Active Conformation of Seven‐Membered‐Ring Benzolactams as New ACAT Inhibitors: Latent Chirality at N5 in the 1,5‐Benzodiazepin‐2‐one Nucleus

Abstract

Nitrogen chirality: Potent new ACAT inhibitors with seven‐membered‐ring benzolactams as the core structures were first prepared, and the axial chirality recognized by the enzyme was clarified (e.g., 1; see scheme). The chirality at the axis (aS) of 1 controls the conformation of the entire lactam ring, causing the N5‐CH3 to arrange in a pseudo‐equatorial position (i.e., the amine at N5 is a chiral center with the S‐configuration) both in the crystal state and in solution.

Approach on design, synthesis and evaluation of Pharmacophore Benzothiazepine form substituted Chalcones

“…The foremost use of 1,5 Benzothiazepine clinically approved was Diltiazem, followed by Clentiazem for Cardio protective agent (Zhang et al, 2010). Few of 1,5-benzothiazepine derivatives were also clinically ruled for CNS disorders like Thiazesim and Quetiapine fumarate (Takada et al, 2012). 1,5-benzothiazepine moiety is a favored group of pharmacophore, as compounds bearing this structural unit possess a broad spectrum of biological activities such as anticancer (Prasad et al, 2018), antimicrobial, V2 arginine vasopressin receptor antagonist, anti arrhythmic, Hypolipidemic, Bradykinin agonist, vasodilator, Anticholinesterase inhibitor, anticonvulsant, HIV-1 reverse transcriptase inhibitor, Glycogen synthase kinase-3β inhibitor, Ca+2 Channel blocking, antiangina, anti HIV and Squalene synthetase inhibitor so on (Raghavendra et al, 2015).…”

Interplay of Nitrogen-Atom Inversion and Conformational Inversion in Enantiomerization of 1H-1-Benzazepines

“…We became interested in the stereochemical issues above with the realization that these simple 1-benzazepines can be seen as model compounds for the pharmacologically important benzazepines and benzodiazepines. , The plethora of stereodynamic processes that characterize these molecules is garnering much attention . Knowledge of how structure affects the Gibbs free energy of activation (Δ G ⧧ ) and thus the rate of a stereodynamic process is crucial if the molecule is to be developed into a drug. , More and more biologically active molecules that possess two stereogenic elementsa nonplanar azepine ring and a potentially chiral nitrogen atomare being discovered. − It is often not clear whether the two processes (rotation–inversion and ring-flip) are interrelated or whether they occur independently of each other. In many cases, the latent chirality of the nitrogen atom either is not recognized or commented upon, ,,− is not taken into account when the energetics of enantiomerization are studied, − or is considered too planar to have an impact on the energetics. , A notable exception is the study by Clayden et al of the enantiomerization energetics of the non-nucleoside reverse transcriptase inhibitor nevirapine (Scheme ).…”

“…The impact of the sense of planar chirality on the pharmacological behavior of seven-membered-ring benzo-fused heterocycles is becoming increasingly evident. Recent examples include a bombesin receptor subtype 3 (BRS-3) agonist, where one planar-chiral enantiomer is much less active than the other, and the ACAT inhibitor 3 , which shows the same sort of eutomer/distomer relationship between the planar-chiral atropisomeric enantiomers. Even when the two planar-chiral enantiomers interconvert rapidly, it has been noted that one of the enantiomers can be bound preferentially to a receptor, as is the case for many members of the benzodiazepine class of heterocycles …”

“…An example of a system with less constraints is ACAT inhibitor 3, studied by Tabata et al 16 The higher saturation level of the diazepine ring versus that of nevirapine's makes it possible that ring-flip and N-inversion are not associated. The seven-membered ring in 3 is significantly puckered, while the non-amide nitrogen atom is more pyramidalized (the sum of the C−N−C bond angles is 340°) than the corresponding nitrogen atom in nevirapine.…”

“…26 A systematic experimental and computational study of the relationship between ring-flip and N-inversion and how these affect the energy barrier to enantiomerization is desirable considering the ever increasing importance of seven-membered-ring heterocycles in pharmacology. 8 It is well-known that varying the steric bulk of the groups attached to atoms around the ring juncture of the 1,4-benzodiazepine system 27 and other benzodiazepine 16 and benzazepine systems 4,16 will strongly affect the rate of the ring-flip. A systematic study of the steric effects of groups around the ring juncture, where one of the atoms bearing those groups is stereolabile, is lacking.…”