Two isomorphous series of 2'-(2,5-dichlorothiophene-3-carbonyl)-1'(aryl)-1',2',5',6',7',7a'-hexahy drospiro[indoline-3,3'-pyrrolizin]-2-one derivatives: X-ray structures, intermolecular interactions, Hirshfeld analysis and molecular docking

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[indo- line-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-dichlor- othiophene-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 center dot center dot center dot O and C-H center dot center dot center dot O hydrogen bonds generates a chain of an alternating centrosymmetric edge-fused rings of R22(8) [(z)N-H center dot center dot center dot O-C (z)] and R42(14) [(z)C/N-H center dot center dot center dot O-C(z)]. These chains are further linked along the b -axis by z center dot center dot center dot z stacks of the thiophene rings. Inter-sheets C-H center dot center dot center dot z contacts propagate along [100] contributing to the supramolecular assembly. In the series (IV-VI), both N-H center dot center dot center dot O and C-H center dot center dot center dot O hydrogen bonds generate sheets in cb plane, composed of centrosymmetric dimers of molecules linked through (z)C-H center dot center dot center dot O-C(z) 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 (z)C-H center dot center dot center dot O-C(z), (z)N-H center dot center dot center dot O-(MeOH) and CH3OH center dot center dot center dot O-C(z) hydrogen bonding. Intermolecular interactions were visualized using Hirshfeld surface analysis and the major contacts found to be delineated into H center dot center dot center dot H, H center dot center dot center dot Cl/Cl center dot center dot center dot H, H center dot center dot center dot C/C center dot center dot center dot H and H center dot center dot center dot O/O center dot center dot center dot H in the triclinic series and H center dot center dot center dot H, H center dot center dot center dot Cl/Cl center dot center dot center dot H, H center dot center dot center dot C/C center dot center dot center dot H and H center dot center dot center dot O/O center dot center dot center dot H in the monoclinic derivatives. Docking results reveal that derivatives (II) and (III) bind to the lipophilic pocket of the phosphoinositide 3-kinase delta PI3K delta, 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 PI3K delta with the lowest binding free energy of -10.02 kcal/mol, and the results demonstrated that phosphoinositide 3-kinase delta PI3K delta 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 (2w3l4b). The docking study suggests that these derivatives have the potential to be further evaluated in vitro and in vivo for cancer drug discovery.