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Novel purine-pyrazole hybrids combining thiazoles, thiazolidinones and rhodanines, were designed and tested as 15-LOX inhibitors, potential anticancer and antioxidant agents. All tested compounds were found to be potent 15-LOX inhibitors with IC 50 ranging from 1.76 to 6.12 µM. The prepared compounds were evaluated in vitro against five cancer cell lines: A549 (lung), Caco-2 (colon), PC3 (prostate), MCF-7 (breast) and HepG-2 (liver). Compounds 7b and 8b displayed broad spectrum anticancer activity against the five tested cell lines (IC 50  = 18.5-95.39 µM). While, compound 7h demonstrated moderate anticancer activity against lung A549 and colon Caco-2 cell lines. Antioxidant screening revealed that six compounds (5a, 5b, 6b, 7b, 7h and 8b) with IC 50 ranging from 0.93 to 14.43 µg/ml were found to be more potent scavengers of 2,2- diphenyl-1-picrylhydrazyl (DPPH) than the reference ascorbic acid with IC 50 value of 15.34 µg/ml. Compounds 7b, 7h and 8b, when evaluated for their antioxidant activity, where found to be potent DPPH scavengers. Moreover, compound 7b displayed twice the potency of ascorbic acid as NO scavenger. Docking study was performed to elucidate the possible binding mode of the most active compounds with the active site of 15-LOX enzyme. Collectively, the purine-pyrazole hybrids having thiazoline or thizolidinone moieties (7b, 7h and 8b) constitute a promising scaffold in designing more potent 15-LOX inhibitors with anticancer and antioxidant potential., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Various mechanisms for regulated cell death include the formation of oxidative mediators such as lipid peroxides and nitric oxide (NO). In this respect, 15-lipoxygenase-1 (15-LOX-1) is a key enzyme that catalyzes the formation of lipid peroxides. The actions of these peroxides are interconnected with nuclear factor-κB signaling and NO production. Inhibition of 15-LOX-1 holds promise to interfere with regulated cell death in inflammatory conditions. In this study, a novel potent 15-LOX-1 inhibitor, 9c (i472), was developed and structure-activity relationships were explored. In vitro, this inhibitor protected cells from lipopolysaccharide-induced cell death, inhibiting NO formation and lipid peroxidation. Thus, we provide a novel 15-LOX-1 inhibitor that inhibits cellular NO production and lipid peroxidation, which set the stage for further exploration of these mechanisms.

Flavonoids are phenolic compounds that have always attracted pharmaceutical researchers and food manufacturers. Nature has indirectly provided us flavones in our daily diet i.e. tea, fruits, juices and vegetables. Flavones have got special position in research field of natural and synthetic organic chemistry due to their biological capabilities. Three substituted flavone derivatives have been synthesized from substituted O-hydroxy acetophenones and 4-trifluoromethyl benzaldehyde in good yield. The structures have been established by different spectroscopic techniques like 1 HNMR 13 CNMR, IR spectroscopy. The compounds were then screened for their enzyme inhibition potential and antinociceptive response in mice models with writhings induced by acetic acid, tail immersion and formalin-induced nociception assay procedures and structure activity relationship was established. The effects following pretreatment with naloxone were also studied to reveal the involvement of opioid receptors in the antinociceptive action. The flavone derivatives showed moderate to weak inhibition against LOX. Moreover, significant to moderate decrease in the number of abdominal constrictions, increase in paw-licking response time in both phases and a significant raise in latency time in nociception models. Moreover, the antinociceptive response was significantly attenuated by pretreatment with opioid receptor antagonist suggesting the involvement of opioidergic system in the analgesic action. The flavone derivatives showed analgesic response in all models of nociception suggesting the possible involvement of opioidergic system in the antinociceptive action.

In this paper, 41 hybrid compounds containing diaryl-1,5-diazole and morpholine structures acting as dual COX-2/5-LOX inhibitors have been designed, synthesized and biologically evaluated. Most of them showed potent antiproliferative activities and COX-2/5-LOX inhibitory in vitro. Among them, compound A33 displayed the most potency against cancer cell lines (IC 50  = 6.43-10.97 μM for F10, HeLa, A549 and MCF-7 cells), lower toxicity to non-cancer cells than celecoxib (A33: IC 50  = 194.01 μM vs.celecoxib: IC 50  = 97.87 μM for 293T cells), and excellent inhibitory activities on COX-2 (IC 50  = 0.17 μM) and 5-LOX (IC 50  = 0.68 μM). Meanwhile, the molecular modeling study was performed to position compound A33 into COX-2 and 5-LOX active sites to determine the probable binding models. Mechanistic studies demonstrated that compound A33 could block cell cycle in G2 phase and subsequently induced apoptosis of F10 cells. Furthermore, compound A33 could significantly inhibit tumor growth in F10-xenograft mouse model, and pharmacokinetic study of compound A33 indicated that it showed better stability in vivo. In general, compound A33 could be a promising candidate for cancer therapy., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

In this study, a range of oxamide ligands were synthesized by the reaction of amines with oxalyl chloride in basic medium. Spectroscopic and analytical techniques such as IR, 1H-NMR and ESI-MS techniques were used for characterization of the synthesized oxamides. The synthesized oxamides were screened for Lipoxygenase inhibition. Biological screening revealed that the oxamides possessed good lipoxygenase inhibition activities, whereas, the unsubstituted oxamide did not show any distinct lipoxygenase inhibition activity. Molecular docking studies of the oxamides were also carried out for lipoxygenase inhibition. The results obtained from molecular docking were well correlated with the empirical data.

Synthesis of new antioxidants and enzyme inhibitors is an active area of research in pharmaceutical sciences. This can be used for development of new active product ingredients which can prevent body from different diseases. This study comprises of preparation of transition metal complexes using 4-(4-bromophenyl)-2,2'-bipyridine (BPBP) and their screening for antioxidant and lipoxygenase inhibition properties. 4-(4-bromophenyl)-[2,2'-bipyridine]-6-carboxylic acid was used as starting material and its decarboxylation resulted in BPBP. Decarboxylation by conventional heating method was compared with microwave decarboxylation method. Selected metal complexes of the ligand were synthesized with Ruthenium (II), Iron (II) and Cobalt (II) ions. The complexes were characterized using UV, IR, 1 H-NMR, ESI-MS and CHNS techniques. It was observed that BPBP acted as a bidentate ligand. The metal to ligand stoichiometry was 1:3 for all the synthesized complexes. The complexes had octahedral structure with C3 symmetry. The antioxidant activity was evaluated using free radical scavenging assay. BPBP showed insignificant antioxidant and lipoxygenase activities while its transition metal complexes showed promising activities. Antioxidant activity of Fe and Co-complexes was found significantly higher than the reference drug used in this study.

