Design, synthesis, biological evaluation, NMR and DFT studies of structurally simplified trimethoxy benzamides as selective P‐glycoprotein inhibitors: the role of molecular flatness

Abstract

In a recent investigation carried out on a panel of trimethoxybenzanilides, we showed that the formation of an intramolecular hydrogen bond is a key element for tuning P-gp inhibitory activity. In this study, we designed new structurally simplified trimethoxy benzamides (5-17, Table ) with the aim to uncover the minimal molecular requirements needed for P-gp inhibition. The new prepared smaller-sized compounds exhibited IC in the low micromolar range. The combined use of NMR and DFT studies suggested that molecular flatness is causatively related to the P-gp inhibition. Our results clearly pointed out that concerted theoretical and experimental approaches herein presented might be very helpful in addressing the design of structurally simplified and highly efficient compounds biasing P-gp protein.

Investigating Structural Requirements for the Antiproliferative Activity of Biphenyl Nicotinamides

“…It is likely that the different behavior of the N ‐(2‐nitrophenyl)nicotinamides 3 and 4 (inhibitors) with respect to the N ‐(2‐cyanophenyl)nicotinamide derivative 36 (ineffective) may be related to the molecular flatness, which in turn should depend on the formation of intramolecular HB (IMHB) between the amide NH (HB donor) and the HB acceptor group in ortho position (NO 2 or CN) . In principle, IMHB formation should be more favored in the case of 2‐NO 2 congeners (e.g., 3 and 4 ), rather than in the case of 2‐CN congeners (e.g., 36 ).…”

“…It is likely that the different behavior of the N-(2-nitrophenyl)nicotinamides 3 and 4 (inhibitors)w ith respectt ot he N-(2cyanophenyl)nicotinamide derivative 36 (ineffective) may be related to the molecularf latness, which in turn should depend on the formation of intramolecular HB (IMHB)b etween the amide NH (HB donor) and the HB acceptorgroup in ortho position (NO 2 or CN). [28] In principle, IMHB formations hould be more favored in the case of 2-NO 2 congeners (e.g., 3 and 4), rather than in the case of 2-CN congeners (e.g., 36). Ab roader and more in-depthS AR study can help in establishing whether and to what extent am ore flat molecular geometry of the biphenyln icotinamides, resulting from IMHB formation, can be causatively related to the inhibition of the tubulin polymerization.…”

Palladium-Mediated CO2 Extrusion Followed by Insertion of Isocyanates for the Synthesis of Benzamides: Translating Fundamental Mechanistic Studies To Develop a Catalytic Protocol

“…12,13 Although not a key motivation for our work, it is worth noting that the trimethoxybenzamide functional group has been demonstrated recently to produce molecules that are selective inhibitors of Pglycoprotein. 14 Available thermochemical data suggest that the formation of an amide via an ExIn reaction (eq 1, Y = O) is exothermic by over 20 kcal/mol, 15 with release of gaseous CO 2 providing a further driving force. The key steps are likely to involve binding of the carboxylate to the metal ion (eq 2, Scheme 2), decarboxylation (eq 3, Scheme 2), 16,17 insertion of the isocyanate, RNCO, into the Pd−C bond (eq 4, Scheme 2) affording the amidate complex 4, 18−20 and release of the amide 5 from the metal ion (eq 5, Scheme 2).…”

“…Nonetheless, these yields are significantly better than those reported for trimethoxybenzamides developed as selective P-glycoprotein inhibitors and prepared from the reaction of the benzoic acid with thionyl chloride followed by the reaction of the resultant acid chloride with aniline. 14 Previously, we observed deinsertion of phenyl isocyanate as the major fragmentation channel for ligated palladium amidate cations in the gas phase (Figure 1c). Indeed, there are several reports of the deinsertion of aryl isocyanates from a latetransition-metal benzamidate complex in solution.…”

“…In this report, we extend the scope of the ExIn class of reactions to target the synthesis of benzamides (Scheme B, Y = O) with the aim of developing an atom-efficient catalytic procedure (Scheme ). We restricted our study to 2,6-dimethoxy- and 2,4,6-trimethoxybenzoic acids, as monosubstituted benzoic acids can undergo undesirable side reactions involving Pd-mediated C–H bond activation at the positions ortho to the carboxylate group. , Although not a key motivation for our work, it is worth noting that the trimethoxybenzamide functional group has been demonstrated recently to produce molecules that are selective inhibitors of P-glycoprotein . Available thermochemical data suggest that the formation of an amide via an ExIn reaction (eq , Y = O) is exothermic by over 20 kcal/mol, with release of gaseous CO 2 providing a further driving force.…”