Structural and Energetic Properties of Weak Noncovalent Interactions in Two Closely Related 3,6-Disubstituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole Derivatives: In Vitro Cyclooxygenase Activity, Crystallography, and Computational Investigations

Abstract

Two 3,6-disubstituted-[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazole derivatives, namely, 3-(adamantan-1-yl)-6-(2-chloro-6-fluorophenyl)-[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazole 1 and 6-(2-chloro-6-fluorophenyl)-3-phenyl-[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazole 2 , were prepared, and the detailed analysis of the weak intermolecular interactions responsible for the supramolecular self-assembly was performed using X-ray diffraction and theoretical tools. Analyses of Hirshfeld surface and 2D fingerprint plot demonstrated the effect of adamant-1-yl/phenyl moieties on intermolecular interactions in solid-state structures. The effect of these substituents on H···H/Cl/N contacts was more specific. The CLP-PIXEL and density functional theory methods provide information on the energetics of molecular dimers observed in these compounds. The crystal structure of compound 1 stabilizes with a variety of weak intermolecular interactions, including C–H···N, C–H···π, and C–H···Cl hydrogen bonds, a directional C–S···π chalcogen bond, and unconventional short F···C/N contacts. The crystal structure of compound 2 is stabilized by π-stacking interactions, C–H···N, C–H···π, and C–H···Cl hydrogen bonds, and highly directional attractive σ–hole interactions such as the C–Cl···N halogen bond and the C–S···N chalcogen bond. In addition, S(lp)···C(π) and short N···N contacts play a supportive role in the stabilization of certain molecular dimers. The final supramolecular architectures resulting from the combination of different intermolecular interactions are observed in both the crystal packing. The molecular electrostatic potential map reveals complementary electrostatic potentials of the interacting atoms. The quantum theory of atoms in molecules approach was used to delineate the nature and strength of different intermolecular interactions present in different dimers of compounds 1 and 2 . The in vitro experiments suggest that both compounds showed selectivity against COX-2 targets rather than COX-1. Molecular docking analysis showed the binding pose of the compounds at the active sites of COX-1/2 enzymes.

Pd(II)- and Pt(II)-Assisted P–C Activation/Cyclization Reactions with a Luminescent α-Aminophosphine

“…Relative orientation of N -phenyl and benzothiazole moieties in compound 5 (Figure S9, SI and description therein) differs from that in other reported NH-Pbt derivatives ,,,, due to the absence of intramolecular hydrogen bonds and the presence of shortened N···S contact. − This conformational feature allows the protonated NH-Pbt moiety to be easily recognizable from the nonprotonated N-Pbt.…”

Unveiling the Intermolecular Interactions between Drug 5-Fluorouracil and Watson–Crick/Hoogsteen Base Pairs: A Computational Analysis

“…In the DNA base pairs, we notice that the red regions match with the blue regions, forming the base pairs. It is well documented that the proximity of the areas of the same color when brought closer would destabilize the system, and the most stable system will be formed by a directional interaction. , In the AT base pair, V s,max is observed on the hydrogen atoms of five-membered adenine and six-membered thymine molecules, while V s,min is observed on the nitrogen and oxygen atoms of A and T bases. Analogous to the AT base pair, in the GC and Hoogsteen HAT base pairs, the hydrogen and oxygen atoms own V s,max and V s,min , respectively.…”

Supramolecular Chemistry: Exploring the Use of Electronic Structure, Molecular Dynamics, and Machine Learning Approaches

“…In addition to the hydrogen bond and the π-stacking interactions, the role of chalcogen bonds has attracted much interest in supramolecular polymerization, and electronic structure methods have been pivotal to furthering the knowledge regarding those interactions. [22][23][24] For the 1D polymerization of cationic 1,2,4-selenodiazoles, Tskhovrebov's group observed experimentally that, in solution, hydrogen and chalcogen bonds are pivotal for the polymerization. [25] Considering the role of noncovalent interactions in the polymerization process, a more in-depth analysis of them is crucial to predict packing and polymerization preferences.…”