The conjugation of diclofenac (DICLH), a Non-Steroidal Anti-inflammatory Drug (NSAID), with biocides such as dimethyl sulfoxide (DMSO) and triphenylphosphine (TPP), through silver(I) ions, results into the chemical [Ag n (DICL) n (L) m ] k (L = DMSO and n = 2, m = 2, k = infinite (1); L = TPP and n = 1, m = 2, k = 1 (2)). The compounds were characterized by m.p., FT-IR, UV-vis and 1 H NMR spectroscopic techniques. The crystal and molecular structures of 1-2 were determined by X-ray crystallography. The in vitro cytotoxic activity of 1-2 against the human breast adenocarcinoma cancer cells MCF-7 (hormone dependent) and MDA-MB-231 (hormone independent) reveals that the 1 inhibits the MCF-7 rather than the MDA-MB-231 cells, suggesting hormone mimetic behaviour. Compound 2 inhibits both cancerous cell lines, stronger than cisplatin. Both compounds inhibit MCF-7 cells migration. Compounds 1-2, exhibit, lower toxicity against fetal lung fibroblast (MRC-5) cells than cisplatin. Their genotoxicity was evaluated on MRC-5 cells. The molecular mechanism of 1-2 against MCF-7 cells was clarified by (i) their cell cycle arrest study (ii) their mitochondrial membrane permeability (iii) their binding affinity towards Calf Thymus (CT)-DNA and (iv) their inhibitory activity against the enzyme lipoxygenase (LOX). Regression analysis of the data obtained for [Ag(NSAID)(Ar 3 P) m ] (NSAID = p‑hydroxy‑benzoic acid (p-HO-BZAH), salicylic acid (SALH 2 ), aspirin (ASPH), naproxen (NAPRH), nimesulide (NIMH); L = TPP, Tri(p‑tolyl)phosphine (TPTP), Tri(o‑tolyl)phosphine (TOTP), Tri(m‑tolyl)phosphine (TMTP); m = 2 or 3) and [Ag(DICL) 2 (DMSO) 2 ] k (k = infinite) was performed. Considering the biological results (IC 50 ) as dependent variable a theoretical equation is obtained for these compounds. The calculated IC 50 values are compared satisfactorily with the corresponding experimental inhibitory activity of the complexes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A series of novel naproxen analogues containing 3-aryl-1,2,4-oxadiazoles moiety (4b-g) and their reaction intermediates aryl carboximidamides moiety (3b-g) was synthesized and evaluated in vitro as dual COXs/15-LOX inhibitors. Compounds 3b-g exhibited superior inhibitory activity than celecoxib as COX-2 inhibitors. Compounds 3b-d and 3g were the most potent COX-2 inhibitors with IC 50 range of 6.4 - 8.13 nM and higher selectivity indexes (3b, SI = 26.19; 3c, SI = 13.73; 3d, SI = 29.27; 3g, SI = 18.00) comparing to celecoxib (IC 50  = 42.60 nM, SI = 8.05). Regarding 15-LOX inhibitory activity, compounds belonging to aryl carboximidamide backbone 3b-e and 3g were the most potent with IC 50 range of 1.77-4.91 nM comparing to meclofenamate sodium (IC 50  = 5.64 µM). Data revealed that The levels of NO released by aryl carboximidamides 3b-g were more higher than 3-aryl-1,2,4-oxadiazole derivatives 4b-g, which correlated well with their COX-2 inhibitory activities., (Copyright © 2019 Elsevier Inc. All rights reserved.)

5-Lipoxygenase (5-LOX) is a key enzyme involved in the biosynthesis of pro-inflammatory leukotrienes, leading to asthma. Developing potent 5-LOX inhibitors especially, natural product based ones, are highly attractive. Coumaperine, a natural product found in white pepper and its derivatives were herein developed as 5-LOX inhibitors. We have synthesized twenty four derivatives, characterized and evaluated their 5-LOX inhibition potential. Coumaperine derivatives substituted with multiple hydroxy and multiple methoxy groups exhibited best 5-LOX inhibition. CP-209, a catechol type dihydroxyl derivative and CP-262-F2, a vicinal trihydroxyl derivative exhibited, 82.7% and 82.5% inhibition of 5-LOX respectively at 20 µM. Their IC 50 values are 2.1 ± 0.2 µM and 2.3 ± 0.2 µM respectively, and are comparable to zileuton, IC 50  = 1.4 ± 0.2 µM. CP-155, a methylenedioxy derivative (a natural product) and CP-194, a 2,4,6-trimethoxy derivative showed 76.0% and 77.1% inhibition of 5-LOX respectively at 20 µM. Antioxidant study revealed that CP-209 and 262-F2 (at 20 µM) scavenged DPPH radical by 76.8% and 71.3% respectively. On the other hand, CP-155 and 194 showed very poor DPPH radical scavenging activity. Pseudo peroxidase assay confirmed that the mode of action of CP-209 and 262-F2 were by redox process, similar to zileuton, affecting the oxidation state of the metal ion in the enzyme. On the contrary, CP-155 and 194 probably act through some other mechanism which does not involve the disruption of the oxidation state of the metal in the enzyme. Molecular docking of CP-155 and 194 to the active site of 5-LOX and binding energy calculation suggested that they are non-competitive inhibitors. The In-Silico ADME/TOX analysis shows the active compounds (CP-155, 194, 209 and 262-F2) are with good drug likeliness and reduced toxicity compared to existing drug. These studies indicate that there is a great potential for coumaperine derivatives to be developed as anti-inflammatory drug., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We investigated twelve benzyl phenyl ketone derivatives which are synthetic precursors of isoflavonoids that are shown be good 5-hLOX inhibitors, especially those that have the catechol group, but these precursors never have been assayed as 5-hLOX inhibitors being a novelty as inhibitors of the enzyme, due to sharing important structural characteristics. Screening assays, half maximal inhibitory concentration (IC 50 ) and kinetic assays of all the studied molecules (5 µg/ml in media assay) showed that 1-(2,4-dihydroxy-3-methylphenyl)-2-(3-chlorophenyl)-ethanone (K205; IC 50  = 3.5 µM; K i  = 4.8 µM) and 1-(2,4-dihydroxy-3-methylphenyl)-2-(2-nitrophenyl)-ethanone (K206; IC 50  = 2.3 µM; K i  = 0.7 µM) were potent, selective, competitive and nonredox inhibitors of 5-hLOX. Antioxidant behavior was also assayed by DPPH, FRAP, and assessing ROS production, and those with antibacterial and antiproliferative properties relating to 1-(2,4-dihydroxy-3-methylphenyl)-2-(2-chlorophenyl)-ethanone (K208) established it as the most interesting and relevant compound studied, as it showed nearly 100% inhibition of bacterial growth of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Finally, docking studies were done that helped to characterize how the inhibitor structures correlated to decreased 5-hLOX activity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Chalcones represent a class of small drug/druglike molecules with different and multitarget biological activities. Small multi-target drugs have attracted considerable interest in the last decade due their advantages in the treatment of complex and multifactorial diseases, since "one drug-one target" therapies have failed in many cases to demonstrate clinical efficacy. In this context, we designed and synthesized potential new small multi-target agents with lipoxygenase (LOX), acetyl cholinesterase (AChE) and lipid peroxidation inhibitory activities, as well as antioxidant activity based on 2-/4- hydroxy-chalcones and the bis -etherified bis -chalcone skeleton. Furthermore, the synthesized molecules were evaluated for their cytotoxicity. Simple chalcone b4 presents significant inhibitory activity against the 15-human LOX with an IC 50 value 9.5 µM, interesting anti-AChE activity, and anti-lipid peroxidation behavior. Bis -etherified chalcone c12 is the most potent inhibitor of AChE within the bis -etherified bis -chalcones followed by c11 . Bis -chalcones c11 and c12 were found to combine anti-LOX, anti-AchE, and anti-lipid peroxidation activities. It seems that the anti-lipid peroxidation activity supports the anti-LOX activity for the significantly active bis -chalcones. Our circular dichroism (CD) study identified two structures capable of interfering with the aggregation process of Aβ. Compounds c2 and c4 display additional protective actions against Alzheimer's disease (AD) and add to the pleiotropic profile of the chalcone derivatives. Predicted results indicate that the majority of the compounds with the exception of c11 (144 Å) can cross the Blood Brain Barrier (BBB) and act in CNS. The results led us to propose new leads and to conclude that the presence of a double enone group supports better biological activities.

