMR and IR data. The hypsochromic shifts observed in the UV-vis spectra upon changing from m-cresol to DMA, DMF or methanol were evaluated in terms of solvent polarity (giving rise to solvated excited state destabilization) and solvent aromaticity (giving rise to solvated excited state stabilization). The fluorescence of the compounds were modest, except for the 2,6-dichloro derivative, with respect to 9-isothiocyanatoacridine.

Regioselectivity and tautomerism of novel five-membered ring nitrogen heterocycles formed via cyclocondensation of acylthiosemicarbazides.

A series of 1-acyl-4-phenyl/(acridin-9-yl)thiosemicarbazides 3, including four new compounds, were prepared in order to study substituent effects on cyclization reactions with oxalyl chloride (producing imidazolidine-4,5-diones 4), dimethyl acetylenedicarboxylate (to give thiazolidin-4-ones 7 and 8) and autocondensation under alkaline conditions (to yield 1,2,4-triazoles 9). A positional isomer, 10 of compound 3f was also prepared. Altogether, twenty new compounds characterized and identified by IR, UV,1H, 13C and 2D NMR and quantum chemical calculations are described. The tautomerism of the products and regioselectivity of the reactions were evaluated. Compounds 3f-h,3h.2HCl, 7b,d and 10 were screened for cytotoxic activity against the L1210 leukemia cell line and all compounds, except for 3f, exhibited promising inhibitions of cell growth.

Configuration and E/Z interconversion mechanism of O(S)-allyl-S(O)-methyl-N-(acridin-9-yl) iminothiocarbonate.

The configuration and dynamic behavior of O-allyl-S-methyl-N-(acridin-9-yl)iminothiocarbonate (1) and its S-allyl-O-methyl regioisomer (2) were studied using quantum chemical calculations and by applying a novel graphical method to scatter maps obtained from MD simulations for evaluation of an NOE-weighted internuclear distance (r(NOE)). Energy calculations indicated that the Z configuration was predominant for each compound and, further, this was supported both by the calculated chemical shifts and the r(NOE). Both N-inversion- and rotation-type transition-state structures were also calculated for the E/Z isomerization process, the results indicating that the preferred interconversion mechanism for 1 is N-inversion, but contrastingly, interconversion via rotation is equally as probable as N-inversion for 2. This supports the notion that one or the other or both pathways can be active and each system needs to be assessed on a case-by-case basis.