TY - JOUR

T1 - The role of S-bond in tenoxicam keto-enolic tautomerization

AU - Arkhipov, Sergey G.

AU - Sherin, Peter S.

AU - Kiryutin, Alexey S.

AU - Lazarenko, Vladimir A.

AU - Tantardini, Christian

PY - 2019/9/28

Y1 - 2019/9/28

N2 - A non-steroidal anti-inflammatory drug, 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno(2,3-e)-1,2-thiazine-3-carboxamide 1,1-dioxide, called tenoxicam (TXM), with important implications in cancer treatment, has a peculiarity with respect to other molecules from the oxicam family. TXM is predominantly found in the zwitterionic form (ZWC) within the crystal structures of pure compounds and their solvates; however, it can be present in the β-keto-enolic form (BKE) or β-diketone (BDK) form. To understand this phenomenon, the combined effects of environment (solvent) and intra-molecular non-covalent interactions on the TXM keto-enol tautomerization were investigated through a combined experimental and computational study. We found that the polarity of a solvent had a minor influence on the crystallization process; this allowed to us synthesize and solve six new solvates with TXM in the ZWC form. Careful investigation of the non-covalent interactions between the sulphur atom of thiophenyl moiety and oxygen of the carbonyl group (S-bond) through a computational approach with the natural bond orbital (NBO) theory has shown that TXM crystallization is modulated by the S-bond. This study further confirms the importance of the S-bond in the drug design; however, nowadays, it is still underestimated.

AB - A non-steroidal anti-inflammatory drug, 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno(2,3-e)-1,2-thiazine-3-carboxamide 1,1-dioxide, called tenoxicam (TXM), with important implications in cancer treatment, has a peculiarity with respect to other molecules from the oxicam family. TXM is predominantly found in the zwitterionic form (ZWC) within the crystal structures of pure compounds and their solvates; however, it can be present in the β-keto-enolic form (BKE) or β-diketone (BDK) form. To understand this phenomenon, the combined effects of environment (solvent) and intra-molecular non-covalent interactions on the TXM keto-enol tautomerization were investigated through a combined experimental and computational study. We found that the polarity of a solvent had a minor influence on the crystallization process; this allowed to us synthesize and solve six new solvates with TXM in the ZWC form. Careful investigation of the non-covalent interactions between the sulphur atom of thiophenyl moiety and oxygen of the carbonyl group (S-bond) through a computational approach with the natural bond orbital (NBO) theory has shown that TXM crystallization is modulated by the S-bond. This study further confirms the importance of the S-bond in the drug design; however, nowadays, it is still underestimated.

KW - CRYSTAL-STRUCTURE

KW - CO-CRYSTALS

KW - MELOXICAM

KW - COCRYSTALS

KW - PHARMACOKINETICS

KW - SOLUBILITY

UR - http://www.scopus.com/inward/record.url?scp=85072305090&partnerID=8YFLogxK

U2 - 10.1039/c9ce00874h

DO - 10.1039/c9ce00874h

M3 - Article

AN - SCOPUS:85072305090

VL - 21

SP - 5392

EP - 5401

JO - CrystEngComm

JF - CrystEngComm

SN - 1466-8033

IS - 36

ER -