In this research, we exploited derivatives of thieno[2,3-b]pyridine as dual inhibitors of the key enzymes in eicosanoid biosynthesis, cyclooxygenase (COX, subtypes 1 and 2) and 5-lipoxygensase (5-LOX). Testing these compounds in a rat paw oedema model revealed potency higher than ibuprofen. The most active compounds 7a, 7b, 8b, and 8c were screened against COX-1/2 and 5-LOX enzymes. Compound 7a was the most powerful inhibitor of 5-LOX with IC 50  = 0.15 µM, while its p-chloro analogue 7b was more active against COX-2 (IC 50  = 7.5 µM). The less desirable target COX-1 was inhibited more potently by 8c with IC 50  = 7.7 µM. Surflex docking programme predicted that the more stable anti- conformer of compound (7a) formed a favourable complex with the active site of 5-LOX but not COX-1. This is in contrast to the binding mode of 8c, which resembles the syn-conformer of series 7 and binds favourably to COX-1.

Given the hepatotoxicity and an unfavorable pharmacokinetic profile of zileuton (Zyflo ® ), currently the only approved and clinically used 5-Lipoxygenase (5-LO) inhibitor, the search for potent and safe 5-LO inhibitors is highly demanded. The action of several phenolic acid phenethyl esters as potential 5-Lipoxygenase (5-LO) inhibitors has been investigated. For this purpose, a series of 14 phenethyl esters was synthesized and their impact on 5-LO inhibition was evaluated. The effects of position and number of hydroxyl and methoxy groups on the phenolic acid were investigated. The shortening of the linker between the carbonyl and the catechol moiety as well as the presence of the α,β-unsaturated carbonyl group was also explored. The sinapic acid phenethyl ester (10), which can be named SAPE (10) by analogy to caffeic acid phenethyl ester (CAPE), inhibited 5-LO in a concentration-dependent manner and outperformed both zileuton (1) and CAPE (2). With an IC 50 of 0.3 μm, SAPE (10) was threefold more potent than CAPE (2) and 10-fold more potent than zileuton (1), the only 5-LO inhibitor approved for clinical use. Unlike CAPE (2), SAPE (10) had no effect on 12-lipoxygenase (12-LO) and less effect on cyclooxygenase 1 (COX-1) which makes it a more selective 5-LO inhibitor., (© 2018 John Wiley & Sons A/S.)

