Cyclooxygenase-2 (COX-2) as a Target of Anticancer Agents: A Review of Novel Synthesized Scaffolds Having Anticancer and COX-2 Inhibitory Potentialities

Cancer is a serious threat to human beings and is the second-largest cause of death all over the globe. Chemotherapy is one of the most common treatments for cancer; however, drug resistance and severe adverse effects are major problems associated with anticancer therapy. New compounds with multi-target inhibitory properties are targeted to surmount these challenges. Cyclooxygenase-2 (COX-2) is overexpressed in cancers of the pancreas, breast, colorectal, stomach, and lung carcinoma. Therefore, COX-2 is considered a significant target for the synthesis of new anticancer agents. This review discusses the biological activity of recently prepared dual anticancer and COX-2 inhibitory agents. The most important intermolecular interactions with the COX-2 enzyme have also been presented. Analysis of these agents in the active area of the COX-2 enzyme could guide the introduction of new lead compounds with extreme selectivity and minor side effects.


Introduction
Cancer is caused by the uncontrolled proliferation of cells and is the most lethal ailment among non-infectious diseases. Invasive cancer is the primary cause of death in developed countries and the second-largest cause of death in developing countries. In 2020, 19.3 million cases and 10 million fatalities were reported due to cancer [1]. In 2022, 1.9 million new cases and 0.6 million deaths are predicted in the United States of America as a result of cancer [2]. The high mortality rate has been maintained over recent decades, despite the increased availability of various anticancer drugs [3]. In the future, cancer incidence is expected to increase, with an estimated 26 million cases predicted in 2030 [4,5]. Still, there is a considerable difference between the supply and requirement of new anticancer agents. The currently available anticancer agents are linked to severe post-treatment adverse effects, due to their lack of selectivity. Therefore, the invention and development of novel and selective anticancer therapies with the fewest side effects and multiple modes of action are urgently needed [6]. The idea that inflammation causes cancer was advanced by Rudolf Virchow after observing the presence of leukocytes in tumor cells [7]. Now, it is a recognized fact that chronic inflammation results in an increased risk of cancer [8]. Various growth factors, such as epidermal growth factor (EGF) and fibroblast growth factors (FG), are released during the process of inflammation, which increases cell proliferation and, hence, causes cancer [9]. Cyclooxygenase (COX) is the fundamental enzyme increased risk of cancer [8]. Various growth factors, such as epidermal growth factor (EGF) and fibroblast growth factors (FG), are released during the process of inflammation, which increases cell proliferation and, hence, causes cancer [9]. Cyclooxygenase (COX) is the fundamental enzyme in the biosynthesis of prostaglandins and is important for the pathophysiological process of inflammation. The COX enzyme occurs in three isoforms, i.e., COX-1, COX-2, and COX-3. COX-1 is found in normal tissues, where it controls prostaglandin production and, hence, is necessary for normal physiological function. COX-2 is produced during the process of inflammation and carcinogenesis [10]. Nonsteroidal anti-inflammatory drugs (NSAIDs) obstruct COX-1 and COX-2 enzymes to different extents and reduce prostaglandin biosynthesis [11]. The blockage of COX-1 causes several complications, the most common of which is GIT ulceration [12]. COX-2 is the key inflammatory mediator and its expression is up-regulated during inflammation [13][14][15]. Therefore, COX-2 has been the target of anti-inflammatory agents for many years [16]. The COX-2 enzyme has a vital role in the initiation of cancer because it inhibits apoptosis and starts the process of angiogenesis. An increased COX-2 level has been observed in colorectal (60%), breast (40%), pancreatic, esophageal, and lung cancer, and in melanoma [17][18][19]. NSAIDs (1-6 Figure 1) are frequently used for the management of cancer-related pain and inflammation. The inhibition of COX-2 by some NSAIDs has led to the inhibition of the process of cancer and the induction of metastasis [20]. Therefore, COX-2 has emerged as a possible target for new anticancer drugs and there is increased research in this direction [21]. The selective COX-2 inhibitor, celecoxib (5), has established anticancer properties regarding some cancers, such as ovarian cancer and adenomas [22]. COX-2 inhibitors have also shown the capability to overcome multidrug resistance because they reduce the expression of efflux pumps and, hence, reveal a different domain [23]. There is currently a great deal of research into the discovery and synthesis of new COX-2 inhibitors due to their unique role in cancer chemotherapy. This review deals with the new anticancer derivatives synthesized over the last five years that have also exhibited COX-2 inhibitory activity.

Drug Molecules with Dual Anticancer and COX-2 Inhibitory Activity
Several drug molecules possessing dual anticancer and COX-2 inhibitory properties have already been reported. Licofelone (7) (Figure 2) is a dual COX and lipoxygenase (LOX) inhibitor. Licofelone showed anticancer activity in the colon (HCA-7) and breast (MCF-7) cancer cell lines by inducing apoptosis [24]. Compound 8 is a triazole derivative that exhibited anticancer activity and also demonstrated COX-2 and LOX enzyme inhibition. Compound 8 also facilitated the process of apoptosis in the A549 cancer cell line. Another derivative of this class will be discussed later in the triazole group [25]. Similarly, compound 9 is an indole derivative that displayed anticancer and anti-inflammatory activities by inhibiting the COX-2 enzyme [26]. Darbufelone (10) also showed anticancer activity in the colorectal cancer (CRC) cell line, accompanied by dual LOX/COX-2 inhibition [27]. Similarly, compound 11 also exhibited dual anticancer and COX-2 inhibitory activities [28]. In the following sections, we have discussed various classes of organic compounds and their anticancer and COX-2 inhibitory activities. Several drug molecules possessing dual anticancer and COX-2 inhibitory properties have already been reported. Licofelone (7) (Figure 2) is a dual COX and lipoxygenase (LOX) inhibitor. Licofelone showed anticancer activity in the colon (HCA-7) and breast (MCF-7) cancer cell lines by inducing apoptosis [24]. Compound 8 is a triazole derivative that exhibited anticancer activity and also demonstrated COX-2 and LOX enzyme inhibition. Compound 8 also facilitated the process of apoptosis in the A549 cancer cell line. Another derivative of this class will be discussed later in the triazole group [25]. Similarly, compound 9 is an indole derivative that displayed anticancer and antiinflammatory activities by inhibiting the COX-2 enzyme [26]. Darbufelone (10) also showed anticancer activity in the colorectal cancer (CRC) cell line, accompanied by dual LOX/COX-2 inhibition [27]. Similarly, compound 11 also exhibited dual anticancer and COX-2 inhibitory activities [28]. In the following sections, we have discussed various classes of organic compounds and their anticancer and COX-2 inhibitory activities.

Pyrazole Derivatives
Organic compounds exhibiting pyrazole scaffolds have drawn major attention as anticancer agents due to their anti-inflammatory and anticancer activities [29][30][31]. The diaryl heterocycle is a common scaffold in many COX-2 inhibitors because of its greater selectivity for this enzyme and better safety profile. The presence of the aminosulfonyl or sulfonylmethyl group is also very significant for COX-2 selectivity [32,33]. These groups interact with His90, Gln192, and Arg513 in the COX-2 enzyme through hydrogen bonding [34]. Inceller and co-workers designed and synthesized 1,3-diarylpyrazole derivatives. The aromatic rings, such as phenyl and pyridyl, were attached to the 1, 3-diarylpyrazole ring through the oxopropenyl linker group. Upon their evaluation as anticancer agents, 12, 13, and 14 ( Figure 3) displayed excellent anticancer activities (IC50 < 10 µM) against

