Synthesis, crystal structure and in vitro anti-proliferative activity of 2-[(4-acetylphenyl)carbamoyl]phenyl acetate

2-[(4-Acetylphenyl)carbamoyl]phenyl acetate, a derivative of aspirin, has been structurally characterized revealing a structure based on intermolecular N—H⋯O hydrogen bonds and π–π interactions.


Chemical context
Acetylsalicylic acid (ASA), or aspirin, is a non-steroidal antiinflammatory drug (NSAID) utilized extensively as an analgesic and antipyretic agent.It has been shown to induce apoptotic cell death in several cancer cell lines ( Brune & Patrignani, 2015;Ranger et al., 2020;Abd-El-Aziz et al., 2021).Aspirin is one of the most prescribed drugs for pain relief as well as for cardiovascular prophylaxis.Decades of investigations have provided substantial evidence indicating potential in the prevention of cancer, particularly colorectal cancer (Drew et al., 2016).Comprehensive clinical benefits of aspirinbased chemoprevention strategies have lately been acknowledged.However, due to the identified risks of long-term aspirin usage, larger scale adoption of an aspirin chemoprevention strategy is likely to involve enhanced identification of individuals for whom the protective benefits compensate the side effects (Drew et al., 2016).Aspirin is recognized as a means for prevention of ischemic heart attack and stroke (Pinto et al., 2013).Although several effects of aspirin are related to its ability to inhibit cyclooxygenase (COX), a key enzyme in prostaglandin biosynthesis, COX-independent effects have also been reported (Alfonso et al., 2014).Aspirin has emerged as a promising intervention in cancer treatment in the past decade (Tran et al., 2021;Lichtenberger et al., 2019), and has a protective effect against several types of cancer (Garcia-Albeniz et al., 2011;Usman et al., 2015).It induces cell death in various cancer cell lines, such as myeloid leukaemia and HeLa cells, chronic lymphocytic leukaemia cells, colon cancer cells (Bellosillo et al., 1998), gastric cancer (Gu et al., 2005), colorectal cancer (Stark et al., 2007) and cholangiocarcinoma (Shen & Shen, 2021).
Motivated by the properties enumerated above and in continuation of our interest in the synthesis of aspirin-based scaffolds, 2-[(4-acetylphenyl)carbamoyl]phenyl acetate was synthesized and characterized.It was anticipated that the compound would present biological activity and it was tested against an NCI 60 cell-line panel.

Structural commentary
The asymmetric unit is shown in Fig. 2. The phenylethanone fragment of the molecule is essentially planar with a twist angle between the phenyl ring (C3-C8) and the acetaldehyde group (C1,C2,O1) of 4.7 (2) � .In the phenylacetate group of the molecule, the acetate group (C16,C17,O3,O4) is almost perpendicular to the phenyl ring (C10-C15) with a twist angle of 82.39 (6) � .This relationship between the acetate group and the ring is similar to that found in aspirin (Tyler et al., 2020).
The twist angles between the various groups in the molecule are similar to those of the N-(4-acetylphenyl)benzamide (Mourad et al., 2020).

Figure 2
The asymmetric unit of (3) showing displacement ellipsoids at the 50% probability level.
Cg1 is the centroid of the C10-C15 ring.

D-H�
Figure 3 A segment of the crystal structure of compound 3 showing intermolecular contacts (N-H� � �O in green, �-� and C-H� � �� in red).

Figure 4
In vitro anti-proliferative activity data of compound 3 at 10 À 5 M.
apeutic Program (DTP) for the estimation of in vitro antiproliferative activity against the NCI 60 cell-line panel.This screen utilizes human tumour cell lines, representing melanoma, leukemia, colon, lung, ovary, brain, prostate, kidney and breast cancers.
The NCI screening service ranks compounds with a promising drug-like mode of action on the basis of computeraided design.The capability of the submitted compounds to convey diversity to the NCI small molecule compound collection is critical to selecting them for screening.
Thus, in general, the compound displays considerable in vitro anti-proliferative activity at 10 �M against most of the tested cancer cell lines.This supports possible future experiments on this compound including the determination of IC 50 (for the most promising cell line) and cytotoxicity in normal cells.

Special details
Geometry.All esds (except the esd in the dihedral angle between two l.s.planes) are estimated using the full covariance matrix.The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry.An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s.planes.

Table 2
Experimental details.