A new series of diaryl heptanones (12a-q) were synthesized and their structures were confirmed by its 1 H, 13 C NMR and Mass spectral data. These analogs were evaluated for their anti-oxidant activity and potential to inhibit 5-lipoxygenase. Compounds 12k and 12o showed potent in vitro 5-lipoxygenase enzyme inhibitory activity with IC 50 values of 22.2, 21.5 μM, which are comparable to curcumin (24.4 μM). Further they also have shown significant antioxidant activity. Molecular docking studies clearly showed correlation between binding energy and potency of these compounds., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Designing of hybrid drugs with specific multitarget profile is a promising line of attack against inflammation. In light of this, a series of benzimidazole scaffold based hybrid molecules were designed by integrating benzimidazoles (containing pharmacophoric elements for COXs and LOXs inhibitors) with phthalimide subunit of thalidomide (pharmacophore element for TNF-α inhibitor) under one construct via molecular hybridization strategy. The designed molecules were synthesized and evaluated for their inhibitory activity against COXs (COX-1, COX-2), LOXs (5-LOX, 15-LOX) enzymes as well as TNF-α inhibitory effect. The results revealed that, compounds (3a-l) obtained showed inhibition in submicromolar range against COXs and LOXs targets whereas milder inhibitory activity was obtained against lipopolysaccharides (LPS)-induced TNF-α secretion by murine macrophage-like cells (RAW264.7). Within this class of compounds, 3j emerged as having alluring multiple inhibitory effects on set of COX-1/2 and 5-/15-LOX enzymes (COX-1 IC 50  = 9.85 µM; COX-2 IC 50  = 1.00 µM; SI = 9.85; 5-LOX IC 50  = 0.32 µM; 15-LOX IC 50  = 1.02 µM) in conjunction with a good anti-inflammatory and analgesic activities. Additionally, compound 3j showed gastrointestinal safety with reduced lipid peroxidation. Docking results of compound 3j with COX-2 and 5-LOX were also consistent with the in vivo anti-inflammatory results., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Selective inhibition of both cyclooxygenase-2 (COX-2) and 15-lipooxygenase (15-LOX) may provide good strategy for alleviation of inflammatory disorders while minimizing side effects associated with current anti-inflammatory drugs. The present study describes the synthesis, full characterization and biological evaluation of a series of thiadiazole-thiazolidinone hybrids bearing 5-alk/arylidene as dual inhibitors of these enzymes. Our design was based on merging pharmacophores that exhibit portent anti-inflammatory activities in one molecular frame. 5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-amine (3) was efficiently synthesized, chloroacetylated and cyclized to give the key 4-thiazolidinone (5). Knovenagel condensation of 5 with different aldehydes afforded the final compounds 6a-m, 7, 8 and 9. These compounds were subjected to in vitro COX-1/COX-2, 15-LOX inhibition assays. Compounds (6a, 6f, 6i, 6l, 6m and 9) with promising potency (IC 50  = 70-100 nM) and selectivity index (SI = 220-55) were further tested for in vivo anti-inflammatory activity and effect on gastric mucosa. The most promising compound (6l) inhibits COX-2 enzyme at a nanomolar concentration (IC 50  = 70 nM, SI = 220) with simultaneous inhibition of 15-LOX (IC 50  = 11 µM). These results are comparable to the potency and selectivity of the standard drugs of both enzymes; celecoxib (COX-2 IC 50  = 49 nM, SI = 308) and zileuton (15-LOX IC 50  = 15 µM) in one construct. Interestingly three compounds (6a, 6l and 9) exhibited equivalent to or even higher than that of celecoxib in vivo anti-inflammatory activity at 3 h interval with good GIT safety profile. Molecular docking study conferred binding sites of these compounds on COX-2 and 15-LOX. Such type of compounds would represent valuable leads for further investigation and derivatization., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Dicoumarol derivatives were synthesized in the InCl 3 catalyzed pseudo three-component reactions of 4-hydroxycoumarin with aromatic aldehydes in excellent yields. The reactions were performed in water under microwave irradiation. All synthesized compounds were characterized using NMR, IR, and UV-Vis spectroscopy, as well as with TD-DFT. Obtained dicoumarols were subjected to evaluation of their in vitro lipid peroxidation and soybean lipoxygenase inhibition activities. It was shown that five of ten examined compounds (3e, 3h, 3b, 3d, 3f) possess significant potential of antilipid peroxidation (84-97%), and that compounds 3b, 3e, 3h provided the highest soybean lipoxygenase (LOX-Ib) inhibition (IC 50  = 52.5 µM) and 3i somewhat lower activity (IC 50  = 55.5 µM). The bioactive conformations of the best LOX-Ib inhibitors were obtained by means of molecular docking and molecular dynamics. It was shown that, within the bioactive conformations interior to LOX-Ib active site, the most active compounds form the pyramidal structure made of two 4-hydroxycoumarin cores and a central phenyl substituent. This form serves as a spatial barrier which prevents LOX-Ib Fe 2+ /Fe 3+ ion activity to generate the coordinative bond with the C13 hydroxyl group of the α-linoleate. It is worth pointing out that the most active compounds 3b, 3e, 3h and 3i can be candidates for further examination of their in vitro and in vivo anti-inflammatory activity and that molecular modeling study results provide possibility to screen bioactive conformations and elucidate the mechanism of dicoumarols anti-LOX activity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A series of new 1,2,3-triazole linked coumarinopyrazole conjugates 4a-e and 5a-e have been synthesized via the Copper(I)-catalysed Alkyne-Azide Cycloaddition (CuAAC). Going through the reaction of compound 2 with the 3-propargyl bromide gave a mixture of propargylated regioisomers 3 + 3' used as a dipolarophile to access to triazoles 4a-e and 5a-e. The structures of the prepared cycloadducts were determined by 1 H, 13 C and 2D-NMR techniques and by HRMS analysis. All the synthesized derivatives have been evaluated for their anticholinesterase, anti-5-lipoxygenase, anti-tyrosinase, and cytotoxic activities., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A new series of 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) analogues were synthesized and evaluated for their lipoxygenase (LOX) inhibitory activity. Prenylated analogues 4a ⁻ g (half maximal inhibitory concentration (IC 50 ) values ranging from 35 μ M to 95 μ M) did not exhibit better inhibitory activity than tHGA ( 3a ) (IC 50 value: 23.6 μ M) due to the reduction in hydrophobic interaction when the alkyl chain length was reduced. One geranylated analogue, 3d , with an IC 50 value of 15.3 μ M, exhibited better LOX inhibitory activity when compared to tHGA ( 3a ), which was in agreement with our previous findings. Kinetics study showed that the most active analogue ( 3e ) and tHGA ( 3a ) acted as competitive inhibitors. The combination of in silico approaches of molecular docking and molecular dynamic simulation revealed that the lipophilic nature of these analogues further enhanced the LOX inhibitory activity. Based on absorption, distribution, metabolism, excretion, and toxicity (ADMET) and toxicity prediction by komputer assisted technology (TOPKAT) analyses, all geranylated analogues ( 3a ⁻ g ) showed no hepatotoxicity effect and were biodegradable, which indicated that they could be potentially safe drugs for treating inflammation.

New quinoline compounds comprising pyrazole scaffold through different amide linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory activity. Eight compounds (5c, 11b,c, 12c, 14a,b, 20a and 21a) were found to exhibit promising anti-inflammatory profiles in acute and sub-acute inflammatory models. They were screened for their ulcerogenic activity and none of them showed significant ulcerogenic activity comparable to the reference drug celecoxib and are well tolerated by experimental animals with high safety margin (ALD 50  > 0.3 g/kg). Compounds 5c, 11b,c, 12c, 14a,b, 20a and 21a showed significant in vitro LOX inhibitory activity higher than that of zileuton. In vitro COX-1/COX-2 inhibition study revealed that compounds 12c, 14a,b and 20a showed higher selectivity towards COX-2 than COX-1. Among the tested compounds, 12c, 14a and 14b showed the highest inhibitory activity against COX-2 with an IC 50 values of 0.1, 0.11 and 0.11 μM respectively. The docking experiments attempted to postulate the binding mode for the most active compounds in the binding site of COX-2 enzymes and confirmed the high selectivity binding towards COX-2 enzyme over COX-1., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Three new series of 5-aminosalicylic acid derivatives; series I (14, 16-18), series II (19-30) and series III (31-41) were synthesized as potential dual COX-2/5-LOX inhibitors. Their chemical structures were confirmed using spectroscopic tools including IR, 1 H NMR, 13 C NMR, mass spectroscopy and elemental analyses. The anti-inflammatory activity for all target compounds was evaluated in vivo using carrageenan-induced paw edema. Compound 36 showed the highest anti-inflammatory activity (114.12%) relative to reference drug indomethacin at 4 h interval. Selected derivatives were evaluated in vitro to inhibit ovine COX-1, human recombinant COX-2 and 5-LOX enzymes. Compounds 34 &35 exhibited significant COX-2 inhibition (IC 50  = 0.10 µM) with significant COX-2 selectivity indices (SI = 135 & 145 respectively) approximate to celecoxib (IC 50  = 0.049 µM, SI = 308.16) and exceeding indomethacin (IC 50  = 0.51 µM, SI = 0.08). Interestingly, all compounds showed superior 5-LOX inhibitory activity about 2-5 times relative to zileuton. Compound 16 was the superlative 5-LOX inhibitor that revealed (IC 50  = 3.41 µM) relative to zileuton (IC 50  = 15.6 µM). Compounds 34, 35, 36 and 41 showed significant dual COX-2/5-LOX inhibitions. The gastric ulcerogenic effect of compound 36 was examined on gastric mucosa of albino rats and they showed superior GI safety profile compared with indomethacin. Molecular docking studies of the compounds into the binding sites of COX-1, COX-2 and 5-LOX allowed us to shed light on the binding mode of these novels dual COX and 5-LOX inhibitors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A series of newly synthesized 4-aryl-hydrazonopyrazolones were designed and their structures were confirmed by spectral and elemental analyses. All synthesized compounds were evaluated for their in vitro COXs, 5-LOX inhibition, in vivo analgesic and anti-inflammatory activities. Compounds 5d, 5f and 5i were found to be the most potent COX-2/5-LOX inhibitors with superior COX-2 selectivity index values (SI = 5.29-5.69) to reference standard celecoxib (SI = 3.52). Four compounds; 5b, 5c, 5d and 5f showed excellent anti-inflammatory activity (% edema inhibition = 72.72-54.54%) and perfect ED 50 values (ED 50  = 0.044-0.104 mmol/kg) relative to celecoxib (ED 50  = 0.032 mmol/kg). To explore the most active compounds, ulcerogenic effect on stomach in comparison with indomethacin and celecoxib in addition to histopathological investigations were performed. Compound 5f showed better gastric profile (UI = 2.33) than celecoxib (UI = 3.00). Also, 5f caused 50% increase in thermal pain threshold close to reference drug indomethacin (53.13%). Docking study of all the target compounds into COX-2 and 5-LOX active sites was performed to rational their anti-inflammatory activities., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The release of pro-inflammatory mediators, such as prostaglandines (PGs) and leukotrienes (LTs), arising from the arachidonic acid (AA) cascade, play a crucial role in initiating, maintaining, and regulating inflammatory processes. New dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E 2 synthase-1 (mPGES-1), that block, at the same time, the formation of PGE 2 and LTs, are currently emerged as a highly interesting drug candidates for better pharmacotherapie of inflammation-related disorders. Following our previous studies, we here performed a detailed structure-based design of benzo[g]indol-3-carboxylate derivatives, disclosing several new key factors that affect both enzyme activity. Ethyl 2-(3,4-dichlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (4b, RAF-01) and ethyl 2-(3,4-dichlorophenyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (7h, RAF-02) emerged as the most active compounds of the series. Additionally, together with selected structure based analogues, both derivatives displayed significant in vivo anti-inflammatory properties. In conclusion, modeling and experimental studies lead to the discovery of new candidate compounds prone to further developments as multi-target inhibitors of the inflammatory pathway., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

