A Computational Evaluation of Bond Order and Charge Distributions in Isomeric Aminotroponiminiums and Their Benzo-Fused Derivatives

This paper reports the results on the nature of bond-order and net charge distributions predicted by Ab initio Hartree- Fock procedures for 1-amino-2-iminio-, 1-amino-3-iminio- and 1-amino-4-iminiotropylium cations that incorporate, in order, the 1,7-, 1,3- and 1,5-diazapentadienium (vinamidinium) elements. There appears to be very little contribution from tropylium-type charge distribution, the positive charges residing largely in the nitrogen atoms. The partial bond fixations and charge distributions show interesting variation in the three isomers. The 1,3-isomer in which the 1,3-diazapentadienium element is preserved in the favoured zigzag conformation appears to be relatively the best stabilized. The six isomeric benzo-fused derivatives arising from the three amino-iminiotropylium cations show similar differences in patterns of behaviour. Interestingly, the isomer in which a zigzag 1,3-diazapentadienium element is conjugated with a styrene moiety receives the deepest stabilization. While showing that the element largely contributes to the relative stabilization among the systems studied, contribution from certain stereochemical destabilizing factors may not be insignificant.

Catalytic Enantioselective Construction of Chiral Benzo-Fused N-Heterocycles through Friedel-Crafts-Type Electrophilic Chlorination

Chiral benzo-fused N-heterocycles are frequently found in natural and synthetic products.However,their synthesis usually suffers from different limitations such as difficulty in accessing appropriate starting materials and unsatisfactory stereoselectivities.In this work,an unprecedented chiral sulfide-catalyzed enantioselective Friedel-Crafts-type electrophilic chlorination is shown to construct various 3,4-functionalized tetrahydroquinolines with excellent enantio-and diastereoselectivities from readily available aniline derivatives.Interestingly,employing N-allyl 1-naphthanilides as substrates,divergent reactions via chlorocarbocyclization and dearomatization occurred to afford two chiral polycyclic benzo-fused N-heterocycles.The system that we developed extends the scope of asymmetric chlorination to general substrateswithout the need of a N-H group,and significantly promotes the synthesis of enantioenriched benzo-fused N-heterocycles.

Structural optimization and biological evaluation of 1,5-disubstituted pyrazole-3-carboxamines as potent inhibitors of human 5-lipoxygenase

Human 5-lipoxygenase(5-LOX)is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders.Our previous work on structural optimization of the hit compound 2 from our in-house collection identified two lead compounds,3a and 3b,exhibiting a potent inhibitory profile against 5-LOX with IC_(50) values less than 1 mmol/L in cell-based assays.Here,we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fusedring system.Several new compounds exhibited more potent inhibitory activity than the lead compounds against 5-LOX.In particular,compound 4e not only suppressed lipopolysaccharide-induced inflammation in brain inflammatory cells and protected neurons from oxidative toxicity,but also significantly decreased infarct damage in a mouse model of cerebral ischemia.Molecular docking analysis further confirmed the consistency of our theoretical results and experimental data.In conclusion,the excellent in vitro andin vivo inhibitory activities of these compounds against 5-LOX suggested that these novel chemical structures have a promising therapeutic potential to treat leukotriene-related disorders.