Pyrazole Derivatives
Organic compounds exhibiting pyrazole scaffolds have drawn major attention as anticancer agents due to their anti-inflammatory and anticancer activities [29][30][31]. The diaryl heterocycle is a common scaffold in many COX-2 inhibitors because of its greater selectivity for this enzyme and better safety profile. The presence of the aminosulfonyl or sulfonylmethyl group is also very significant for COX-2 selectivity [32,33]. These groups interact with His90, Gln192, and Arg513 in the COX-2 enzyme through hydrogen bonding [34]. Inceller and co-workers designed and synthesized 1,3-diarylpyrazole derivatives. The aromatic rings, such as phenyl and pyridyl, were attached to the 1, 3-diarylpyrazole ring through the oxopropenyl linker group. Upon their evaluation as anticancer agents, breast (MCF-7), liver (Huh-7), and colon (HCT-116) cancer cell lines. Derivatives having a 4-pyridyl ring displayed superior activity compared with the 3-pyridyl derivatives. The introduction of 4-sulfonylmethyl phenyl at position 1 of pyrazole produced inactive compounds. Derivative 14 also displayed excellent antiplatelet (71.43%) and COX-2 (25.45%) inhibitory activities but was not found to be selective for COX-2 because COX-1 inhibitions were also observed [35]. These derivatives showed excellent drug-likeness values and followed the Lipinski rule of five [36]. Mukarram et al. synthesized new 1,3diaryl pyrazole derivatives, into which the α-difluoro-β-hydroxyl carbonyl fragment was incorporated. Derivatives 15, 16, and 17 demonstrated prominent antiproliferative activity against the MCF-7 cell line (40.59-51.03% inhibition), compared to the standard drug methotrexate (54.29-68.42% inhibition) and showed less cytotoxicity for the normal cell line. Derivative 17 is an acid derivative with a terminal carboxyl group, while 15 and 16 are hydrazide derivatives, with a terminal hydrazide group. The hydrazide and acid derivatives presented better activity compared to the ester derivatives. Derivative 17 also showed excellent COX-2 inhibitory (38.56%) activity, while using aspirin (11.11 ± 0.13%) as the standard drug. Compounds having halogen-substituted aromatic rings at position 3 of the pyrazole scaffold presented greater activity levels. Derivative 16 showed prominent DPPH radical scavenging activity (72.76%) when using ascorbic acid (88.63%) as a standard drug [37].  presented prominent COX-2 (IC 50 = 0.28 µM: SI = 142.96) inhibitory activity, compared to the standard drug, celecoxib (IC 50 = 0.38 ± 0.08 µM: SI = 97.29). An evaluation of the mode of action studies showed that 18 induced the process of apoptosis in the Hela cell line in a dose-(1.25-10 µM) and time (0-36 h)-dependent manner [38]. Yamali et al. synthesized new pyrazole derivatives in which positions 3 and 5 were modified. The ester and hydrazide groups were introduced at position 3 and different aryl, as well as heteroaryl, rings were introduced at position 5. Compounds 19 (CC 50 = 37.7 µM) and 20 (CC 50 = 58.1 µM) showed less activity against the human squamous cell carcinoma (HSC-2) cancer cell line, compared to the standard drug, doxorubicin (CC 50 = 0.2 µM). These compounds were found to be more active than fluorouracil (CC 50 > 400 µM) and methotrexate (CC 50 > 1000 µM). Derivatives 19 and 20 showed selectivity for the cancer cell lines, and 20 also exhibited the most prominent inhibition of human carbonic anhydrase (hCA-II) isoform-II, with a ki value of less than 7.4 nM. Compounds 19 and 20 are ester derivatives; the conversion of ester into the hydrazide linkage leads to a further decline in activity [39]. Zhang et al. reported new pyrazole derivatives, to which an aminophosphonyl moiety was attached. Upon an evaluation of the anticancer activity, 21 demonstrated excellent anticancer activity (IC 50 = 4.37 ± 0.49 µM) against the MCF-7 cell line by using paclitaxel (IC 50 = 5.74 ± 0.39 µM) as a standard drug. Compound 21 also showed inhibition (IC 50 = 0.22 ± 0.04 µM; SI = 179.18) of COX-2 and presented more selectivity for this enzyme than the standard drug, celecoxib (IC 50 = 0.39 ± 0.08 µM, SI= 97.79). The substitution of the N-1 aromatic ring at the para position was important for COX-2 inhibition. The fluorine-substituted aromatic rings manifested greater activity, and the replacement of the fluorine atom by the bromine or sulfonamide group produced less active derivatives. Derivatives with a naphthalene ring at position number 5 showed prominent anticancer activity. Compound 21 also showed the process of apoptosis in MCF-7 cells, via mitochondrial depolarization [40]. . The substitution of the N-1 aromatic ring at the para position was important for COX-2 inhibition. The fluorinesubstituted aromatic rings manifested greater activity, and the replacement of the fluorine atom by the bromine or sulfonamide group produced less active derivatives. Derivatives with a naphthalene ring at position number 5 showed prominent anticancer activity. Compound 21 also showed the process of apoptosis in MCF-7 cells, via mitochondrial depolarization [40].  (18), ester (19,20), and aminophosphonyl (21) groups.

Pyrazole-and Pyrazolone-Based Hybrid Molecules
Molecular hybridization is a trend in drug design and discovery in which the pharmacophores of active drug molecules are combined to produce new molecules. The molecular hybridization approach has also been employed to produce new compounds with dual biological activities [46,47]. In 2019, Abdellatif and co-workers carried out the
El-Zahar and co-workers synthesized new hybrid compounds by the attachment of pyrazole/thiazole heterocyclic rings to the triazole scaffold. The thiazole, pyrazole, and thiosemicarbazone derivatives showed significant inhibition of COX-2. The molecular interaction studies of 30 with COX-2 presented hydrogen bonding between sulfonamide oxygen and Arg120, as well as Tyr355. Other hy-drogen bonds were observed between Gly354 and the thiazole ring nitrogen, hydrazine NH, and Gln192 [51]. Fadaly and co-workers synthesized new 1,2,4-triazole and pyrazole hybrid molecules, in which the nitric oxide (NO)-releasing group and sulfamoyl groups were introduced. In that study, the authors tried to boost the anticancer and antiinflammatory activities. Elsewhere, the NO group augmented the impact of anticancer agents by enhancing their invasion into cancer cells and reducing the resistance [52]. Derivatives 33 (IC 50 = 3.66 ± 0.12-5.34 ± 0.91 µM), 34 (IC 50 = 4.37 ± 0.27-6.48 ± 0.21 µM), 35 (IC 50 = 1.48 ± 0.08 µM) and 36 (IC 50 = 0.33 ± 0.06-6.38 ± 1.19 µM) presented excellent activities against A549, MCF-7, HCT-116, and PC-3 cancer cell lines compared to doxorubicin as standard drug. The sulfamoyl-substituted derivatives showed greater activity compared to sulfonylmethyl and un-substituted analogs, probably due to their resemblance to the celecoxib pharmacophore. These hybrid molecules were found to be more potent COX-2 inhibitors, compared to COX-1. These compounds also showed a substantial release of NO and a lower ulcer index than ibuprofen as the standard. ) also presented more prominent inhibition of the COX-2 enzyme than the standard drug, celecoxib (IC50 = 1.11 µM; SI = 6.61). The anticancer activity of these hybrids was related to COX-2 inhibition. Therefore, the introduction of the pyrazolone ring to benzoxazole or benzothiazole increased the activity, while 4-chlorobenzladehyde-substituted agents showed better activity [50].    Van der Waals and hydrophobic interactions were also observed [55].