A new series of 4-((5-fluoro-6-(substituted)-1H-benzo[d]imidazol-2-ylthio)methyl)-benzoic acids 4a-o and 2-(5-fluoro-6-(substituted)-1H-benzo[d]imidazol-2-ylthio)-2-methylpropanoic acids 8a-e were synthesized, and their inhibitory potencies against soluble epoxide hydrolase (sEH) and 5-lipoxygenase (5-LOX) were investigated. These molecules were designed based on the combination of 5-LOX and sEH pharmacophores, resulting in hybrid analogs with potent sEH and 5-LOX inhibitory activity. Compound 4g showed remarkable activity with IC 50 values of less than 1 μM (0.9 μM) against 5-LOX, while compound 4k displayed promising activity against sEH with IC 50  ≤ 1 μM (0.7 μM). These compounds were evaluated for their in vivo potential using the carrageenan-induced rat paw edema assay. Based on the obtained results, the structure-activity relationship was established and a correlation between the activities was observed. Compounds 4f, 4g, 4k, 4n, and 8e showed potent anti-inflammatory activity and significant inhibition of edema (64.13, 67.39, 66.30, 65.21, and 58.69%, respectively) at a dose of 100 mg/kg, comparable to the standard drug ibuprofen (70.65%) at 3 h., (© 2018 Deutsche Pharmazeutische Gesellschaft.)

A new series of 1,2-diaryl-4-substituted-benzylidene-5(4H)-imidazolone derivatives 4a-l was synthesized. Their structures were confirmed by different spectroscopic techniques (IR, 1 H NMR, DEPT-Q NMR, and mass spectroscopy) and elemental analyses. Their cytotoxic activities in vitro were evaluated against breast, ovarian, and liver cancer cell lines and also normal human skin fibroblasts. Cyclooxygenase (COX)-1, COX-2 and lipoxygenase (LOX) inhibitory activities were measured. The synthesized compounds showed selectivity toward COX-2 rather than COX-1, and the IC 50 values (0.25-1.7 µM) were lower than that of indomethacin (IC 50  = 9.47 µM) and somewhat higher than that of celecoxib (IC 50  = 0.071 µM). The selectivity index for COX-2 of the oxazole derivative 4e (SI = 3.67) was nearly equal to that of celecoxib (SI = 3.66). For the LOX inhibitory activity, the new compounds showed IC 50 values of 0.02-74.03 µM, while the IC 50 of the reference zileuton was 0.83 µM. The most active compound 4c (4-chlorobenzoxazole derivative) was found to have dual COX-2/LOX activity. All the synthesized compounds were docked inside the active site of the COX-2 and LOX enzymes. They linked to COX-2 through the N atom of the azole scaffold, while CO of the oxazolone moiety was responsible for the binding to amino acids inside the LOX active site., (© 2018 Deutsche Pharmazeutische Gesellschaft.)

Age-related diseases, such as osteoarthritis, Alzheimer's disease, diabetes, and cardiovascular disease, are often associated with chronic unresolved inflammation. Neutrophils play central roles in this process by releasing tissue-degenerative proteases, such as cathepsin G, as well as pro-inflammatory leukotrienes produced by the 5-lipoxygenase (5-LO) pathway. Boswellic acids (BAs) are pentacyclic triterpene acids contained in the gum resin of the anti-inflammatory remedy frankincense that target cathepsin G and 5-LO in neutrophils, and might thus represent suitable leads for intervention with age-associated diseases that have a chronic inflammatory component. Here, we investigated whether, in addition to BAs, other triterpene acids from frankincense interfere with 5-LO and cathepsin G. We provide a comprehensive analysis of 17 natural tetra- or pentacyclic triterpene acids for suppression of 5-LO product synthesis in human neutrophils. These triterpene acids were also investigated for their direct interference with 5-LO and cathepsin G in cell-free assays. Furthermore, our studies were expanded to 10 semi-synthetic BA derivatives. Our data reveal that besides BAs, several tetra- and pentacyclic triterpene acids are effective or even superior inhibitors of 5-LO product formation in human neutrophils, and in parallel, inhibit cathepsin G. Their beneficial target profile may qualify triterpene acids as anti-inflammatory natural products and pharmacological leads for intervention with diseases related to aging., Competing Interests: The authors declare no conflict of interest.

