Design and Evaluation of Bispidine-Based SARS-CoV-2 Main Protease Inhibitors

Abstract

For the first time, derivatives of 3,7-diazabicyclo[3.3.1]nonane (bispidine) were proposed as potential inhibitors of the SARS-CoV-2 main viral protease (3-chymotrypsin-like, 3CLpro). Based on the created pharmacophore model of the active site of the protease, a group of compounds were modeled and tested for activity against 3CLpro. The 3CLpro activity was measured using the fluorogenic substrate Dabcyl-VNSTLQSGLRK(FAM)MA; the efficiency of the proposed approach was confirmed by comparison with literature data for ebselen and disulfiram. The results of the experiments performed with bispidine compounds showed that 14 compounds exhibited activity in the concentration range 1–10 μM, and 3 samples exhibited submicromolar activity. The structure–activity relationship studies showed that the molecules containing a carbonyl group in the ninth position of the bicycle exhibited the maximum activity. Based on the experimental and theoretical results obtained, further directions for the development of this topic were proposed.

Bispidine Platform as a Tool for Studying Amide Configuration Stability

“…Compounds 1a [42], 1b-d, 1b -1d , [25] 1l, 2, [19] 1f, 1h-1k [27] were prepared as described earlier.…”

“…In the frames of our studies on bispidine-type molecules as SARS-CoV-2 main protease inhibitors [27] and as components of catalytic systems for the Henry reaction [34], we focused our efforts on a group of symmetrical bispidine-based bis-amides. In this paper, we describe two crystal structures of new bispidinone bis-amides and an NMR study of the solution behavior of a group of bis-amides, 1-3 (Figure 1).…”

“…N,N′-Diacyl bispidines have found various different applications in: medicinal chemistry [26] (a review), [27,28]; crystal engineering [29]; macroheterocycle synthesis [13,[18][19][20]23,[29][30][31]; secondary structure nucleators in peptides [22,32]; conformational switching [12,13]; lipid bilayer modifiers [15,33].…”

“…Bis-amides 1 and 2 were synthesized previously either from 5,7-dimethyl-1,3-diazaadamantan-6-one by methylene bridge cleavage in the biphasic system benzene-water (compounds 1a [12,35] (for this compound, the acetic acid anhydride was used), 1b, 1c, 1b', 1c' [25], and 1f [27], Scheme 3) or from 1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9one by direct acylation with the corresponding acid chlorides (compounds 1h-1k [27], 1l, and 2 [19], Scheme 4). Amides 1d, 1d', and 1e were prepared by nucleophilic substitution reactions with sodium iodide and sodium azide in acetone, from the corresponding dichlorides (1b and 1b'); the same approach was used for dopamine derivative 3 (Scheme 5; for experimental details, see Section 3 and Supplementary Materials, SM).…”

Computationally driven discovery of SARS-CoV-2 Mproinhibitors: from design to experimental validation

“…Many studies have been devoted to the design of new M pro inhibitors 3,5,[15][16][17][18][19][20][21][22][23][24][25] through joint computational and experimental approaches. In particular, a recent study by the Jorgensen group highlighted the usefulness of relative binding free energy (RBFE) computations as part of the drug design process.…”