Natural Product-Based Hybrid Molecules
Natural products have endured thus far and also have an optimistic future in terms of being the origin of active drug molecules [59]. Organic and medicinal chemists are drawing benefits from natural products despite the advent of new drug discovery approaches, such as high-throughput screening and combinatorial chemistry. The chemical scaffolds of natural products are used as lead compounds, and the derivatization of these products produces new compounds [60,61]. Ren and co-workers prepared hybrid molecules in which chrysin was attached to 1,5-diarylpyrazole derivatives. Chrysin was selected due to its wide range of activities. Derivative 47 ( Figure 10) demonstrated prominent anticancer activity against the Hela (IC 50 = 1.12 ± 0.62 µM) and MCF-7 (IC 50 = 3.23 ± 0.55 µM) cancer cell lines and manifested less toxicity for the normal cell line, 293T (IC 50 = 193.94 ± 2.85 µM). Derivative 47 also showed COX-2 (IC 50 = 2.23 µM, SI = 206.45) inhibitory activity by using celecoxib (IC 50 = 0.36 ± 0.05 µM; SI = 130.25) as standard. The introduction of electron-donating groups on the phenyl rings of pyrazole showed better results than the electron-withdrawing groups. Derivative 47 showed the phenomenon of apoptosis and achieved cell-cycle arrest in the G1 phase. Compound 47 interacted with COX-2 (docking = −83.77 kcal/mol) and the oxygen atoms of chrysin formed two hydrogen bonds with the Arg222 and His207 amino acids. Van der Waals interactions were also observed [62]. Shen and co-workers synthesized new hybrid molecules by combining pyrazole and coumarin to produce more potent and less toxic agents. The two pharmacophores were joined by using different linker groups to increase the polarity and flexibility. Upon its evaluation as an anticancer agent, 48 showed prominent activity against the A549 (IC 50 = 4.48 ± 0.57 µM) and Hela (IC 50 = 5.51 ± 1.28 µM) cancer cell lines, in comparison to the standard drug, celecoxib (IC 50 = 7.68 ± 0.55-11.06 ± 0.93 µM). Compound 48 carries the trimethoxy phenyl group at position 5 of pyrazole, which displayed extra hydrogen bonding with the target proteins. The longer linker group between pyrazole and coumarin may be the reason for its increased potency. Derivative 48 showed the process of apoptosis and blocked the cell cycle in the G2 phase. Compound 48 also showed the prominent inhibition of COX-2 (IC 50 = 0.23 ± 0.16 µM; SI = 230) and LOX (IC 50 = 0.87 ± 0.07 µM) enzymes, in comparison to celecoxib (IC 50 = 0.41 ± 0.28 µM; SI = 88). Docking studies of 48 with the COX-2 enzyme showed that it interacted (score = −64.387 kcal/mol) with Trp387, His386, Tyr385, and Thr212. Therefore, the introduction of the coumarin ring to the pyrazole scaffold enhanced the anticancer activity of the resulting derivatives [63]. El-Miligy and co-workers synthesized thymol-4-thiazolidinone hybrid molecules, in which the pharmacophoric features of the COX-2 inhibitor, 5-LOX, and PIM-1 (proviral integration Moloney) kinase, were combined. Compound 49 showed the process of apoptosis in the Caco-2 (66.38 ± 0.83%) and HCT-116 (65.27 ± 0.38%) cancer cell lines. Compound 49 (72.33 ± 4.54%) also showed antiinflammatory activity compared to diclofenac (52.53 ± 4.59%) and also appeared to be the most potent inhibitor (IC 50 = 0.091 ± 0.0016 µM; SI= 103) of the COX-2 enzyme, compared to standard celecoxib (IC 50 = 0.045 ± 0.79 µM, SI = 327). Compound 49 carries the ethanoic acid group at position 5 of the thiazolidinone ring. Compound 49 also showed the inhibition of PIM-1 (IC 50 = 2.96 ± 0.12 µM) and PIM-2 (IC 50 = 1.38 ± 0.05 µM) kinases, compared to the standard drug staurosporine (IC 50 = 1.34 ± 0.15 µM; IC 50 = 0.662 ± 0.02 µM). Compound 49 expressed (docking score = −8.09 kcal/mol) hydrophobic interactions (Val355, Leu517, Trp373, Met508, and Val509) as well as hydrogen bonding (Arg499, His75, Tyr371, Gln178, and Gly512) with COX-2 [64].

Derivatives of Natural Compounds
Marine-derived natural products show excellent biological activities; the structural modification of marine-derived compounds can enhance the pharmacological activities of the lead compound [65][66][67]. Chen et al. synthesized sclerotiorin derivatives in which the pyran ring was modified to produce amine derivatives. The amino group was attached to various acyclic, alicyclic, and heterocyclic scaffolds. Derivatives 50-54 ( Figure 11) showed prominent anticancer activity versus the A549 cancer cell line, presenting IC 50 values in the range of 6.39-9.08 µM. Compounds 51, 53, and 54 also showed prominent COX-2 inhibitory activities, ranging from 46.7% to 58.7%. Therefore, an association was observed between COX-2 inhibitory activity and cytotoxicity. Derivative 55 presented excellent inhibition of COX-2 (66.1%) and showed no cytotoxicity. Compound 55 should be further investigated as an anti-inflammatory agent. The docking interaction of 50 with COX-2 revealed that the ester linkage interacted with Gln92, while the hydrophilic groups showed hydrogen bonding with COX-2. The alkyl chains and cyclohexene showed hydrophobic interactions [68]. El-Naggar et al. synthesized new ricinin derivatives and evaluated their activity against oral cell carcinoma. Compound 56 showed excellent cytotoxicity (69.22% inhibition; IC 50 = 90 µM) in comparison to the standard drug, fluorouracil (100%). Compound 56 possesses a biphenyl group that is linked to the ricinin scaffold. Derivative 56 showed docking scores of −7.8 kcal/mol and −7.6 kcal/mol with protein tyrosine phosphatase (PTP1B) and COX-2, respectively. In terms of interactions with PTP1B, hydrophobic interaction was observed with Phe182. Derivative 57 showed the highest docking score of −8.5 with the COX-2 enzyme. The carbonyl group of compound 56 is hydrogen-bonded with the Tyr385 of COX-2. These derivatives were found to be non-toxic for normal cells. Therefore, it was concluded that compound 56 presented anticancer activity by the inhibition of COX-2 and PTP1B [69].

Quinoline Derivatives
Manohar and co-workers synthesized new quinoline acetohydrazide and hydrazone derivatives as anticancer agents while using a drug repurposing strategy [71].

Quinoline Derivatives
Manohar and co-workers synthesized new quinoline acetohydrazide and hydrazone derivatives as anticancer agents while using a drug repurposing strategy [71]. Derivatives 60 (IC 50 = 2.416 µM), 61 (IC 50 = 2.071 µM) and 62 (IC 50 = 2.224 µM) exhibited excellent anticancer activity against the MCF-7 cancer cell line, compared to doxorubicin (IC 50 = 2.444 µM). Derivatives 61 (IC 50 = 0.13 µM) and 62 (IC 50 = 0.14 µM) presented the prominent inhibition of the COX-2 enzyme, compared to the standard drug (IC 50 = 0.38 µM). Derivatives with a trifluoromethyl substituent showed excellent activities. Molecular docking studies revealed that the amino (NH) group, methoxy (OCH 3 ), and the nitrogen atom of quinoline interact with the COX-2 enzyme through hydrogen bonding [72]. Compounds 61 and 62 ( Figure 13) also followed the Lipinski rule of five, except for some violations [36]. Pallavi et al. synthesized quinoline glycoconjugates, based on the activity of quinoline and its glycoconjugates. Compound 63 produced a maximum cytotoxic effect (53% inhibition) against the Hela cancer cell line. Derivative 63 also followed the pattern of concentration-dependent killing. Compounds 63 (80%) and 64 (83%) showed prominent COX-2 inhibitory activities. A molecular docking investigation with 4DEP presented docking scores of −6.1 and −5.6 kcal/mol. The carbonyl group of quinoline carboxylic acid and the carbonyl group of sugar molecules exhibited intermolecular interactions. In the case of 63, the oxygen of the amide group exhibited hydrogen bond interactions with Trp50 and Lys74. The NH group of amides interacted with the Trp50 of interleukin 1β (IL-1β) [73].

