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Abstract

The functional groups of cage dimeric N-alkyl substituted 3,5-bis(hydroxymethyl)-4-(4-methoxyphenyl)-1,4-dihydropyridines are similar to those of cyclic and azacyclic ureas that are potent inhibitors of HIV-1 protease of the dihydroxyethylene- and hydroxyethylene type, respectively. In the following study the conformity of common functional groups is investigated concerning their orientation in space as well as in the enzyme HIV-1 protease. Starting from X-ray crystal data of the centrosymmetric cage dimeric N-benzyl derivative with ester groups, the derivative with hydroxymethylene groups was built and a systematic conformational search was performed for the conformationally important torsion angles considering electrostatic and van der Waals interactions. From the huge number of conformations those comprising centrosymmetrical and C2-symmetrical energy minima were selected and minimized. The three remaining conformers were fitted to the azacyclic urea A-98881 selected from the HIV-1 protease enzyme-inhibitor complex using the centroids of the corresponding aromatic residues and additionally by the field fit option of the Advanced CoMFA module of SYBYL. Interestingly, the energetically most favourable one, which, additionally, possesses C2-symmetry like the active site cavity of HIV-1 protease, showed the best fit. Comparing the electrostatic potential (EP) of the latter with the EP of A-98881 the aromatic residues show excellent accordance. Slight differences in the extent of the EP were found in the areas of the hydroxymethylene groups of the cage dimer and the single hydroxy group as well as the urea carbonyl group of A-98881, respectively. In order to compare the binding possibilities to the enzyme HIV-1 protease for the cage dimer and A-98881, their interaction fields with certain probes (CH3 for alkyl, NHamide, and carbonyl, O- of COO-), representing the decisive functional groups of the active site, have been calculated using GRID and projected into the enzyme placing the structures according to the position of A-98881 in the enzyme-inhibitor complex. The strongest calculated fields of the O- probe were found near Asp 25 for both structures. Another respective conformity consists in the overlap of the fields for the NHamide probe near Ile 50 and 50' for the investigated cage dimer and A-98881.

Solution-Dimerization of 4-Aryl-1,4-dihydropyridines

“…structure of cage dimer 2b corresponds to that of the cage dimer formed by the solid-state reaction, [3] a centrosymThe great difference in the yields of the cage dimers 2aϪe, and those of the anti dimers 3aϪe, was nevertheless somemetrical structure for the solution dimer 2b was confirmed ( Figure 1). how surprising.…”

“…[2] [3] As the reported solid-state synthesis was shown to be partly limited by certain conformationally determined packing restraints, [1] the photoreactivity of 4-aryl-1,4-dihydropyridines in solution had to be investigated as alternative reaction pathway to those interesting cage compounds. The given products and their stereochemical properties proved by 1 H-NMR data and X-ray crystal structures will be presented.…”

QSAR study of novel 1,1,3-trioxo[1,2,4]-thiadiazine (TTDs) analogues as potent anti-HIV agents

“…The therapeutic efficacy of the drug is mainly restricted due to the development of viral resistance associated with mutations that includes K103N, L1001 and Y188L. 5 Comparative molecular field analysis (CoMFA) and Comparative molecular similarity indices analysis (CoMSIA) are powerful and versatile tools to build and design an activity model (QSAR) for a given set of molecules in rational drug design and related applications, 6,7 HIV-1 reverse transcriptase inhibitors, [8][9][10] HIV-1 protease inhibitors [11][12][13][14][15] and HIV-1 integrase inhibitors [16][17][18] and gp 120 envelope glycoprotein. 19 In search of effective TTDs analogues with minimal viral resistance problems, Arranz M. E. et al, 20 synthesized and evaluated a novel set of TTDs for their anti-HIV activity.…”

Cage Dimeric 4-Aryl-1,4-dihydropyridines as Promising Lead Structures for the Development of a Novel Class of HIV-1 Protease Inhibitors

“…The results listed in Table 1 suggest that with the exception of R 2 = CH 3 compounds with R 1 = H are better inhibitors than those with R 1 = OCH 3 . Moreover, inhibition increases within each series of N-acyl and acyloxyderivatives, respectively, from Me to Bzl, OPh and, finally, Boc.Following the suggested binding mode for the N-benzyl derivatives [10] the N-substituent may bind to the S2 and S2′ region of the enzyme. Thus our results with the best inhibition for the Boc derivatives in this region would correlate with recently reported results of numerous studied PI that found Boc substituents to be most favourable substituents for binding to the S2 and S2′ region [20] .…”

“…N-Alkyl substituted derivatives have recently been suggested as potential PI by comparison with A-98881 in a molecular modeling study [9,10] . In the series of N-acyl and -acyloxy derivatives 5 compounds reached IC50 and better values at tested concentrations of 25 and 50 µM, respectively.…”