The interactions of cannabinoids with membranes as studied by DSC and solid state NMR

Abstrac

Novel Lipophilic Acetohydroxamic Acid Derivatives Based on Conformationally Constrained Spiro Carbocyclic 2,6-Diketopiperazine Scaffolds with Potent Trypanocidal Activity

We describe novel acetohydroxamic acid derivatives with potent activity against cultured bloodstream-form Trypanosoma brucei and selectivity indices of >1000. These analogues were derived from conformationally constrained, lipophilic, spiro carbocyclic 2,6-diketopiperazine (2,6-DKP) scaffolds by attaching acetohydroxamic acid moieties to the imidic nitrogen. Optimal activity was achieved by placing benzyl groups adjacent to the basic nitrogen of the 2,6-DKP core. S-Enantiomer 7d was the most active derivative against T. brucei (IC(50) = 6.8 nM) and T. cruzi (IC(50) = 0.21 μM)

Stereodynamics of ring and nitrogen inversion in spiroheterocycles. Conformational analysis of N-methylspiro[morpholine-3,2′-adamantane] and N-methylspiro[piperidine-2,2′-adamantane] using NMR spectroscopy and theoretical calculations

Adamantane forces the N-methyl group of N-methylspiro[morpholine-3,2′-adamantane] 1 and N-methylspiro[piperidine-2,2′-adamantane] 2 to adopt an axial orientation and to undergo a slow enantiomerization as depicted by dynamic 1H and 13C NMR spectroscopy. The observed enantiomerization freezes below 0°C as evidenced by the fully resolved protons and carbons of adamantane in NMR spectra. The observed resonances are interpreted using 2D NMR spectroscopy. Interconversion between the two enantiomeric forms is demonstrated by exchange spectroscopy (EXSY). The activation energy at the coalescence point is calculated from the 13C NMR spectra and found to be 14.3 and 15.2 kcal mol-1 for molecules 1 and 2, respectively. Theoretical calculations suggest a mechanism of interconversion where the significant transition state is the one separating two twist-boat forms

Ranking the effect of [1A(ax), 1B(eq)] versus [1A(eq), 1B(ax)] cyclohexane ring substitution on the 1H chemical shifts of γ-methylene cyclohexane ring protons using 2,2-disubstituted adamantanes as models

When two different substituents are placed in the nonbridgehead position of adamantane, the two [1A(ax), 1B(eq)] and [1A(eq), 1B(ax)] cyclohexane chair conformers are modeled and features of their NMR spectra can be studied from a single spectrum at 298 K. The effect of [1A(ax), 1B(eq)] and [1A(eq), 1B(ax)] cyclohexane ring substitution on the 1H resonance separation within the γ-CH2s of cyclohexane ring is compared for various substituent pairs; this aim is approached by measuring the 1H chemical shift separation within the 4′,9′-H and 8′,10′-H methylenes from the 1H NMR spectrum of the model 2A,2B-disubstituted adamantane at 298 K. © 2007 Elsevier Ltd. All rights reserved

C-Hax⋯Yax contacts in cyclohexane derivatives revisited-identification of improper hydrogen-bonded contacts

The structure of 111 cyclohexane derivatives bearing the axial substitution Yax-C was optimized at the B3LYP/6-31+G(d,p) level. The natural bond orbital analysis revealed the presence of overlap interactions between the axial substituent and the antibonding σ*(C-Hax) orbitals; these calculated hyperconjugative interactions suggest the presence of improper H-bonded contacts. The addition of an appropriate bridging fragment between the axial substituent and cyclohexane carbon strengthens significantly the hydrogen-bonding component of the contact and several structures of axially substituted cyclohexane derivatives including such hydrogen-bonded C-H ax⋯Yax-C contacts were retrieved from the Cambridge Crystal-lographic Database. Overall, the calculations predicted that the C-Hax⋯Yax-C contacts in common cyclohexane derivatives that are generally thought to be steric in nature (Pauli repulsive forces) include an improper hydrogen-bonding component. © 2009 American Chemical Society

The effect of spiroadamantane substitution on the conformational preferences of N-Me pyrrolidine and N-Me piperidine: a description based on dynamic NMR spectroscopy and ab initio correlated calculations