Quinazolinone Derivatives
Sakr and co-workers synthesized new quinazolinone analogs, in which quinazolinone was attached to ibuprofen, indole acetamide and thioacetohydrazide scaffolds ( Figure 14

Quinazolinone Derivatives
Sakr and co-workers synthesized new quinazolinone analogs, in which quinazolinone was attached to ibuprofen, indole acetamide and thioacetohydrazide scaffolds ( Figure 14). Compounds 65 (IC 50 = 15.42 ± 0.06 µM), and 66 (IC 50 = 13.42 ± 0.17 µM) showed accept-able anticancer activities versus the HT-29 cell line. Compounds 65 (IC 50 = 0.04 ± 0.08 µM), 66 (IC 50 = 0.07 ± 0.22 µM) and 67 (IC 50 = 0.037 ± 0.20 µM) also demonstrated prominent COX-2 inhibitory activities compared to standard celecoxib (IC 50 = 0.04 ± 0.20 µM). Analogs 66 (49.47%) and 67 (45.37%) also displayed noticeable in vivo anti-inflammatory potential that was comparable to ibuprofen (47.18%) and celecoxib. Derivative 65 has an indole ring in its structure and the aromatic ring is attached to a chlorine atom at the para position. Compound 65 formed a hydrogen bond with Ala527, while compound 67 formed two hydrogen bonds with the Arg120 and Val523 of COX-2. These molecules have acceptable physicochemical properties, which are within the limits of the Lipinski rule of five [74]. El-Sayed and co-workers synthesized new Schiff bases of quinoxaline and quinazoline-4-one with aromatic and heteroaromatic aldehydes. Compound 68 demonstrated anticancer activity toward HCT-116 and the LoVo cell line, presenting IC 50 values of 217 µM and 277 µM, respectively. Compound 68 was found to be non-toxic for the normal cell line. Derivatives 68-70 showed prominent suppression (> 80%) of the COX-2 enzyme. Derivative 68 showed hydrogen bonding with the Tyr355 and Arg120 of COX-2 through the oxygen and nitrogen of the aminoquinazoline scaffold. Furthermore, π-π interactions were observed with Tyr355 through the methoxyphenyl ring. The azomethine (CH = N) linkage was involved in hydrogen bonding with Arg120. The methoxy group of quinazolinone presented hydrophobic interactions with Met522. Compounds with a methoxy group and a chlorine atom attached to the quinazolinone core showed prominent activity. Structure 68 showed favorable pharmacokinetic properties, such as absorption, distribution, metabolism, and excretion, which makes it the leading compound for future modifications [75]. properties, such as absorption, distribution, metabolism, and excretion, which makes it the leading compound for future modifications [75].    Figure 15) showed anticancer activity toward the glioma cell line (T98) and also showed apoptosis by 11% and 12% at doses of 50 µM and 100 µM. Structure 71 also showed an interaction with the COX-2 enzyme in a similar way to indomethacin. The increased activity of 71 was correlated to the introduction of the 4-methyl group, which has +π and −δ effects. In the molecular docking interactions, 71 showed a similar binding interaction with COX-2 as with indomethacin, involving the amino acids His90, Arg120, Leu352, Tyr355, and Tyr385. Structure 71 also decreased the COX-2 mRNA level [76]. Kumari and co-workers synthesized the c-glycosides of indole by using isoxazole and pyrazoline as linker groups. The carbohydrate molecule was introduced to incorporate stereochemical diversity in these molecules. Upon evaluation of anticancer activity, analogs 72 (IC 50  Compound 74 also presented apoptosis via mitochondrial depolarization. The cytotoxic effect was related to COX-2 inhibitory activity. In molecular docking investigations, 74 exhibited interactions with the COX-2 active site and interacted with the His90, Arg120, Gln192, and Tyr355 amino acids [78].

Pyrrolizines as Anticancer and COX-2 Inhibitors
Pyrrolizine is a promising scaffold and has displayed both anticancer and antiinflammatory activities. Pyrrolizine is being considered in the context of new drug design, due to its multiple pharmacological activities [81,82]. In 2017, Gouda and co-workers synthesized pyrrolizines-5-carboxamide in a continuation of the structure-activity relationship studies of licofelone. Into these analogs, thiophene and naphthalene rings were introduced. Derivative 78 (Figure 17

Pyrrolizines as Anticancer and COX-2 Inhibitors
Pyrrolizine is a promising scaffold and has displayed both anticancer and anti-inflammatory activities. Pyrrolizine is being considered in the context of new drug design, due to its multiple pharmacological activities [81,82]. In 2017, Gouda and co-workers synthesized pyrrolizines-5-carboxamide in a continuation of the structure-activity relationship studies of licofelone. Into these analogs, thiophene and naphthalene rings were introduced. Derivative 78 ( Figure 17) presented prominent activity toward the MCF-7 cell line (IC 50 = 4.72 µM). This derivative is attached to the para-chloro-substituted aromatic ring. Compound 79 was most active toward the A549 (IC 50 = 3.24 ± 0.3 µM) and Hep3B (IC 50 = 8.69 ± 0.4 µM) cancer cell lines. Compounds 79 (IC 50 = 0.11 µM) and 77 (IC 50 = 0.36 µM) also achieved better inhibition of COX-2 than COX-1. Compound 79 showed hydrogen bonding with the Tyr355, Arg120, and Phe518 of COX-2. The naphthyl ring showed hydrophobic interactions with Leu352 and Trp387. The 4-tolyl also formed hydrophobic interactions. The pyrrolizine formed π-cationic interactions with Arg513. Compound 79 also showed the inhibition (7-12%) of various kinases, such as BRAF, MSK1, PDK1, and EGFR. A cell cycle and apoptotic assay showed that 79 is accumulated in the S phase and also showed the phenomenon of apoptosis [83]. In 2019, Attalah and coworkers carried out further modifications of the pyrrolizine-indolizine scaffold, in which ethyl benzoate esters were introduced. The structural features of licofelone and ketorolac were combined to produce new derivatives. The anticancer activity was evaluated via an MTT assay. Derivatives 80 (IC 50   showed that it is involved in interactions with telomerase, COX-2, and cyclin-dependent kinase (CDK). This compound was found to be non-toxic for the normal VERO cell line. Derivative 87 is the trihydroxyxanthone derivative. Compound 87 showed interactions with the Arg120, Tyr355, and Tyr385 of COX-2. An equation was developed from the QSAR calculations, in which the logP and dipole moment values were positive, indicating the significance of these parameters [87]. Kavalisukas and co-workers synthesized 1,4-naphthoquinone derivatives into which aromatic rings were introduced. Compounds 88 (IC 50  The attachment of the phenylamino ring at position 3 of naphthoquinone was significant for anticancer activity. The addition of substituents, i.e., F, Cl, Br, and OC 2 H 5 groups in the phenylamino ring further decreased the activity. Compound 88 also exhibited excellent pharmacokinetic properties and followed the Lipinski rule of five. Compound 88 presented a binding energy of −9.4 kcal/mol and interacted with COX-2 via hydrogen bonding, van der Waal interactions, and π-sulfur interactions [88]. Rai and co-workers evaluated the in vivo anticancer activities of the 1,4-benzothiazine hydrazone derivatives in dimethylhydrazine (DMH)-induced cancer models. Compounds 90 and 91 produced anticancer effects via inhibiting COX-2-induced JAK-2 and STAT-3 phosphorylation. These derivatives showed no toxicity at a 25 mg/kg bodyweight dose. Derivatives 90 and 91 showed protective effects and reduced elevated levels of the hepatic enzymes AST, ALT, LDH, and ALP. These derivatives restored the glutathione concentration in the body and also reduced the level of COX-2 enzymes at a 25 mg/kg bodyweight dose. Overall, these agents demonstrated prominent anticancer activity in inhibiting CRC and are excellent candidates for future investigations [89].