New candidates of 3-(4,5-dihydro-1H-pyrazol/isoxazol-5-yl)-2-phenyl-1H-indole derivatives (4-7) were designed combining the pyrazoline/isoxazoline heterocycles and 2-phenylindole to explore its potential as 15-lipoxygenase (15-LOX) inhibitors. The design of the new derivatives was based on utilizing the antioxidant properties of pyrazoline, 2-phenylindole and the good 15-LOX inhibition properties of indolylpyrazoline. The derivatives were synthesized adopting simple and laboratory friendly reaction conditions to give the target compounds in quantitative yields. The resulting indolylpyrazolines/isoxazolines were evaluated as antioxidants against 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and superoxide dismutase (SOD); indolylpyrazoline (4b) was the most potent antioxidant against SOD assay (IC 50  = 1.78 μM) to be superior to ascorbic by 2 folds. Consistently, (4b) was the most potent inhibitor when tested against Soybean 15-LOX (IC 50  = 3.84 μM) excelling quercetin as standard inhibitor by 1.8 folds. Some of the new derivatives were docked into the active binding site of human 15-LOX (PDB entry 4NRE) emphasizing the most potent derivative (4b) and the least potent one (4c). Docking solutions of compounds (4b), (4c), (5b) and (6c) revealed that (4b) was the only compound that got stabilized into the catalytic pocket of enzyme by π-cation interaction with the catalytic Fe + and formation of one hydrogen bond with Ile 676 amino acid. Other derivatives including the least potent one variably got stabilized into the active binding pocket by π-cation interaction with the catalytic Fe + but failed to form hydrogen bond with Ile 676. For the future optimization of the generated inhibitors, (i) antioxidant activity against SOD, (ii) the inhibitor stabilization by π-cation interaction with the catalytic Fe +3 and (iii) formation of hydrogen bond with Ile 676 should be regarded., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Click chemistry was used to synthesize a new series of thioquinazolinone molecules equipped with propargyl moiety,1,2,3-triazolyl and isoxazolyl rings. Our design was based on merging pharmacophores previously reported to exhibit COX-2 inhibitory activities to a thioquinazolinone-privileged scaffold. The synthesized compounds were subjected to in vitro cyclooxygenase COX-1/COX-2 and 15-LOX inhibition assays. Compounds 2c, 3b, 3h, 3j, and 3k showed COX-2 inhibition with IC 50 (μM) 0.18, 0.19, 0.11, 0.16 and 0.17 respectively. These values were compared to celecoxib (IC 50 0.05 μM), diclofenac (IC 50 0.8 μM) and indomethacin (IC 50 0.49 μM) reference drugs. They also showed 15-LOX inhibition with IC 50 (μM) 6.21, 4.33, 7.62, 5.21 and 3.98 respectively. These values were compared with Zileuton (IC 50 2.41 μM) and Meclofenamate sodium (IC 50 5.64 μM) as positive controls. These compounds were further challenged by PMA-induced THP-1 differentiation assay where compounds 2c and 3j inhibited monocyte to macrophage differentiation efficiently with IC 50 values of 4.78 μM and 5.63 μM, respectively, compared to that of diclofenac sodium (4.86 μM). On the other hand, 3h demonstrated a significantly increased potency compared to diclofenac in this assay (IC 50  = 0.13 μM). The same compounds exhibited significant in vivo anti-inflammatory effect as indicated by the formalin-induced rat-paw edema test. Docking experiments of compounds 2c, 3b, 3h, 3j, and 3k into COX-2 binding pocket have been conducted, where strong binding interactions have been identified and effective overall docking scores have been recorded. Their drug-likeness has been assessed using Molinspiration, Molsoft and Pre-ADMET software products., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

A series of carboxamide derivatives of 6- and 7-substituted coumarins have been prepared by an original procedure starting from the corresponding 6- or 7-hydroxycoumarins which were alkylated with ethyl iodoacetate, and the obtained ester was converted to the corresponding carboxylic acids which were thereafter reacted with a series of aromatic/aliphatic/heterocyclic amines leading to the desired amides. The new derivatives were investigated as inhibitors of two enzymes, human carbonic anhydrases (hCAs) and soy bean lipoxygenase (LOX). Compounds 4a and 4b were potent LOX inhibitors, whereas many effective hCA IX inhibitors (K I s in the range of 30.2-30.5 nM) were detected in this study. Two compounds, 4b and 5b , showed the phenomenon of dual inhibition. Furthermore, these coumarins did not significantly inhibit the widespread cytosolic isoforms hCA I and II, whereas they were weak hCA IV inhibitors, making them hCA IX-selective inhibitors. As hCA IX and LOX are validated antitumor targets, these results are promising for the investigation of novel drug targets involved in tumorigenesis., Competing Interests: The authors declare no conflict of interest.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of molecules which have been found to be active against cancer cells with chemopreventive properties by targeting cyclooxygenase (COX-1 and COX-2) and lipoxygenase (LOX), commonly upregulated (particularly COX-2) in malignant tumors. Arene ruthenium(ii) complexes with a pseudo-octahedral coordination environment containing different ancillary ligands have shown remarkable activity against primary and metastatic tumors as reported earlier. This work describes the synthesis of four novel ruthenium(ii)-arene complexes viz. [Ru(η 6 -p-cymene)(nap)Cl] 1 [Hnap = naproxen or (S)-2-(6-methoxy-2-naphthyl)propionic acid], [Ru(η 6 -p-cymene)(diclo)Cl] 2 [Hdiclo = diclofenac or 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, [Ru(η 6 -p-cymene)(ibu)Cl] 3 [Hibu = ibuprofen or 2-(4-isobutylphenyl)propanoic acid] and [Ru(η 6 -p-cymene)(asp)Cl] 4 [Hasp = aspirin or 2-acetoxy benzoic acid] using different NSAIDs as chelating ligands. Complexes 1-3 have shown promising antiproliferative activity against three different cell lines with GI 50 (concentration of drug causing 50% inhibition of cell growth) values comparable to adriamycin. At the concentration of 50 μM, complex 3 is more effective in the inhibition of cyclooxygenase and lipooxygenase enzymes, followed by complex 2 and complex 1 in comparison to their respective free NSAID ligands indicating a possible correlation between the inhibition of COX and/or LOX and anticancer properties. Molecular docking studies with COX-2 reveal that complexes 1 and 2 having naproxen and diclofenac ligands exhibit stronger interactions with COX-2 than their respective free NSAIDs and these results are in good agreement with their relative experimentally observed COX inhibition as well as anti-proliferative activities.

Ebselen is a potent competitive inhibitor of the active form of rabbit 15-lipoxygenase, an enzyme involved in many inflammatory diseases. Light-induced Z-to-E isomerization of the ebselen-like 2-(3-benzylidene)-3-oxo-2,3-dihydrobenzo[b]thiophene-7-carboxylic acid methyl ester (BODTCM) molecule was used to convert the weak (Z)-BOTDCM inhibitor into the (E)-isomer with much higher inhibitory capacity. In this study, the binding modes of ebselen, (E)-BOTDCM and (Z)-BOTDCM, have been analyzed to provide molecular insights on the inhibitory potency of ebselen and on the geometric-isomer specificity of (E)- and (Z)-BOTDCM inhibitors. The inhibitor-enzyme structures obtained from docking and molecular dynamics simulations as well as from QM/MM calculations show that the inhibitor molecules are not coordinated to the nonheme iron in the active site. Thermal motion allows ebselen and (E)-BOTDCM to visit a wide range of the configurational space competing with the polyunsaturated fatty acid for binding at the active site. Both molecules present similar MM/PBSA binding free energies. The energy penalty for the bigger geometric deformation undergone by (E)-BODTCM would explain its lower inhibitor potency. The (Z)-isomer is the weakest inhibitor because thermal motion moves it to a region very far from the first coordination sphere of Fe, where it could not compete with the fatty acid substrate.

