Fluorobenzoyl dipeptidyl derivatives as inhibitors of the Fasciola hepatica cysteine protease cathepsin L1.

Cathepsins are known to have many important physiological roles and provide a viable target for inhibition. Fluorobenzoyl dipeptide derivatives were synthesized and tested for biological activity in an effort to find an efficient inhibitor of the cysteine protease cathepsin L. Thirty-six novel inhibitors (1-36) were synthesized from protected amino acids via the standard DCC/HOBt coupling protocol, containing a benzyl ester or a nitrile as an electrophilic warhead. The activity of the inhibitors was evaluated against cathepsin L and IC50 values calculated. Modification of both amino acids and terminal groups afforded compounds with single digit micromolar inhibition. Results utilizing the benzoyl-L-leucine-glycine nitrile backbone are comparable to that for the commercially available inhibitor 39.

A structural systematic study of four isomers of difluoro-N-(3-pyridyl)benzamide.

The four isomers 2,4-, (I), 2,5-, (II), 3,4-, (III), and 3,5-difluoro-N-(3-pyridyl)benzamide, (IV), all with formula C(12)H(8)F(2)N(2)O, display molecular similarity, with interplanar angles between the C(6)/C(5)N rings ranging from 2.94 (11) degrees in (IV) to 4.48 (18) degrees in (I), although the amide group is twisted from either plane by 18.0 (2)-27.3 (3) degrees. Compounds (I) and (II) are isostructural but are not isomorphous. Intermolecular N-H...O=C interactions form one-dimensional C(4) chains along [010]. The only other significant interaction is C-H...F. The pyridyl (py) N atom does not participate in hydrogen bonding; the closest H...N(py) contact is 2.71 A in (I) and 2.69 A in (II). Packing of pairs of one-dimensional chains in a herring-bone fashion occurs via pi-stacking interactions. Compounds (III) and (IV) are essentially isomorphous (their a and b unit-cell lengths differ by 9%, due mainly to 3,4-F(2) and 3,5-F(2) substitution patterns in the arene ring) and are quasi-isostructural. In (III), benzene rotational disorder is present, with the meta F atom occupying both 3- and 5-F positions with site occupancies of 0.809 (4) and 0.191 (4), respectively. The N-H...N(py) intermolecular interactions dominate as C(5) chains in tandem with C-H...N(py) interactions. C-H...O=C interactions form R(2)(2)(8) rings about inversion centres, and there are pi-pi stacks about inversion centres, all combining to form a three-dimensional network. By contrast, (IV) has no strong hydrogen bonds; the N-H...N(py) interaction is 0.3 A longer than in (III). The carbonyl O atom participates only in weak interactions and is surrounded in a square-pyramidal contact geometry with two intramolecular and three intermolecular C-H...O=C interactions. Compounds (III) and (IV) are interesting examples of two isomers with similar unit-cell parameters and gross packing but which display quite different intermolecular interactions at the primary level due to subtle packing differences at the atom/group/ring level arising from differences in the peripheral ring-substitution patterns.

Synthesis, structural characterisation and biological evaluation of fluorinated analogues of resveratrol.

Resveratrol is a potential chemopreventive agent and can be isolated from grape skins and other dietary sources. The Wittig reaction and the decarbonylative Heck reaction were employed to synthesise analogues of this stilbene. Fluorinated derivatives of this stilbene were synthesised maintaining the 3,4',5-substitution pattern. The hydroxyl groups were also replaced by amino groups and the biological activity evaluated. The compounds were assayed on a variety of cell lines, primarily the non-small lung carcinoma cell line DLKP-A. Analogues were evaluated alone and in combination with a known chemotherapeutic agent epirubicin.

A structural systematic study of three isomers of difluoro-N-(4-pyridyl)benzamide.

The isomers 2,3-, (I), 2,4-, (II), and 2,5-difluoro-N-(4-pyridyl)benzamide, (III), all with formula C(12)H(8)F(2)N(2)O, all exhibit intramolecular C-H...O=C and N-H...F contacts [both with S(6) motifs]. In (I), intermolecular N-H...O=C interactions form one-dimensional chains along [010] [N...O = 3.0181 (16) A], with weaker C-H...N interactions linking the chains into sheets parallel to the [001] plane, further linked into pairs via C-H...F contacts about inversion centres; a three-dimensional herring-bone network forms via C-H...pi(py) (py is pyridyl) interactions. In (II), weak aromatic C-H...N(py) interactions form one-dimensional zigzag chains along [001]; no other interactions with H...N/O/F < 2.50 A are present, apart from long N/C-H...O=C and C-H...F contacts. In (III), N-H...N(py) interactions form one-dimensional zigzag chains [as C(6) chains] along [010] augmented by a myriad of weak C-H...pi(arene) and O=C...O=C interactions and C-H...O/N/F contacts. Compound (III) is isomorphous with the parent N-(4-pyridyl)benzamide [Noveron, Lah, Del Sesto, Arif, Miller & Stang (2002). J. Am. Chem. Soc. 124, 6613-6625] and the three 2/3/4-fluoro-N-(4-pyridyl)benzamides [Donnelly, Gallagher & Lough (2008). Acta Cryst. C64, o335-o340]. The study expands our series of fluoro(pyridyl)benzamides and augments our understanding of the competition between strong hydrogen-bond formation and weaker influences on crystal packing.

2,3-Difluoro-N-(2-pyrid-yl)benzamide.

The title compound, C(12)H(8)F(2)N(2)O, crystallizes with two independent mol-ecules in the asymmetric unit. The independent mol-ecules differ slightly in conformation; the dihedral angles between the benzene and pyridine rings are 51.58 (5) and 49.97 (4)°. In the crystal structure, mol-ecules aggregate via N-H⋯N(pyridine) inter-actions as hydrogen-bonded dimers with the structural motif R(2) (2)(8), and these dimers are linked via C-H⋯O inter-actions to form a supra-molecular chain.

Ethyl and isopropyl 4-ferrocenyl-benzoate.

The title compounds, [Fe(C(5)H(5))(C(14)H(13)O(2))] and [Fe(C(5)H(5))(C(15)H(15)O(2))], respectively, contain the ferrocenyl eta(5)(C(5)H(4)) and phenylene -C(6)H(4)- rings in a nearly coplanar arrangement, with interplanar angles of 6.88 (12) and 10.5 (2) degrees, respectively. Molecules of the ethyl ester form dimers through eta(5)(C(5)H(5))C-H...O=C hydrogen bonds, with graph set R(2)(2)(20), and, together with Csp(3)-H.pi(C(5)H(5)) interactions, generate a one-dimensional column (irregular ladder). Molecules of the isopropyl ester aggregate through eta(5)(C(5)H(5))C-H.pi(C(6)H(4)) interactions.