Miscellaneous Fused Heterocyclic Rings
Condensed heterocyclic rings containing nitrogen or sulfur as heteroatoms are very important and are commonly used in the synthesis of biologically active molecules. Razik and co-workers synthesized pyrazolo [3,4-d]pyrimidine analogs as the bio-isosteres of the purine nucleus, in which the imidazole ring of purines was replaced by the pyrazole ring. The pyrazole ring was added to increase the level of COX-2 inhibitory activity. The pyrazolo [3,4-d]pyrimidine nucleus was attached to various substituted phenyl piperazine rings, through amide linkers. The anticancer activity was evaluated by the WST-1 assay. Derivative 92 (Figure 19) was found to be the most active (IC 50  ) also presented prominent activity as a COX-2 inhibitor. The selectivity of these agents for the COX-2 enzyme was due to the larger pocket of COX-2 than COX-1; the presence of a sulfonylmethyl group was vital for the potency of these derivatives. A correlation was found between the anticancer and COX-2 inhibitory activities of these derivatives. Compound 96 is involved in interactions with the His90, Arg120, Tyr355, and Arg513 of COX-2. The capacity of the COX-2 inhibitor to counteract platelet aggregation is regarded as a prophylactic action to reduce the side effects of CVS. Derivatives 95 (80.74%) and 96 (78.02%) also showed the inhibition of platelet aggregation [92]. Kirwen et al. synthesized 2,3-diaryl-substituted imidazo [4,5b]pyridine derivatives. Upon the evaluation of anticancer activity via an MTT assay, these derivatives displayed mild activity toward MCF-7, MDA-MB-231, SaoS-2, and k-562. This prominent activity was displayed against the k-562 cancer cell line, with IC 50 values ranging from 42-57 µmol/L. Compound 97 showed the prominent obstruction of COX-2 and displayed an IC 50 value of 9.2 ± 0.02 µmol/L. In the molecular docking investigation of 97 against COX-2, the n-phenyl ring, imidazo [4,5b]pyridine, and the chlorine atom of the phenyl ring interacted with the COX-2 enzyme [93].  anticancer effects via inhibiting COX-2-induced JAK-2 and STAT-3 phosphorylation. These derivatives showed no toxicity at a 25 mg/kg bodyweight dose. Derivatives 90 and 91 showed protective effects and reduced elevated levels of the hepatic enzymes AST, ALT, LDH, and ALP. These derivatives restored the glutathione concentration in the body and also reduced the level of COX-2 enzymes at a 25 mg/kg bodyweight dose. Overall, these agents demonstrated prominent anticancer activity in inhibiting CRC and are excellent candidates for future investigations [89]. Figure 18. Xanthone, naphthoquinone, and benzothiazine derivatives.

Miscellaneous Fused Heterocyclic Rings
Condensed heterocyclic rings containing nitrogen or sulfur as heteroatoms are very important and are commonly used in the synthesis of biologically active molecules. Razik and co-workers synthesized pyrazolo [3,4-d]pyrimidine analogs as the bio-isosteres of the purine nucleus, in which the imidazole ring of purines was replaced by the pyrazole ring. The pyrazole ring was added to increase the level of COX-2 inhibitory activity. The pyrazolo [3,4-d]pyrimidine nucleus was attached to various substituted phenyl piperazine rings, through amide linkers. The anticancer activity was evaluated by the WST-1 assay.

Heterocyclic Compounds as Anticancer and COX-2 Inhibitors
Heterocyclic compounds are extensively utilized in drug design and synthesis, owing to their broad range of pharmacological activities [94]. There are many known heterocyclic compounds, and new heterocyclic compounds are also being discovered, due Figure 19. Xanthone, naphthoquinone, and benzothiazine derivatives.

Heterocyclic Compounds as Anticancer and COX-2 Inhibitors
Heterocyclic compounds are extensively utilized in drug design and synthesis, owing to their broad range of pharmacological activities [94]. There are many known heterocyclic compounds, and new heterocyclic compounds are also being discovered, due to ongoing research in synthetic chemistry. The presence of the methoxy group in aromatic aldehyde showed selectivity for the COX-2 enzyme. In the molecular mode of action, these derivatives interacted mainly with the His90 of COX-2 via the N atom of benzoxazole/benzothiazole [95]. Cai et al. reported hybrid molecules in which caffeic acid was linked with a COX-2 inhibitor diaryl-1,2,4-triazole by using ester and amide linkages. Hybrid molecules with an amide linkage were found to be important COX-2 blockers, while the ester analogs displayed prominent anticancer activity. Compound 103 was found to be the most active anticancer agent against Caco-2, A549, B16-F10, and the prostate (PC-3) cancer cell lines (IC 50 = 6.78 ± 0.21 µM to 9.05 ± 0.07 µM), compared to the standard drug cis-diaminplatinum dichloride (IC 50 = 6.93 ± 0.01 µM to 9.71 ± 0.11 µM). Compound 103 displayed better COX-2 (IC 50 = 0.21 ± 0.05 µM) inhibition than COX-1 (IC 50 = 20.5 ± 1.52 µM). In 103, the methylsulfonyl group also showed hydrogen bonding with His89 and Arg513. The trifluoromethyl-substituted phenyl group exhibited hydrophobic interactions with Phe518, Trp387 and Leu352. The attachment of electron-withdrawing groups at the N-1 of triazole resulted in the formation of potent anticancer and COX-2 agents. Compound 103 also showed in vivo anticancer activity (58.9% inhibition) in a mouse model, with BF-16-F10 melanoma at a dose of 40 mg/kg of body weight [25].

Thiadiazole and Cyclopentole Derivatives
Raj and co-workers evaluated the anticancer activity of 1,3,4-thiadiazole-derived compounds (121 and 122, Figure 24) in a dimethylhydrazine (DMH)-induced colorectal cancer model and investigated the mode of action at the molecular level. These compounds corrected the DMH-induced biological parameters, such as body weight, tumor volume, etc., and also restored the hepatic enzymes, such as AST, ALT, ALP, and LDH, in serum. These derivatives also reinstated the elevated levels of COX-2, Il-2, and IL-6 to normal levels. The molecular mode of action studies showed that these compounds inhibited the COX-2-and IL-6-mediated JAK-2 and STAT-3. The in vitro results were also confirmed by the in vivo results and these agents were found to be safe at a dose of 25 mg/kg body weight [103]. El-Husseiny and coworkers synthesized 2-cyclopentole oxyanisole-derivative compounds. Analogs 124 (IC50 = 1.08 µM) and 125 (IC50 = 1.88 µM) showed prominent COX-2 inhibitory activity compared to the standard drug, celecoxib (IC50 = 0.38 µM). Compounds 123 and 125 showed more prominent anticancer activity (IC50 = 4.38 ± 0.4 µM-11.45 ± 1.1 µM) versus the MCF-7, HepG2, PC-3, HCT-116, and Hela cancer cell lines than with the standard drug, doxorubicin (IC50 = 5.4 ± 0.25-11.4 ± 1.26 µM). Therefore, the replacement of cycloalkanone with piperidone increased the anticancer activity. Similarly, the piperidine derivatives showed greater activity, as

Thiadiazole and Cyclopentole Derivatives
Raj and co-workers evaluated the anticancer activity of 1,3,4-thiadiazole-derived compounds (121 and 122, Figure 24) in a dimethylhydrazine (DMH)-induced colorectal cancer model and investigated the mode of action at the molecular level. These compounds corrected the DMH-induced biological parameters, such as body weight, tumor volume, etc., and also restored the hepatic enzymes, such as AST, ALT, ALP, and LDH, in serum. These derivatives also reinstated the elevated levels of COX-2, Il-2, and IL-6 to normal levels. The molecular mode of action studies showed that these compounds inhibited the COX-2-and IL-6-mediated JAK-2 and STAT-3. The in vitro results were also confirmed by the in vivo results and these agents were found to be safe at a dose of 25 mg/kg body weight [103]. El-Husseiny and coworkers synthesized 2-cyclopentole oxyanisole-derivative compounds. Analogs 124 (IC 50 = 1.08 µM) and 125 (IC 50 = 1.88 µM) showed prominent COX-2 inhibitory activity compared to the standard drug, celecoxib (IC 50 = 0.38 µM). Compounds 123 and 125 showed more prominent anticancer activity (IC 50 = 4.38 ± 0.4 µM-11.45 ± 1.1 µM) versus the MCF-7, HepG2, PC-3, HCT-116, and Hela cancer cell lines than with the standard drug, doxorubicin (IC 50 = 5.4 ± 0.25-11.4 ± 1.26 µM). Therefore, the replacement of cycloalkanone with piperidone increased the anticancer activity. Similarly, the piperidine derivatives showed greater activity, as compared to the pyridine derivatives. Compounds 123 (IC 50 = 5.62 µM) and 125 (IC 50 = 3.98 µM) also inhibited the PDEB enzyme upon in vitro evaluation. The docking interactions of compounds 124 and 125 revealed that the piperidione fragment interacted with Arg513, His90, Leu352, and Gln192. The carbonyl group of piperidione showed hydrogen bond interactions with the hydroxyl group of Tyr355 and, similarly, other hydrogen bonds were also observed. The methylene (CH 2 ) groups of piperidone, cyclopentyl, and methoxy groups also showed hydrogen bonding. In the case of 125, the nitrile group formed hydrogen bonding with Tyr355 and Arg120. The 4-oxopyrimidine ring showed hydrogen bonding interactions with His90 and Arg513. The methoxy group interacted with Tyr348 by means of hydrophobic interactions [104].

