Inflammation is a protracted evolved process linked with the activation, recruitment, and efficiency of innate as well as adaptive immune system cells. It is considered as a causal factor in the progression of several types of inflammatory diseases including cancer. Due to some external or internal stimuli, membrane phospholipids are hydrolyzed by phospholipase A2 to liberate arachidonic acid and lysophosphatidic acid; the former on oxidation by two independent lipoxygenase (LOX) and cyclooxygenase (COX) pathways, yields biologically active mediators involved in the inflammatory processes [1]. LOX pathway is regulated by the rate limiting step carried out by 5-LOX, 12-LOX or 15-LOX, depending upon the number of double bond being oxidized to give 5-hydroperoxyeicosatetraenoic acid (5-HPETE), 12-HPETE, and 15-HPETE which further produce leukotrienes (LTs). 15-LOX is implemented in chronic bronchitis, asthma and cancer development [2], [3]. The 12-HPETE interacts with G protein-coupled receptor in the PI3K/Akt/NF-κB pathway and increases the TNFα and IL-1β production which in turn increase reactive oxygen species (ROS) production. 5-LOX is involved in the synthesis of mediators implemented in bronchoconstrictor and several types of cancers [4], [5], [6].

The expression of 5-LOX and 12-LOX mRNA in four human pancreatic cancer cell lines (PANC-1, MiaPaca2, Capan2, and ASPC-1) was estimated by nested RT-PRC. The first type of 12-LOX, termed human platelet-type 12-LOX, accumulates in platelets, human erythroleukemia cells, and umbilical vein endothelial cells. The second type, porcine leukocyte-type 12-LOX, can metabolize both arachidonic acid and linoleic acid and can produce 12(S)-HETE and a trace amount of 15-(S)-HETE. The third type, called epithelium leukocyte-type 12-LOX and reticulocyte 15-lipoxygenase are both enzymes that catalyze the formation of 12(S)-HETE and 15(S)-HETE [5]. In humans, two types of 15-LOX have been identified: reticulocyte type 15-LOX-1 and epidermis type 15-LOX-2. In a rabbit reticulocyte mass, 15-LOX-1 was found as a single, 75-kD polypeptide chain, while 15-LOX-2 was subsequently discovered in the human prostate, skin, and cornea.

The small molecules to be used as enzyme inhibitors are heterocycles containing nitrogen, sulfur or other heteroatoms. The design, synthesis and development of these bioactive molecules each with unique pharmacological properties is the most challenging [7]. In the last few decades, azolic derivatives like triazole, thiazole, thiadiazole and oxadiazole have attracted much attention because of their biological and synthetic importance and involvement in the formation of their fused heterocyclic-derived products [8]. Triazoles are five-member ring structures of three nitrogen atoms and their derivatives can interact easily towards various receptors and enzymes as hydrogen bond acceptors and donors resulting in a wide range of biological activities [9], [10], [11]. 1,2,4-Triazoles have garnered the attention because of their diverse pharmacological actions, minimal toxicities, powerful pharmacokinetic and pharmacodynamic features. Further, these molecules afford great variety of molecules, straight forward synthetic plans and usage in an array of combined analogues and non-fused scaffolds [8].

1,2,4-Triazole skeletons are incorporated in drugs including triazolam, estazolam, alprazolam (tranquillizer and anticonvulsant), fluconazole, itraconazole (antifungal), ribavirin (antiviral), anastrozole and rizatriptan (anti-migraine agents) and many others [12]. It is shown that the triazole ring can serve various weak interactions, including hydrophobic effects, coordination bonds, ion–dipole and hydrogen bonding providing a linker of pharmacophore with the targeted multiple binding sites [13]. In addition, 1,2,4-triazole nucleus exhibits stability against chemical and metabolic degradation. It can increase the solubility of the ligand and its polar nature can significantly enhance the pharmacokinetics and pharmacodynamics properties of the drug [8].

According to the pharmacodynamical principle of superposition, 1,2,4-triazole is a versatile scaffold reported to have potential pharmacological activities, such as anticancer [14], antifungal [15], antiurease [16], antiinflammatory [17], antioxidant [18] as well as anticonvulsant [19] properties. Currently, letrozole, anastrozole and vorozole are commonly used to treat estrogen-dependent breast cancer [20] (Fig. 1). Some derivatives of clotrimazole have been reported as antifungal agents [21]. Song et al synthesized a series of 4-N-nitrophenylsubstituted amino-4H-1,2,4-triazole derivatives as promising aromatase inhibitors [22] Further, Cevik et al explored a new benzimidazole-triazolothiadiazine hybrid with potent aromatase inhibitory activities [23]. Akhter et al reported a series of 1,2,4-triazole derivatives with potent inhibitory activity against the HepG2 cancer cell line [24].

In addition, Ouyang et al showed that a set of 1,2,4-triazole derivatives completely inhibited the tubulin polymerization by inducing cell cycle arrest at the G2/M phase of the A431 cell line [25]. Acetamide and azinane-bearing lead compounds are significant and essential pharmacophores of anticancer drugs [26]. Cefatrizine and tazobactam are triazole based antimicrobial and anticancer drugs, respectively. Therefore, 1,2,4-triazole nucleus can certainly provide avenues for researchers to find inventive potential drug candidates with more efficacy and selectivity [27].

Literature survey revealed that the piperidine analogues as vital components of the molecular structure of some important drugs in the treatment of various kinds of cancer, including cervical, pancreatic, colon, and breast cancer [28], [29]. Piperidine carboxamide and the benzamide ring linked scaffolds are also found effective against SARS-CoV [30]. Triazole caffeic acid esters (i-iii) are found potent LOX inhibitors in sub-micromolar concentrations [31]. Compound (iv) with sulfone or sulfonamide groups also inhibited 5-LOX due to the involvement of hydrogen bonding and electrostatic interactions with various OH and NH functionalities of amino acids that supported the inhibitions [32]. Likewise, triazolylpyrazole oximes with sulfonamido derivative (v) showed potent inhibition (Fig. 2). The inhibitory potential compounds (v,vi) revealed that they fitted easily into the hydrophobic U-shaped pocket of the active site of the enzyme [33]. 4-Phenyl-1,2,4-triazole and N-(4-chlorophenyl)acetamide (vii) had various substituents (R = OMe, R1 = Phenyl, R2 = Cl) which increased the possibilities of hydrogen bonding and several hydrophobic interactions though the replacement of phenyl ring with an allyl group substantially decreased the binding affinity for 5-LOX [34]. Nevertheless, the conjugation of two or more biologically active scaffolds presents innovative hybrid pharmacophores with retained predetermined features. On this premise, earlier we synthesized and reported several pharmacologically active triazole and oxadiazole-based polyvalent derivatives (viii-xi) with acetamide functionalities as LOX inhibitors [35], [36], [37], [38], [39], [40], [41], [42]. In the present study, triazole and propanamide hybrid pharmacophore with phenylcarbamoylpiperidine-4-carboxylate core was designed and derivatized decorated with hydrophobic aryl rings on each side of the triazole ring in search for potential leads as antiinflammatory agents (Fig. 2).