RESUMO
COVID-19 is a global pandemic caused by infection with the SARS-CoV-2 virus. Remdesivir, a SARS-CoV-2 RNA polymerase inhibitor, is the only drug to have received widespread approval for treatment of COVID-19. The SARS-CoV-2 main protease enzyme (MPro), essential for viral replication and transcription, remains an active target in the search for new treatments. In this study, the ability of novel thiazolyl-indazole derivatives to inhibit MPro is evaluated. These compounds were synthesized via the heterocyclization of phenacyl bromide with (R)-carvone, (R)-pulegone and (R)-menthone thiosemicarbazones. The binding affinity and binding interactions of each compound were evaluated through Schrödinger Glide docking, AMBER molecular dynamics simulations, and MM-GBSA free energy estimation, and these results were compared with similar calculations of MPro binding various 5-mer substrates (VKLQA, VKLQS, VKLQG) and a previously identified MPro tight-binder X77. From these simulations, we can see that binding is driven by residue specific interactions such as π-stacking with His41, and S/π interactions with Met49 and Met165. The compounds were also experimentally evaluated in a MPro biochemical assay and the most potent compound containing a phenylthiazole moiety inhibited protease activity with an IC50 of 92.9 âµM. This suggests that the phenylthiazole scaffold is a promising candidate for the development of future MPro inhibitors.
RESUMO
The bicyclic imidazo[1,2-a]pyridine core of the title compound, C19H19N3, is relatively planar with an r.m.s. deviation of 0.040â Å. The phenyl ring is inclined to the mean plane of the imidazo[1,2-a]pyridine unit by 18.2â (1)°. In the crystal, mol-ecules are linked by N-Hâ¯H hydrogen bonds, forming chains along the c-axis direction. The chains are linked by C-Hâ¯π inter-actions, forming slabs parallel to the ac plane. The Hirshfeld surface analysis and fingerprint plots reveal that the crystal structure is dominated by Hâ¯H (54%) and Câ¯H/Hâ¯C (35.6%) contacts. The crystal studied was refined as an inversion twin.
RESUMO
The title compound, C25H34N2O5, was synthesized from 9α-hy-droxy-parthenolide (9α-hy-droxy-4,8-dimethyl-12-methylen-3, 14-dioxa-tri-cyclo-[9.3.0.0(2,4)]tetra-dec-7-en-13-one), which in turn was isolated from the chloro-form extract of the aerial parts of Anvillea radiata. The mol-ecule comprises a ten-membered ring fused to a five-membered ring with an additional ep-oxy ring system fused to the ten-membered ring. The five-membered ring also carries a 4-hy-droxy-phenyl-piperazin-1-ylmethyl substituent. The ten-membered ring adopts an approximate chair-chair conformation, while the piperazine ring displays a chair conformation and the five-membered ring shows an envelope conformation with the C atom closest to the hy-droxy group forming the flap. Two C atoms in the phenyl ring and the O atom of the hydroxyl group are disordered over two sites, with an occupancy ratio of 0.53â (5):0.47â (5). An intra-molecular O-Hâ¯N hydrogen-bond stabilizes the mol-ecular conformation. In the crystal, C-Hâ¯O hydrogen bonds link the mol-ecules into zigzag chains running along the a-axis direction.
RESUMO
The title compound, C15H26O2, was synthesized from ß-himachalene (3,5,5,9-tetra-methyl-2,4a,5,6,7,8-hexa-hydro-1H-benzo-cyclo-heptene), which was isolated from the Atlas cedar (cedrus atlantica). The mol-ecule is built up from a seven-membered ring to which a six- and a three-membered ring are fused. The seven- and six-membered rings each have a twist-boat conformation. In the crystal, O-Hâ¯O hydrogen bonds link the mol-ecules into zigzag chains running along the b-axis direction.
RESUMO
The title compound, C25H33BrN2O4, was synthesized from 9α-hy-droxy-parthenolide (9α-hy-droxy-4,8-dimethyl-12-methylen-3,14-dioxa-tri-cyclo-[9.3.0.0(2,4)]tetra-dec-7-en-13-one), which was isolated from the chloro-form extract of the aerial parts of Anvillea radiata. The mol-ecule is built up from two fused five- and ten-membered rings with an additional ep-oxy ring system and a bromo-phenyl-piperazine group as a substituent. The ten-membered ring adopts an approximate chair-chair-chair conformation, while the piperazine ring displays a chair conformation and the five-membered ring shows an envelope conformation with the C atom closest to the hy-droxy group forming the flap. An intra-molecular O-Hâ¯N hydrogen bond stabilizes the mol-ecular conformation. The crystal packing features C-Hâ¯O hydrogen bonds, which link the mol-ecules into zigzag chains running along the b-axis direction.