Nitrogen-Walk Approach to Explore Bioisosteric Replacements in a Series of Potent A_2B Adenosine Receptor Antagonists

Abstract

A systematic exploration of bioisosteric replacements for furan and thiophene cores in a series of potent A 2B AR antagonists has been carried out using the nitrogen-walk approach. A collection of 42 novel alkyl 4-substituted-2-methyl-1,4dihydrobenzo [4,5]imidazo[1,2-a]pyrimidine-3-carboxylates, which contain 18 different pentagonal heterocyclic frameworks at position 4, was synthesized and evaluated. This study enabled the identification of new ligands that combine remarkable affinity (K i < 30 nM) and exquisite selectivity. The structure−activity relationship (SAR) trends identified were substantiated by a molecular modeling study, based on a receptor-driven docking model and including a systematic free energy perturbation (FEP) study. Preliminary evaluation of the CYP3A4 and CYP2D6 inhibitory activity in optimized ligands evidenced weak and negligible activity, respectively. The stereospecific interaction between hA 2B AR and the eutomer of the most attractive novel antagonist (S)-18g (K i = 3.66 nM) was validated.

Identification of V6.51L as a selectivity hotspot in stereoselective A2B adenosine receptor antagonist recognition

“…To experimentally validate this hypothesis, the ISAM-140 enantiomers were separated and their absolute configuration unequivocally assigned. Besides this goal, the enantiomeric separation and pharmacological characterization of this reference A 2B AR antagonist allowed to confirm the expected higher affinity of the S enantiomer, in line with the original modeling hypothesis 11 and recent similar results obtained with derivatives of this scaffold 10 , 13 , 14 .…”

“…1 ) 11 , 12 . The prediction of the active stereoisomer for this chemotype was later confirmed indirectly by experimental characterization of the active stereoisomers for representative compounds of a series of cyanopyrimidines 10 , fluorinated tricyclic derivatives 13 and aza-bioisosteres of the pentagonal heterocycle 14 . This binding model proposed that the stereospecific complementarity to the A 2B AR cavity was due to the optimal accommodation of the thiophene/furan ring around the chiral center of the core scaffold (Fig.…”

Enantiomeric Separation and Molecular Modelling of Bioactive 4-Aryl-3,4-dihydropyrimidin-2(1H)-one Ester Derivatives on Teicoplanin-Based Chiral Stationary Phase

“…The investigated DHP derivatives were assembled in excellent yields by modification of the versatile and highly robust Biginelli reaction [2,3], a three-component transformation involving the catalysed condensation of a 1,3-dinucleophile (urea/thiourea or cyclic derivatives), and an aldehyde and β-ketoester [4]. A diverse series of DHP derivatives were explored [5][6][7][8][9][10][11] and optimal substituents in different positions of the heterocyclic core were identified as follows: (i) 2-or 3-furyl as well as 2-or 3-thienyl moiety at C4, (ii) ethyl or isopropyl ester group at C5, (iii) a methyl group at C6, and (iv) NH at position 1. Further diversification of the original 4-aryl-DHP scaffold [5,[12][13][14][15] produced new ligands with improved affinity and selectivity profiles.…”

“…Regarding the enantioselective binding of racemic DHPs to A 2B AR, it was demonstrated that the receptor affinity is almost exclusively due to the (S)-enantiomer [6,[8][9][10][11]. The pharmacological evaluation of chiral DHP ligands investigated herein, 6, 7, and 13, resolved into their enantiomers by chiral HPLC with polysaccharide-based CSPs in NP mode, demonstrated highly enantioselective recognition at the A 2B AR binding site, with the eutomers (S) showing K i values in the low nanomolar range (6.30, 15.1, and 11.1 nM for 6, 7, and 13, respectively) and the distomers (R) achieving less than 25% inhibition in all cases [6,11].…”

One‐Pot Synthesis of Benzo[4,5]imidazo[1,2‐a]pyrimidin‐2‐ones Using a Hybrid Catalyst Supported on Magnetic Nanoparticles in Green Solvents

“…This approach has been developed by other groups using various catalysts and conditions. [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ] In the rest of these works, we report a new consecutive four‐component reaction for the synthesis of 3,4‐dihydrobenzo[4,5]imidazo[1,2‐ a ]pyrimidin‐2(1 H )‐ones by successive addition of aniline, DMAD, benzaldehyde derivatives and 2‐aminobenzimidazole in the presence of new organic‐inorganic hybrid nanomagnetic catalyst in water/EtOH as a green solvent.…”