Abstract

Two isomorphous series of 2′-(2,5-dichlorothiophene-3-carbonyl)-1′-(aryl)-1′,2′,5′,6′,7′,7a'-hexahydrospiro[indoline-3,3′-pyrrolizin]-2-one derivatives are reported. The first series contains namely, 1′-(2-bromophenyl)-2′-(2,5-dichlorothiophene-3-carbonyl)-1′,2′,5′,6′,7′,7a'-hexahydrospiro[indoline-3,3′-pyrrolizin]-2-one, C25H19BrCl2N2O2S, (I), 2′-(2,5-dichlorothiophene-3-carbonyl)-1′-(o-tolyl)-1′,2′,5′,6′,7′,7a'-hexahydrospiro[indoline- 3,3′-pyrrolizin]-2-one, C26H22Cl2N2O2S, (II), and (1′R,2′S,7a'S)-2′-(2,5-dichlorothiophene-3-carbonyl)-1′-(m-tolyl)-1′,2′,5′,6′,7′,7a'-hexahydrospiro[indoline-3,3′-pyrrolizin]-2-one, C26H22Cl2N2O2S, (III), are isomorphous in space group P1¯. The second series of 2′-(2,5-dichlorothiophene-3-carbonyl)-1′-(4-methoxyphenyl)-1′,2′,5′,6′,7′,7a'-hexahydrospiro[indoline-3,3′-pyrrolizin]-2-one, C27H26Cl2N2O4S, (IV), 2′-(2,5-dichlorothiophene-3-carbonyl)-1′-(p-tolyl)-1′,2′,5′,6′,7′,7a'-hexahydrospiro[indoline-3,3′-pyrrolizin]-2-one, C27H26Cl2N2O3S, (V) and 1′-(3-bromophenyl)-2′-(2,5-dichlorothiophene-3-carbonyl)-1′,2′,5′,6′,7′,7a'-hexahydrospiro[indoline-3,3′-pyrrolizin]-2-one, C26H23BrCl2N2O3S, (VI) are isomorphous in space group P21/c. In each of compounds (I–III), a combination of N—H∙∙∙O and C—H∙∙∙O hydrogen bonds generates a chain of an alternating centrosymmetric edge-fused rings of R22(8) [(π)N—H∙∙∙O—C(π)] and R42(14) [(π)C/N—H∙∙∙O—C(π)]. These chains are further linked along the b-axis by π∙∙∙π stacks of the thiophene rings. Inter-sheets C—H∙∙∙π contacts propagate along [100] contributing to the supramolecular assembly. In the series (IV–VI), both N—H∙∙∙O and C—H∙∙∙O hydrogen bonds generate sheets in cb plane, composed of centrosymmetric dimers of molecules linked through (π)C—H∙∙∙O—C(π) hydrogen bonding into R22(24) [in (IV)] or R22(14) [in (V and VI)] ring motifs. The dimers are further connected by the solvent MeOH molecules by another ring motif R32 (8) rings through (π)C—H∙∙∙O—C(π), (π)N—H∙∙∙O—(MeOH) and CH3OH∙∙∙O—C(π) hydrogen bonding. Intermolecular interactions were visualized using Hirshfeld surface analysis and the major contacts found to be delineated into H∙∙∙H, H∙∙∙Cl/Cl∙∙∙H, H∙∙∙C/C∙∙∙H and H∙∙∙O/O∙∙∙H in the triclinic series and H∙∙∙H, H∙∙∙Cl/Cl∙∙∙H, H∙∙∙C/C∙∙∙H and H∙∙∙O/O∙∙∙H in the monoclinic derivatives. Docking results reveal that derivatives (II) and (III) bind to the lipophilic pocket of the phosphoinositide 3-kinase delta PI3Kδ, androgen receptor SARMs, epidermal growth factor receptor EGFR kinases, and apoptosis regulator BCL-2 with high affinities. In addition, compound (III) formed a very stable complex with phosphoinositide 3-kinase delta PI3Kδ with the lowest binding free energy of –10.02 kcal/mol, and the results demonstrated that phosphoinositide 3-kinase delta PI3Kδ complex (4xe0-4c) and epidermal growth factor receptor complex (1xkk-4b) promoted higher stability than the androgen receptor complex (5t8e-4c) and the apoptosis regulator BCL-2 (2w3l-4b). The docking study suggests that these derivatives have the potential to be further evaluated in vitro and in vivo for cancer drug discovery.

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