Computational Evaluation of N-Based Transannular Interactions in Some Model Fused Medium-Sized Heterocyclic Systems and Implications for Drug Design

Abstract

As part of a project on fused medium-sized ring systems as potential drugs, we have previously demonstrated the usefulness of Density Functional Theory (DFT) to evaluate amine nitrogen-based transannular interactions across the central 10-membered ring in the bioactive dibenzazecine alkaloid, protopine. A range of related hypothetical systems have been investigated, together with transannular interactions involving ring-embedded imino or azo group nitrogens and atoms or groups (Y) across the ring. Electrostatic potential energies mapped onto electron density surfaces in the different ring conformations were evaluated in order to characterise these conformations. Unexpectedly, the presence of sp2 hybridised nitrogen atoms in the medium-sized rings did not influence the conformations appreciably. The strength and type of the N…Y interactions are determined primarily by the nature of Y. This is also the case when the substituent on the interacting nitrogen is varied from CH3 (protopine) to H or OH. With Y = BOH, very strong interactions were observed in protopine analogues, as well as in rings incorporating imino or azo groups. Strong to moderate interactions were observed with Y = CS, CO and SO in all ring systems. Weaker interactions were observed with Y = S, O and weaker ones again with an sp3 hybridised carbon (Y = CH2). The transannular interactions can influence conformational preferencing and shape and change electron distributions at key sites, which theoretically could modify properties of the molecules while providing new or enhanced sites for biological target interactions, such as the H or OH substituent. The prediction of new strong transannular interaction types such as with Y = BOH and CS should be helpful in informing priorities for synthesis and other experimental studies.

NRF2 Activation by Nitrogen Heterocycles: A Review

“…Fused nitrogen heterocycles contain at least one nitrogen heterocyclic ring fused with either a heterocyclic or carbocyclic ring. They have been extensively studied [ 105 , 106 , 107 , 108 ]. They are found in a wide range of bioactive natural products and synthetic compounds.…”

“…The pharmacokinetics and pharmacodynamics of derivatives of 13 have been evaluated by [ 153 ]. The cytotoxicity of pyridine derivative 16 shows 100% cell survival up to 10 µM, plasma and microsomal stability with about 97% and 66% of the intact remaining [ 107 ]. It also exhibits blood brain barrier permeability (P e : 65.16 × 10 −6 ) which could be beneficial in CNS-related diseases [ 107 ].…”

“…The cytotoxicity of pyridine derivative 16 shows 100% cell survival up to 10 µM, plasma and microsomal stability with about 97% and 66% of the intact remaining [ 107 ]. It also exhibits blood brain barrier permeability (P e : 65.16 × 10 −6 ) which could be beneficial in CNS-related diseases [ 107 ]. Pyrimidine derivative 18 binds directly to KEAP1 with high affinity and dissociation constant (Kd) of 5.84 × 10 −10 M and causes an alteration in the plasma resonance [ 108 ].…”

“…Among the drugs approved by the USA FDA, the pyridine moiety remains the second most commonly introduced aromatic N-heterocycle [ 159 , 160 ]. According to [ 107 ], the replacement of chlorobenzene with a pyridine ring and OMe with Cl- in vinyl sulfone ( 45 : EC 50 = 530 nM) improves its NRF2-inducing activity ( 46 : EC 50 = 0.618 µM). Furthermore, the insertion of 3-Cl into the pyridine ring of 46 confers the highest NRF2-inducing activity ( 16 : EC 50 = 0.026 µM).…”

An Update Review of Approaches to Multiple Action-Based Antibacterials

“…Other synthetic possibilities in the future could also include some analogues which may mimic the shape and charge distributions found in the core heterocyclic skeletons in the protoberberines and related systems through N-based transannular interactions. Such systems have the added possibility for different atom or group interactions with bacterial targets to improve selectivity and efficacy [40].…”