Derivatives of NSAIDs as Anticancer and COX-2 Inhibitors
NSAIDs have also received the attention of medicinal chemists in order to produce new anticancer agents [105][106][107]. Selected COX-2 inhibitors, celecoxib and rofecoxib, showed anticancer potential and, therefore, stimulated further research into NSAIDs [108,109]. Drug repositioning is a technique in which old drugs are tested against new targets rather than synthesizing new ones [110]. The chemical scaffold of NSAIDs, such as indomethacin, celecoxib, rofecoxib, naproxen, and ketoprofen have been modified to produce new analogs. El-Azab and co-workers synthesized thiocarboxylic acid derivatives of NSAIDs as anticancer agents. These derivatives were also evaluated for their COX-1/COX-2 and kinase inhibitory activities.

Derivatives of NSAIDs as Anticancer and COX-2 Inhibitors
NSAIDs have also received the attention of medicinal chemists in order to produce new anticancer agents [105][106][107]. Selected COX-2 inhibitors, celecoxib and rofecoxib, showed anticancer potential and, therefore, stimulated further research into NSAIDs [108,109]. Drug repositioning is a technique in which old drugs are tested against new targets rather than synthesizing new ones [110]. The chemical scaffold of NSAIDs, such as indomethacin, celecoxib, rofecoxib, naproxen, and ketoprofen have been modified to produce new analogs. El-Azab and co-workers synthesized thiocarboxylic acid derivatives of NSAIDs as anticancer agents. These derivatives were also evaluated for their COX-1/COX-2 and kinase inhibitory activities. 127 showed hydrogen bonding with Tyr355, electrostatic interaction with Met535, and pi-cationic interaction with Arg513 of COX-2. In the kinase inhibitory activity assay, these derivatives presented very little in the way of inhibitory activities against EGFR, HER2, HER4, and cSrc [111]. Coskun and co-workers synthesized new diflunisal derivatives in which the carboxylic group was converted into thiosemicarbazide and 1, 2, 4-triazole-3-thione. Compounds 128 (IC 50 = 11.7 ± 2.6 µM), 129 (IC 50 = 43.4 ± 2.72 µM), and 130 (IC 50 = 6.2 ± 3.1 µM) presented prominent anticancer activities against PC-3, T-47D and HCT-166 cancer cell lines, respectively, compared to cisplatin (IC 50 = 0.836-1.25 µM). Compounds including triazole presented prominent activities; the methoxy-substituted compounds proved more active against the T-47D cell line. The thiosemicarbazide functional group showed greater activity against the PC-3 cell line. Fluorine-substituted derivatives were found to be most active, while the substitution of fluorine by chlorine or bromine atoms produced less active derivatives. Derivatives 129 (binding score = −10.57 kcal/mol) and 130 (binding score = −9.60 kcal/mol) presented excellent binding affinities with the COX-2 enzyme by means of hydrophobic interactions (Phe518, Trp387, Tyr385, Tyr348, Phe381, Phe205), hydrogen bonding (Ser530, Tyr355, Glu198, His90), and π-sulfur interactions (Met522) [112]. In the kinase inhibitory activity assay, these derivatives presented very little in the way of inhibitory activities against EGFR, HER2, HER4, and cSrc [111]. Coskun and co-workers synthesized new diflunisal derivatives in which the carboxylic group was converted into thiosemicarbazide and 1, 2, 4-triazole-3-thione. Compounds 128 (IC50 = 11.7 ± 2.  El-Husseiny and co-workers synthesized new non-carboxylic acid derivatives of naproxen, in which the carboxylic group was converted into cyclic imides, triazole, oxadiazole, and cycloalkane scaffolds.  . Compounds 133 and 134 carry the arylidene ring and 132 is the oxadiazole derivative. The attachment of the 4-hydroxyphenyl group with oxadiazole produced the COX-2 active derivative. Derivative 134 showed selectivity for COX-2 and presented hydrogen bonding interactions with Ile517 and Gln192 through the hydroxyl group. The methoxy group interacts with Ser530 and Tyr385, while the 4-amino-1,2,4-triazole-5-thione forms hydrogen bonds with Tyr355 and Arg513 [113].  El-Sayyed et al. synthesized new naproxen derivatives in which heterocyclic rings, such as pyridine, pyrazole, pyrazoline, and pyrazolopyridazine were attached to the 6methoxy naphthalene scaffold. Compounds 135 and 136 ( Figure 27) showed 64.6% and 82.6% growth inhibitions, respectively, against non-small cell lung cancers (NCI-H522). Compounds 135 and 136 carry the pyrazole ring attached to the naphthalene, through the carbonyl group. Compound 137 was highly selective toward the MCF-7 cancer cell line, showing 60.9% inhibition. Derivative 137 showed an equal inhibition of COX-1 and COX-2, while 138 showed some selectivity for COX-2. Compound 138 is the hybrid of naproxen with pyrazoline. Therefore, the introduction of pyrazole and pyrazoline rings into the naphthalene scaffold produced interesting activities. In molecular docking investigations with COX-2, 137 mainly showed hydrophobic interactions with the side chains of Val102, Leu517, and Val335, while 138 showed hydrophobic interactions with Leu345, Leu517, and Val509 [114]. Mareedy and co-workers synthesized the nimesulide-1, 2, 3-triazole hybrid molecules. The click chemistry technique was used, in which the nitro group was reduced to the amino group, then into azide, and finally into the triazole molecule.  Compound 138 is the hybrid of naproxen with pyrazoline. Therefore, the introduction of pyrazole and pyrazoline rings into the naphthalene scaffold produced interesting activities. In molecular docking investigations with COX-2, 137 mainly showed hydrophobic interactions with the side chains of Val102, Leu517, and Val335, while 138 showed hydrophobic interactions with Leu345, Leu517, and Val509 [114]. Mareedy and co-workers synthesized the nimesulide-1, 2, 3-triazole hybrid molecules. The click chemistry technique was used, in which the nitro group was reduced to the amino group, then into azide, and finally into the triazole molecule. Compounds 139 (IC 50 = 6.44 ± 0.31 µM against DU-145), 140 (IC 50 = 5.9 ± 0.15 µM against DU-145), and 141 (IC 50 = 6.6 ± 0.23 µM against A549) showed prominent anticancer activities against different cancer cell lines. PDE4 has emerged as a new target for anticancer drugs and the docking studies of these compounds with PDE4 showed better scores (−87.42-−94.65 kcal/mol) than nimesulide. In the case of 140, the NH group of methane sulfonamide presented hydrogen bonding with the Asp346 and Ser442 of the PDE4 enzyme. Therefore, it was assumed that the compound's anticancer activities are due to its interaction with these proteins [115]. PDE4 enzyme. Therefore, it was assumed that the compound's anticancer activities are due to its interaction with these proteins [115]. Celik and co-workers synthesized a new ionic liquid by reacting caprolactam with salicylic acid (CL-SA). In the structure determination, two hydrogen bonds were observed between salicylic acid and caprolactam. The dipole moment of compound 142 ( Figure 28) was found to be 5.012D, showing its ionic environment. The molecules were evaluated for interaction with COX-2 and DNA Top-II enzymes, via molecular docking. The binding energy of 142 was found to be −8.6 kcal/mol with DNA. The carbonyl group of caprolactam and the hydroxyl group of salicylic acid are involved in hydrogen bonding. Similarly, the docking interactions of 142 with COX-2 yield a binding energy of −8.4 kcal/mol and showed hydrogen bonding with His388. Alkyl and π-alkyl interactions were also observed with Ala202, Val295, and Leu391. The binding energy of this compound with the Top-II enzyme was found to be −7.9 kcal/mol. The evaluation of the SA-CL pharmacokinetic properties and toxicities showed drug-like properties [116]. Punganuru et al. synthesized combretastatin and rofecoxib hybrid molecules, in which the olefinic linkage of combretastatin was replaced with rigid and stable structures. Analog 143, the new hybrid molecule, showed excellent anticancer activity against the HT-29 (IC50 = 258 ± 110 nM) and HCT-116 (IC50 = 302 ± 116 nM) cancer cell lines. The structure of the new molecule preserved the cis configuration of combretastatin, due to the presence of a heterocyclic furanone ring, and prevented its conversion into the trans form. This conversion was unsuitable in combretastatin because the trans form was inactive. Compound 143 showed a comparable docking score (−7.87 kcal/mol) with COX-2 and the standard drug, rofecoxib (−8.39 kcal/mol). Compound 143 also presented in vivo anticancer activity in mice infected with the HT-29 cancer cell line and showed the reduction of COX-2 levels. The analog 143 also showed the phenomenon of apoptosis and increased the concentration of the apoptotic proteins, BAX and PUMA. In the molecular docking interaction with COX-2, the furan ring interacted with Val349, Ala527, Leu531, and Arg120. The oxygen atom of the furyl ring showed hydrogen bonding with the Celik and co-workers synthesized a new ionic liquid by reacting caprolactam with salicylic acid (CL-SA). In the structure determination, two hydrogen bonds were observed between salicylic acid and caprolactam. The dipole moment of compound 142 ( Figure 28) was found to be 5.012D, showing its ionic environment. The molecules were evaluated for interaction with COX-2 and DNA Top-II enzymes, via molecular docking. The binding energy of 142 was found to be −8.6 kcal/mol with DNA. The carbonyl group of caprolactam and the hydroxyl group of salicylic acid are involved in hydrogen bonding. Similarly, the docking interactions of 142 with COX-2 yield a binding energy of −8.4 kcal/mol and showed hydrogen bonding with His388. Alkyl and π-alkyl interactions were also observed with Ala202, Val295, and Leu391. The binding energy of this compound with the Top-II enzyme was found to be −7.9 kcal/mol. The evaluation of the SA-CL pharmacokinetic properties and toxicities showed drug-like properties [116]. Punganuru et al. synthesized combretastatin and rofecoxib hybrid molecules, in which the olefinic linkage of combretastatin was replaced with rigid and stable structures. Analog 143, the new hybrid molecule, showed excellent anticancer activity against the HT-29 (IC 50 = 258 ± 110 nM) and HCT-116 (IC 50 = 302 ± 116 nM) cancer cell lines. The structure of the new molecule preserved the cis configuration of combretastatin, due to the presence of a heterocyclic furanone ring, and prevented its conversion into the trans form. This conversion was unsuitable in combretastatin because the trans form was inactive. Compound 143 showed a comparable docking score (−7.87 kcal/mol) with COX-2 and the standard drug, rofecoxib (−8.39 kcal/mol). Compound 143 also presented in vivo anticancer activity in mice infected with the HT-29 cancer cell line and showed the reduction of COX-2 levels. The analog 143 also showed the phenomenon of apoptosis and increased the concentration of the apoptotic proteins, BAX and PUMA. In the molecular docking interaction with COX-2, the furan ring interacted with Val349, Ala527, Leu531, and Arg120. The oxygen atom of the furyl ring showed hydrogen bonding with the Arg120 of COX-2. The iodine atom of methoxy phenyl showed electrostatic interaction with the hydroxyl group of Ser530. The second aryl ring is involved in π-π interaction with Tyr355. Compound 143 can be useful in treating cancer [117]. Similarly, the modification of one or more hydroxyl groups into methoxy groups produced active compounds. However, the exchange of the hydroxyl group with the methoxy group decreased the selectivity for COX-2 enzymes. The nitro group interacted with the Met522 of COX-2 by means of a sulfur-oxygen interaction and the hydroxyl group exhibited hydrogen bonding with Tyr355. Hydrophobic and pi-cationic interactions were also observed [125].