A new series of pyrazole-hydrazone derivatives 4a-i were designed and synthesized, their chemical structures were confirmed by IR, 1 H NMR, 13 C NMR, MS spectral data and elemental analysis. IC 50 values for all prepared compounds to inhibit COX-1, COX-2 and 5-LOX enzymes were determined in vitro. Compounds 4a (IC 50 =0.67μM) and 4b (IC 50 =0.58μM) showed better COX-2 inhibitory activity than celecoxib (IC 50 =0.87μM) with selectivity index (SI=8.41, 10.55 in sequent) relative to celecoxib (SI=8.85). Also, compound 4a and 4b exhibited superior inhibitory activity against 5-LOX (IC 50 =1.92, 2.31μM) higher than zileuton (IC 50 =2.43μM). All target pyrazoles were screened for their ability to reduce nitric oxide production in LPS stimulated peritoneal macrophages. Compounds 4a, 4b, 4f and 4i displayed concentration dependent reduction and were screened for in vivo anti-inflammatory activity using carrageenan-induced rat paw edema assay. Compound 4f showed the highest anti-inflammatory activity (% edema inhibition=15-20%) at all doses when compared to reference drug celecoxib (% edema inhibition=15.7-17.5%). Docking studies were carried out to investigate the interaction of target compounds with COX-2 enzyme active site., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The synthetic methodology is carried out in multistep which was initiated as phase I by utilizing Fischer esterification methodology of 2-phenylacetic acid (1) to ethyl-2-phenylacetate (2). The ester was reacted with hydrazine hydrate form 2-phenylacetohydrazide (3) which underwent ring closure with carbon disulfide in alcoholic base to achieve 5-benzyl-1,3,4-oxadiazole-2-thiol (4). Phase II, involved the reaction of electrophiles with 2-bromoacetylbromide (5) with arylated/arenylated amines (6a-e) in aqueous alkaline medium under vigorous shaking to generate N-substituted-2-bromoacetamides (7a-e). Finally in phase III, the parent oxadiazole reacted with N-substituted-2-bromoacetamides and in DMF/LiH to yield 2-[(5-benzyl-1,3,4-oxadiazole-2yl)sulfanyl]-N-(arylated/arenylated) acetamides (8a-e). All the derivatives were screened for their anti-enzymatic potential against acetyl/butyrylcholinesterase and lipoxygenase and for the antibacterial activity. They were found to be weak enzyme inhibitors and also possessed weak antibacterial action with the exception of 8e, which demonstrated prominent anti-enzymatic and antibacterial activity, which may be attributed to the presence of 3,4-dimethoxyphenylacetamide moiety. The LD50 data revealed that most of the N-substituted derivatives were found to be less cytotoxic.

Heterocyclic molecules have been frequently investigated to possess various biological activities during the last few decades. The present work elaborates the synthesis and enzymatic inhibition potentials of a series of sulfonamides. A series of 1-arylsulfonyl-4-Phenylpiperazine (3a-n) geared up by the reaction of 1-phenylpiperazine (1) and different (un)substituted alkyl/arylsulfonyl chlorides (2a-n), under defined pH control using water as a reaction medium. The synthesized molecules were characterized by 1H-NMR, 13C-NMR, IR and EI-MS spectral data. The enzyme inhibition study was carried on α-glucosidase, lipoxygenase (LOX), acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE) enzymes supported by docking simulation studies and the IC 50 values rendered a few of the synthesized molecules as moderate inhibitors of these enzymes where, the compound 3e exhibited comparatively better potency against α-glucosidase enzyme. The synthesized compounds showed weak or no inhibition against LOX, AChE and BChE enzymes.

Some novel indolizine derivatives were synthesized by bioisosteric modification of imidazo[1,2-a]pyridine for anti-inflammatory activity. The physicochemical characterization and structure of compounds were elucidated by state of the art spectroscopic technique. Induced fit docking was performed for initial screening to elucidate the interactions with corresponding amino acids of cyclooxygenase (COX-1, COX-2) and lipoxygenase (LOX) enzymes. The target compounds 53-60 were then evaluated against in vivo carrageenan and arachidonic acid induced rat paw edema models for anti-inflammatory activity. Amongst all the synthesized derivatives, compound 56 showed the significant anti-inflammatory activity in both rat paw edema models with very less ulcerogenic liability in comparison to standard diclofenac, celecoxib, and zileuton. The compounds 56 was further assessed to observe in vitro enzyme inhibition assay on both cyclooxygenase and lipoxygenase enzyme where it showed a preferential and selective non-competitive enzyme inhibition towards the COX-2 (IC 50 =14.91μM, Ki=0.72µM) over COX-1 (IC 50 >50μM) and a significant non-competitive inhibition of soybean lipoxygenase enzyme (IC 50 =13.09μM, Ki=0.92µM). Thus, in silico, in vivo, and in vitro findings suggested that the synthesized indolizine compound 56 has a dual COX-2 and LOX inhibition characteristic and parallel in vivo anti-inflammatory activity in comparison to the standard drugs., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In our previous study, we designed a series of pyrazole derivatives as novel COX-2 inhibitors. In order to obtain novel dual inhibitors of COX-2 and 5-LOX, herein we designed and synthesized 20 compounds by hybridizing pyrazole with substituted coumarin who was reported to exhibit 5-LOX inhibition to select potent compounds using adequate biological trials sequentially including selective inhibition of COX-2 and 5-LOX, anti-proliferation in vitro, cells apoptosis and cell cycle. Among them, the most potent compound 11g (IC 50 =0.23±0.16μM for COX-2, IC 50 =0.87±0.07μM for 5-LOX, IC 50 =4.48±0.57μM against A549) showed preliminary superiority compared with the positive controls Celecoxib (IC 50 =0.41±0.28μM for COX-2, IC 50 =7.68±0.55μM against A549) and Zileuton (IC 50 =1.35±0.24μM for 5-LOX). Further investigation confirmed that 11g could induce human non-small cell lung cancer A549 cells apoptosis and arrest the cell cycle at G2 phase in a dose-dependent manner. Our study might contribute to COX-2, 5-LOX dual inhibitors thus exploit promising novel cancer prevention agents., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Single-target inhibition is an unsatisfactory therapeutic option to treat multifactorial pathologies, brought into limelight 'paradox of inflammation' beside dearth of innovation, rationalizes a shift toward 'multiple-target' design concept in anti-inflammatory research field. To improvise, two platform strategies, drugs mixture or multitarget drugs, are plausible. Dual cyclooxygenase/lipoxygenase inhibitor 'licofelone' developed after the backfire of rofecoxib due to safety concerns has fetched first light of triumph of the latter strategy. As hitting multiple targets in restraint is perhaps more viable strategy rather than single target, this review, outlines the most germane multiple target agents of synthetic and natural origin placing clear advantage in favors of multitarget strategy as real therapeutic solution for inflammation.

