Hany F. Nour

Probing the dynamic reversibility and generation of dynamic combinatorial libraries in the presence of bacterial model oligopeptides as templating guests of tetra‐carbohydrazide macrocycles using electrospray mass spectrometry

RATIONALE Over the past few decades, bacterial resistance to antibiotics has emerged as a real threat to human health. Accordingly, there is an urgent demand for the development of innovative strategies for discovering new antibiotics. We present the first use of tetra-carbohydrazide cyclophane macrocycles in dynamic combinatorial chemistry (DCC) and molecular recognition as chiral hosts binding oligopeptides, which mimic bacterial cell wall. This study introduces an innovative application of electrospray ionisation time-of-flight mass spectrometry (ESI-TOF MS) to oligopeptides recognition using DCC. METHODS A small dynamic library composed of eight functionalised macrocycles has been generated in solution and all members were characterised by ESI-TOF MS. We also probed the dynamic reversibility and mechanism of formation of tetra-carbohydrazide cyclophanes in real-time using ESI-TOF MS. RESULTS Dynamic reversibility of tetra-carbohydrazide cyclophanes is favored under thermodynamic control. The mechanism of formation of tetra-carbohydrazide cyclophanes involves key dialdehyde intermediates, which have been detected and assigned according to their high-resolution m/z values. Three members of the dynamic library bind efficiently in the gas phase to a selection of oligopeptides, unique to bacteria, allowing observation of host/guest complex ions in the gas phase. CONCLUSIONS We probed the mechanism of the [2+2]-cyclocondensation reaction forming library members, proved dynamic reversibility of tetra-carbohydrazide cyclophanes and showed that complex ions formed between library members and hosts can be observed in the gas phase, allowing the solution of an important problem of biological interest.

Probing the mechanism and dynamic reversibility of trianglimine formation using real-time electrospray ionization time-of-flight mass spectrometry

RATIONALE The [3+3]-cyclocondensation reactions of chiral (1R,2R)-1,2-diaminocyclohexane with aromatic or aliphatic bis-aldehydes to form trianglimine macrocycles were reported a decade ago and were believed to proceed through a stepwise mechanistic pathway; however, no intermediates were ever isolated or detected and characterized. METHODS We investigated the mechanism of the [3+3]-cyclocondensation reaction using a selection of dialdehyde starting materials using real-time electrospray ionization time-of-flight mass spectrometry. RESULTS We observed up to a maximum of 16 reaction intermediates along the reaction pathway, more than for any other multistep reaction reported. We also probed the dynamic reversibility of trianglimines using selected small dynamic combinatorial libraries and showed that trianglimine formation is indeed fully reversible. CONCLUSIONS This study represents a significant contribution towards understanding the mechanism of trianglimine formation and its potential applicability can be extended to include other cascade reactions.

Hill coefficients of dietary polyphenolic enzyme inhibitiors: can beneficial health effects of dietary polyphenols be explained by allosteric enzyme denaturing?

Inspired by a recent article by Prinz, suggesting that Hill coefficients, obtained from four parameter logistic fits to dose–response curves, represent a parameter allowing distinction between a general allosteric denaturing process and real single site enzyme inhibition, Hill coefficients of a number of selected dietary polyphenol enzyme inhibitions were compiled from the available literature. From available literature data, it is apparent that the majority of polyphenol enzyme interactions reported lead to enzyme inhibition via allosteric denaturing rather than single site inhibition as judged by their reported Hill coefficients. The results of these searches are presented and their implications discussed leading to the suggestion of a novel hypothesis for polyphenol biological activity termed the insect swarm hypothesis.

Synthesis and pharmacological activities of some condensed 4-chloro-2,2-dialkyl chromene-3-carbaldehyde derivatives

Synthesis and pharmacological activities of some condensed 4-chloro-2,2-dialkyl chromene-3-carbaldehyde derivatives Some new hydrazono 5a,b, thiosemicarbazono 6a-c, and oximo chromenes 7a-c were prepared via the reaction of the corresponding β-chlorocarbaldehyde 3 with hydrazine, aromatic hydrazine, thiosemicarbazide and hydroxylamine hydrochloride, respectively. In addition, ether derivatives 8a-h were prepared from the corresponding aldoximes 7a-c. The new products were tested for anti-inflammatory and ulcerogenic score activities compared to indomethacin. Sinteza i farmakološko djelovanje derivata kondenziranih 4-klor-2,2-dialkil kromen-3-karbaldehida Novi hidrazono- 5a,b, tiosemikarbazono- 6a-c i oksimo kromeni 7a-c sintetizirani su iz odgovarajućeg β-klorkarbaldehida 3 i hidrazina, aromatskog hidrazina, tiosemikarbazida ili hidroksilamin hidroklorida, dok su eterski derivati 8a-h pripremljeni iz pripadajućih aldoksima 7a-c. Novi spojevi ispitani su na protuupalno i ulcerogeno djelovanje, a njihovo djelovanje uspoređeno je s djelovanjem indometacina.

Synthesis of dendronic triazolo-pyridazinones and their self-assembly into nanofibers and nanorods

A series of first-, second-, and third-generation dendronic triazolo-pyridazinones were synthesized in good yields via the CuI-catalyzed azide–alkyne cycloaddition reactions of 4,6-diphenyl-2-(prop-2-yn-1-yl)pyridazin-3(2H)-one, possessing a terminal alkyne functional group with aromatic mono- and diazides with long alkyl and chiral glycol side-chain substituents. The chemical structures of the new compounds were characterized using different spectroscopic methods. The morphology of the dendrons was examined using the scanning electron microscope (SEM) analysis, which revealed the formation of highly ordered nanofiber and nanorod aggregations, directed by π-stacking interactions and van der Waals forces.Graphical abstract

Click Synthesis of Shape-Persistent Azodendrimers and their Orthogonal Self-Assembly to Nanofibres

The copper(i)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction has been efficiently utilized to synthesize a series of dendrons with amino functionalities. The aminodendrons successfully underwent azodimerization to furnish a series of pyridyl- and phenyl-based azodendrimers with peripheral alkyl or ether side chain substituents. The molecular structures of the azodendrimers were fully assigned using different spectroscopic techniques, such as 1H NMR and 13C NMR, and the molecular weights were determined using MALDI-TOF mass spectrometry. The molecular self-assembly of the azodendrimers was investigated by scanning electron microscopy and transmission electron microscopy, which revealed the formation of highly ordered and uniform self-assembled nanofibres.