Hydrazone Derivatives
Senkarde and co-workers synthesized sulfonyl hydrazone derivatives as anticancer agents. Compound 149 showed prominent activity against the PC-3 (IC50 = 1.38 µM; SI = 432.30) cancer line, in comparison to cisplatin (IC50 = 3.3 µM, 22.2 µM) and showed selectivity for this cell line. The analog 149 exhibited excellent inhibition of COX-2 (91%) as compared to the COX-1 enzyme and showed the process of apoptosis. This compound carries a 2-chloro-3-methoxy phenyl group attached to the hydrazone linkage. In the molecular mode of action, the sulfonyl group of 149 presented hydrogen bonding with Tyr341 and Ser339 of COX-2. The hydrazine group showed hydrogen bond interaction

Metal Complexes as Anticancer Agents and COX-2 Inhibitors
Platinum-containing drugs, such as cisplatin and carboplatin, have been used as anticancer agents but produce severe adverse effects [118]. Currently, metals other than platinum are also being investigated as anticancer and COX-2 inhibitor agents [119]. Obermoser and co-workers synthesized new chlorine-substituted acetylsalicylic acid derivatives, in which cobalt carbonyl complexes were introduced via the alkyne bridge. The introduction of a chlorine atom at the aromatic ring reduced the activity against the COX-1 enzyme and increased the activity against COX-2. The 4-Cl chlorine complex, 144, showed prominent activity against the HT-29 (IC 50 = 1.51 ± 0.12 µM) and MDA-MB-231 (IC 50 = 5.24 ± 0.33 µM) cancer cell lines, in comparison to cisplatin (IC 50 = 3.52 ± 0.48 µM-3.57 ± 1.06 µM). Compound 144 also showed superior inhibition of COX-2 (69.9 ± 2.7%), compared to COX-1 (22.9 ± 1.7%). These complexes showed selectivity for cancer cells and were inactive against the non-cancerous cell line. These derivatives showed the process of apoptosis and demonstrated high penetration in the HT-29 cancer cell line, but there was less uptake in the MCF-7 and MDA-MB-231 cancer cell lines [120]. One year later, the same research group prepared cobalt-acetyl salicylic acid complexes, in which the fluorine atom was introduced at positions 3, 4, 5, and 6 in the aromatic ring to produce different derivatives. Compound 145 exhibited activity against the HT-29 and MDA-MB-231 cell lines, presenting IC 50 values of 1.73 µM and 5.33 µM, respectively, upon evaluation via a crystal violet assay. Although these derivatives showed the inhibition of COX-2, they were nonselective for this enzyme [121]. The cobalt-alkyne acetylsalicylic acid complex served as the lead compound for further modifications and methyl-substituted derivatives were synthesized. These derivatives expressed better inhibition of COX-2, compared to COX-1. Compound 146 emerged as the most active anticancer agent against the HT-29 (IC 50 = 1.25 ± 0.14 µM) cell line and also showed noticeable COX-2 (58.8 ± 9.8%) inhibition [122]. Zeise salt is a potassium trichlorido[ethylene]palatinate organometallic complex and has shown the capacity to inhibit the COX enzyme [123]. Weninger et al. synthesized the Zeise salt derivatives of acetylsalicylic acid, in which the two units were linked together using the alkyl linker groups. These derivatives (147 a-d) showed mild anticancer activity (IC 50 = 30.1 µM->50 µM) against the MCF-7 and HT-29 cancer cell lines. However, these derivatives presented the dominant inhibition of COX-1 and COX-2, selectivity was not achieved [124].

