147291-56-3Relevant articles and documents
Trypanocidal Activity of Melamine-Based Nitroheterocycles
Stewart, Mhairi L.,Bueno, Gorka Jimenez,Baliani, Alessandro,Klenke, Burkhard,Brun, Reto,Brock, Janice M.,Gilbert, Ian H.,Barrett, Michael P.
, p. 1733 - 1738 (2004)
A series of nitroheterocyclic compounds were designed with linkages to melamine or benzamidine groups that are known substrates of the P2 aminopurine and other transporters in African trypanosomes of the brucei group. Several compounds showed in vitro trypanotoxicity with 50% inhibitory concentrations in the submicromolar range. Although most compounds interacted with the P2 transporter, as judged by their ability to inhibit adenosine transport via this carrier, uptake through this route was not necessary for activity since TbAT1-null mutant parasites, deficient in this transporter, retained sensitivity to these drugs. One compound, a melamine-linked nitrofuran, also showed pronounced activity against parasites in mice. Studies into the mode of action of this compound indicated that neither reductive, nor oxidative, stress were related to its trypanocidal activity ruling out a genotoxic effect in T. brucei, distinguishing it from some other, mammalian cell toxic, trypanocidal nitroheterocycles.
Conformational preferences in a benzodiazepine series of potent nonpeptide fibrinogen receptor antagonists
Keenan, Richard M.,Callahan, James F.,Samanen, James M.,Bondinell, William E.,Calvo, Raul R.,Chen, Lichong,DeBrosse, Charles,Eggleston, Drake S.,Haltiwanger, R. Curtis,Hwang, Shing Mei,Jakas, Dalia R.,Ku, Thomas W.,Miller, William H.,Newlander, Kenneth A.,Nichols, Andrew,Parker, Michael F.,Southhall, Linda S.,Uzinskas, Irene,Vasko-Moser, Janice A.,Venslavsky, Joseph W.,Wong, Angela S.,Huffman, William F.
, p. 545 - 559 (2007/10/03)
Previously, we reported the direct design of highly potent nonpeptide 3- oxo-1,4-benzodiazepine fibrinogen receptor antagonists from a constrained, RGD-containing cyclic semipeptide. The critical features incorporated into the design of these nonpeptides were the exocyclic amide at the 8-position which overlaid the Arg carbonyl, the phenyl ring which maintained an extended Gly conformation, and the diazepine ring which mimicked the γ-turn at Asp. In this paper, we investigate conformational preferences of the 8-substituted benzodiazepine analogues by examining structural modifications to both the exocyclic amide and the seven-membered diazepine ring and by studying the conformation of the benzodiazepine ring using molecular modeling, X-ray crystallography, and NMR. We found that the directionality of the amide at the 8-position had little effect on activity and the (E)-olefin analogue retained significant potency, indicating that the trans orientation of the amide, and not the carbonyl or NH groups, made the largest contribution to the observed activity. For the diazepine ring, with the exception of the closely analogous 3-oxo-2-benzazepine ring system described previously, all of the modifications led to a significant reduction in activity compared to the potent 3-oxo-1,4-benzodiazepine parent ring system, implicating this particular type of ring system as a desirable structural feature for high potency. Energy minimizations of a number of the modified analogues revealed that none could adopt the same low-energy conformation as the one shared by the active (S)-isomer of the 3-oxo-1,4-benzodiazepines and 3-oxo-2- benzazepines. The overall data suggest that the features contributing to the observed high potency in this series are the orientation of the 3-4 amide and the conformational constraint imposed by the seven-membered ring, both of which position the key acidic and basic groups in the proper spatial relationship.