Dynamic NMR spectroscopy and ab initio correlated calculations revealed that the attachment of a spiroadamantane entity at the C-2 position of N-methylpyrrolidine or N-methylpiperidine induces a severe steric crowding around nitrogen, which changes the conformational space of the heterocycle resulting in: (a) the complete destabilization of the N-Me(eq) conformer in spiranic structures; in contrast the N-Me(eq) conformer corresponds to the global minimum in N-methylpyrrolidine or N-methylpiperidine. The spiroadamantane structure raises the energy of the equatorial conformer because of the severe van der Waals repulsion between the N-Me(eq) group and adamantane C-H bonds. (b) The interconversion between the only populated enantiomeric N-Me(ax) conformers ax→[eq]→ax′; the interconversion eq→ax between N-Me(eq) and N-Me(ax) conformers, which are both populated, is observed in N-methylpyrrolidine or N-methylpiperidine. (c) The raising of ring and nitrogen inversion barriers ax→ts by ∼4-6 kcal mol-1. The dynamic NMR study provides evidence that the most important process required for the enantiomerization between the axial N-Me conformers in spiropiperidine 4 and spiropyrrolidine 5 are different, i.e., a nitrogen inversion in 5 (9.10 kcal mol-1) and a ring inversion in 4 (15.2 kcal mol-1). While an enantiomerization interconverts N-Me axial conformers in spiropiperidine 5 and spiropyrrolidine 4, substitution of the pyrrolidine ring of 5 with a C-Me group effects a diastereomerization between two N-Me axial conformers and reduces effectively the nitrogen inversion barrier according to the protonation experiments and the calculations. In general, all the calculations levels used, i.e., the MM3, B3LYP/6-31+G** and MP2/6-311++G**//B3LYP/6-31+G**, predict correctly the different stability of the local minima; however only MP2/6-311++G**//B3LYP/6-31+G** was found to be reliable for the calculation of the nitrogen inversion barriers. © 2009 Elsevier Ltd. All rights reserved

Improper hydrogen-bonded cyclohexane C-Hax⋯Yax contacts: experimental evidence from 1H NMR spectroscopy of suitable axial cyclohexane models

B3LYP/6-31+G(d,p) calculations predicted the presence of improper hydrogen-bonded C-Hax⋯Yax contacts of different strength in cyclohexane derivatives;1 it was predicted that the addition of an appropriate bridging fragment Xax between an axial substituent Y1 and a cyclohexane carbon would strengthen the improper hydrogen-bonded contact C-Hax⋯Y1 when the Xax-Y1 bond vector bisects the cyclohexane ring. To support the theoretical predictions with experimental evidence for this effect, several 2-substituted adamantane analogues with suitable improper H-bonded C-Hax⋯O contacts of different strength were synthesized, as models of the corresponding cyclohexane derivatives, and their 1H NMR spectra were recorded at 298 K. The 1H NMR signal separation within the cyclohexane ring γ-CH2s is increased when the B3LYP/6-31+G(d,p)-calculated strength of the H-bonded C-Hax⋯O=Cax contact interaction is increased. © 2010 Elsevier Ltd. All rights reserved

Improved Synthesis of the Antitubercular Agent SQ109

We present here an improved procedure for the preparation of the promising antitubercular drug SQ109 that is currently in phase Ib/III of clinical trials against Mycobacterium tuberculosis. We investigated and tested the literature synthetic procedure that enables the development of structure-activity relationships and report the observed inconsistencies as well as presenting improvements or novelties for the more efficient preparation of SQ109. Most significantly we applied a novel reduction step of the aminoamide precursor using Me3SiCl/LiAlH4under mild conditions. These findings are important for research groups investigating the efficacy of this drug and analogues in academia and industry. © 2022 Society of Rheology. All rights reserved

The effect of neighboring 1- and 2-adamantyl group substitution on the conformations and stereodynamics of N-methylpiperidine. Dynamic NMR spectroscopy and molecular mechanics calculations

When a 1-adamantyl or a 2-adamantyl substituent is introduced at the 2-position in N-methylpiperidine, four different chair conformations are possible. Experimental observation using dynamic NMR spectroscopy and molecular mechanics calculations agree that the chair conformation with an equatorial adamantyl group and an axial methyl group is by far the most stable, but in both cases a minor population of a second conformation is demonstrated and characterized. Interaction between adamantyl and methyl groups is much more conformation-determining than any preference for equatorial over axial location which predominates in simpler 2-substituted N-methylpiperidines