Stilbene Derivatives
Regulski et al. reported new trans-stilbene derivatives, along with their anticancer activity. Upon evaluation by an MTT assay, 148 ( Figure 29) displayed prominent activity against the MCF-7 cell line. Derivative 148 also showed excellent inhibition of the COX-2 enzyme (IC 50 = 0.09 µM; SI = 62.81), compared to the standard drug, celecoxib (IC 50 = 0.11 µM; SI = 132.97). The presence of the nitro group was vital for the anticancer activity and the replacement of the nitro group by a chlorine atom produced less active derivatives. Similarly, the modification of one or more hydroxyl groups into methoxy groups produced active compounds. However, the exchange of the hydroxyl group with the methoxy group decreased the selectivity for COX-2 enzymes. The nitro group interacted with the Met522 of COX-2 by means of a sulfur-oxygen interaction and the hydroxyl group exhibited hydrogen bonding with Tyr355. Hydrophobic and pi-cationic interactions were also observed [125]. showed prominent anticancer activity against renal cell adenocarcinoma (769-P) and HepG2 cancer cell lines. The chlorine and nitro-substituted agents showed greater activity. Compound 151 is the nitro-substituted agent and showed excellent activity against the HepG2 cancer cell line. These derivatives showed low toxicity for the normal cell line. The derivative 153 presented slight inhibition of COX-2 (9.78%) and carries an indole ring attached through the aromatic linker that is important for its activity [127].

Peptides as COX-2 Inhibitors
Peptides have been used as therapeutic agents since 1920 when insulin was isolated from animal sources. With the passage of time, the synthesis of peptides became easier and various synthetic peptides were used as therapeutic agents. Nowadays, various medicinal chemistry techniques, such as combinatorial chemistry and high throughput

Hydrazone Derivatives
Senkarde and co-workers synthesized sulfonyl hydrazone derivatives as anticancer agents. Compound 149 showed prominent activity against the PC-3 (IC 50 = 1.38 µM; SI = 432.30) cancer line, in comparison to cisplatin (IC 50 = 3.3 µM, 22.2 µM) and showed selectivity for this cell line. The analog 149 exhibited excellent inhibition of COX-2 (91%) as compared to the COX-1 enzyme and showed the process of apoptosis. This compound carries a 2-chloro-3-methoxy phenyl group attached to the hydrazone linkage. In the molecular mode of action, the sulfonyl group of 149 presented hydrogen bonding with Tyr341 and Ser339 of COX-2. The hydrazine group showed hydrogen bond interaction with Val509 and the methoxy group with Ser516. Derivative 149 showed binding energy of −8.6 kcal/mol as compared to celecoxib (−12 kcal/mol). These derivatives followed the Lipinski rule of five and showed favorable physicochemical properties, such as molecular weight, logP, TPSA, logS, and molar refractivity values [126]. Popiolik et al. synthesized hydrazone-hydrazide derivatives of 5-bromo-2-iodobenzoic acid. Upon evaluation by MTT assay, analogs 150 (IC 50 = 11.94 µM), 151 (IC 50 = 22.20 µM) and 152 (IC 50 = 4.11 µM) showed prominent anticancer activity against renal cell adenocarcinoma (769-P) and HepG2 cancer cell lines. The chlorine and nitro-substituted agents showed greater activity. Compound 151 is the nitro-substituted agent and showed excellent activity against the HepG2 cancer cell line. These derivatives showed low toxicity for the normal cell line. The derivative 153 presented slight inhibition of COX-2 (9.78%) and carries an indole ring attached through the aromatic linker that is important for its activity [127].

Peptides as COX-2 Inhibitors
Peptides have been used as therapeutic agents since 1920 when insulin was isolated from animal sources. With the passage of time, the synthesis of peptides became easier and various synthetic peptides were used as therapeutic agents. Nowadays, various medicinal chemistry techniques, such as combinatorial chemistry and high throughput screening, are being used to produce synthetic peptides with different pharmacological properties [128,129]. Ahmaditaba and co-workers used the solid-phase synthesis technique to produce peptide molecules. The COX-2 pharmacophores, such as 4-methylsulfonyl phenyl or 4-azidophenyl, were introduced ( Figure 30). Compounds 155 (IC 50 = 19.3 ± 0.02 µM, 19.9 ± 0.03 µM) and 156 (IC 50 = 4.8 ± 0.12 µM, 5.7 ± 0.04 µM) exhibited anticancer activity against the HepG2 and A549 cancer cell lines, in comparison to the standard drug, celecoxib (IC 50 = 16 ± 0.02 µM). Derivative 154 was the most active COX-2 inhibitor (IC 50 = 0.2 µM, SI > 500) and demonstrated a prominent selectivity index, compared to the standard drug, celecoxib (IC 50 = 0.06 µM; SI = 405). Analogs with the proline and tyrosine amino acids presented greater antiproliferative activities. Derivatives of the methylsulfonyl group showed better COX-2 inhibitory activities. Compound 154 showed two hydrogen bonds with the His90 and Arg513 of COX-2. The acidic functional group showed one hydrogen bond with Trp387. The phenyl group communicates with a hydrophobic pocket, formed by Leu531, Leu359, and Val349. Compounds 154 and 155 showed a good correlation between anticancer (IC 50 = 16 ± 0.13 µM and 12.1 ± 0.23 µM) and COX-2 (IC 50 = 0.2 µM and 0.12 µM) inhibitory activities [130].

Conclusions
Cancer is a global health problem and the discovery of novel, effective, and safer agents is still of great importance. Herein, we have mainly focused on the anticancer compounds that have also shown COX-2 inhibition. Diarylheterocyclic compounds with pyrazole or pyrazoline as the main core are widely recognized COX-2 inhibitors. The pyrazole/pyrazoline scaffolds with sulfonylmethyl or sulfonamide groups have been attached to other molecules having anticancer properties, to produce new hybrid molecules. The majority of the molecules have been synthesized by the attachment of a pyrazole scaffold with other pharmacophores, such as coumarin, chrysin, caffeic acid, and other natural products. Hybrid molecules of pyrazole with coumarin have displayed excellent anticancer as well as COX-2 inhibitory properties. Hybrid molecules comprising caffeic acid and triazole have demonstrated prominent anticancer activity, accompanied by COX-2 inhibition. The addition of heterocyclic rings in the lead molecules increased the selectivity for COX-2 by increasing the intermolecular interaction with this enzyme. A correlation was also found between these two properties. The modification of NSAIDs such as naproxen has also produced highly potent anticancer molecules and few of them proved selective for COX-2. Similarly, the hybrid molecules of celecoxib and rofecoxib also proved highly effective. Many compounds exhibited anticancer activity by inducing apoptosis in cancer cells. The derivatives of heterocyclic compounds, such as cyanopyrimidine, pyrazolo-pyrimidines, pyrrolizine, and tetrazoles showed significant anticancer properties and better selectivity for the COX-2 enzyme. However, the presence of reactive groups in some compounds makes them unfavorable for in vivo assays and

Conclusions
Cancer is a global health problem and the discovery of novel, effective, and safer agents is still of great importance. Herein, we have mainly focused on the anticancer compounds that have also shown COX-2 inhibition. Diarylheterocyclic compounds with pyrazole or pyrazoline as the main core are widely recognized COX-2 inhibitors. The pyrazole/pyrazoline scaffolds with sulfonylmethyl or sulfonamide groups have been attached to other molecules having anticancer properties, to produce new hybrid molecules. The majority of the molecules have been synthesized by the attachment of a pyrazole scaffold with other pharmacophores, such as coumarin, chrysin, caffeic acid, and other natural products. Hybrid molecules of pyrazole with coumarin have displayed excellent anticancer as well as COX-2 inhibitory properties. Hybrid molecules comprising caffeic acid and triazole have demonstrated prominent anticancer activity, accompanied by COX-2 inhibition. The addition of heterocyclic rings in the lead molecules increased the selectivity for COX-2 by increasing the intermolecular interaction with this enzyme. A correlation was also found between these two properties. The modification of NSAIDs such as naproxen has also produced highly potent anticancer molecules and few of them proved selective for COX-2. Similarly, the hybrid molecules of celecoxib and rofecoxib also proved highly effective. Many compounds exhibited anticancer activity by inducing apoptosis in cancer cells. The derivatives of heterocyclic compounds, such as cyanopyrimidine, pyrazolopyrimidines, pyrrolizine, and tetrazoles showed significant anticancer properties and better selectivity for the COX-2 enzyme. However, the presence of reactive groups in some compounds makes them unfavorable for in vivo assays and drug development. This review highlights the recent heterocyclics and hybrid anticancer molecules that have displayed anti-inflammatory and COX-2 inhibitory properties.