Our research to discover potential new multitarget agents led to the synthesis of 10 novel derivatives of cinnamic acids and propranolol, atenolol, 1-adamantanol, naphth-1-ol, and (benzylamino) ethan-1-ol. The synthesized molecules were evaluated as trypsin, lipoxygenase and lipid peroxidation inhibitors and for their cytotoxicity. Compound 2b derived from phenoxyphenyl cinnamic acid and propranolol showed the highest lipoxygenase (LOX) inhibition (IC 50 = 6 μΜ) and antiproteolytic activity (IC 50 = 0.425 μΜ). The conjugate 1a of simple cinnamic acid with propranolol showed the higher antiproteolytic activity (IC 50 = 0.315 μΜ) and good LOX inhibitory activity (IC 50 = 66 μΜ). Compounds 3a and 3b , derived from methoxylated caffeic acid present a promising combination of in vitro inhibitory and antioxidative activities. The S isomer of 2b also presented an interesting multitarget biological profile in vitro . Molecular docking studies point to the fact that the theoretical results for LOX-inhibitor binding are identical to those from preliminary in vitro study.

The progression of cancer is accelerated by increased proliferation, angiogenesis, and inflammation. These processes are mediated by leukotrienes. Several cancer cell lines overexpress 5-lipoxygenase, an enzyme that converts arachidonic acid into leukotrienes. An early inhibitor of the 5-lipoxygenase pathway is Rev-5901, which, however, lacks in in vivo efficacy, as it is rapidly metabolized. We investigated the introduction of carboranes as highly hydrophobic and metabolically stable pharmacophores into lipoxygenase inhibitors. Carboranes are icosahedral boron clusters that are remarkably stable and used to increase the metabolic stability of unstable pharmaceutics without changing their biological activity. By introduction of meta-carborane into Rev-5901, the first carborane-based inhibitor of the 5-lipoxygenase pathway was obtained. We report the synthesis and inhibitory and cytotoxic behavior of these compounds toward several melanoma and colon cancer cell lines and their related anticancer mechanisms., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The undertaken research was initiated by transforming 2-(1H-Indol-3-yl)acetic acid (1) in catalytic amount of sulfuric acid and ethanol to ethyl 2-(1H-Indol-3-yl)acetate (2), which was then reacted with hydrazine monohydrate in methanol to form 2-(1H-Indol-3-yl)acetohydrazide (3). Further, The reaction scheme was designed into two pathways where, first pathway involved The reaction of 3 with substituted aromatic aldehydes (4a-o) in methanol with few drops of glacial acetic acid to generate 2-(1H-Indol-3-yl)-N'-[(un)substitutedphenylmethylidene]acetohydrazides (5a-o) and in second pathway 3 was reacted with acyl halides (6a-e) in basic aqueous medium (pH 9-10) to afford 2-(1H-Indol-3-yl)-N'-[(un)substitutedbenzoyl/2-thienylcarbonyl]acetohydrazides (7a-e). All The synthesized derivatives were characterized by IR, EI-MS and 1H-NMR spectral techniques and evaluated for their anti-bacterial potentials against Gram positive and Gram negative bacterial strains and it was found that compounds 7a-d exhibited antibacterial activities very close to standard Ciprofloxacin. The synthesized derivatives demonstrated moderate to weak anti-enzymatic potential against α-Glucosidase and Butyrylcholinesterase (BChE) where, compounds 7c and 5c exhibited comparatively better inhibition against these enzymes respectively. Compounds 7a, 7d and 7e showed excellent anti-enzymatic potentials against Lipoxygenase (LOX) and their IC 50 values were much lower than the reference standard Baicalein. Enzyme inhibitory activities were also supported by computational docking results. Compounds 5c, 7a, 7b and 7c also showed low values of % hemolytic activity as well, showing that these molecules were not toxic, indicating that these molecules can be utilized as potential therapeutic agents against inflammatory ailments.

New molecular hybrids combining benzothiophene or its bioisostere benzofuran with rhodanine were synthesized as potential dual COX-2/5-LOX inhibitors. The benzothiophene or benzofuran scaffold was linked at position -2 with rhodanine which was further linked to various anti-inflammatory pharmacophores so as to investigate the effect of such molecular variation on the anti-inflammatory activity. The target compounds were evaluated for their in vitro COX/LOX inhibitory activity. The results revealed that, compound 5h exhibited significant COX-2 inhibition higher than celecoxib. Furthermore, compounds 5a, 5f and 5i showed COX-2 inhibitory activity comparable to celecoxib. Compound 5h showed selectivity index SI=5.1 which was near to that of celecoxib (SI=6.7). Compound 5h displayed LOX inhibitory activity twice than that of meclofenamate sodium. Moreover, compounds 5a, 5e and 5f showed significant LOX inhibitory activity higher than that of meclofenamate sodium. Compound 5h was screened for its in vivo anti-inflammatory activity using formalin-induced paw edema and gastric ulcerogenic activity tests. The results revealed that, it showed in vivo decrease in formalin-induced paw edema volume higher than celecoxib. It also displayed gastrointestinal safety profile as celecoxib. The biological results were also consistent with the docking studies at the active sites of the target enzymes COX-2 and 5-LOX. Also, compound 5h showed physicochemical, ADMET, and drug-like properties within those considered adequate for a drug candidate., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Two series of benzodioxole-pyrazole hybrids were synthesized and the IC 50 values for in vitro inhibition of the enzymes cyclooxygenase 1/2 (COX-1, COX-2) and 5-lipoxygenase (5-LOX) were investigated. All compounds were tested for their in vivo anti-inflammatory and analgesic potentials using diclofenac sodium as a reference standard. Compounds 4, 11, 17, 20, 21, 26, and 27, which showed good analgesic and/or anti-inflammatory activities, were also evaluated for their ability to inhibit tumor necrosis factor (TNF)-α production, myeloperoxidase and proteinase, beside their antioxidant activity. Collectively, compounds 11, 17, and 26 displayed significant anti-inflammatory, analgesic, and antioxidant activities, beside dual COX-2 and 5-LOX inhibition. Among these, compound 26 showed high selectivity for in vitro COX-1/COX-2 inhibition, whereas the analogs 11 and 17 noticeably ameliorated the TNF-α level by 85.19 and 97.71%, respectively. A molecular docking study was performed to investigate the possible binding mode of compounds 11, 17, and 26 with the active sites of the COX-2 and 5-LOX enzymes, where they showed nearly the same binding pattern as that of celecoxib and meclofenamic acid, respectively., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Two series of diaza derivatives were prepared by solvent-free condensation of benzoic acid and 4-substituted phenylhydrazines in order to obtain phenylhydrazides (HYD series) and, by oxidation of these compounds, the corresponding benzoyldiazenes (DIA series). Both sets were evaluated as inhibitors of soybean 15-lipoxygenase activity and antioxidant capability in the FRAP and CUPRAC assays. The most potent inhibitors of both series exhibited IC 50 values in the low micromolar range. Kinetic studies showed that at least the more active compounds were competitive inhibitors. Docking results indicated that the most potent inhibitor interacts strongly with Ile-839 and iron in the active site., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aim: Simultaneous inhibition of 5-LOX/COX may enhance anti-inflammatory effects and reduce side effects. Hence, synthesis of novel dual inhibitors of 5-LOX/COX is an important strategy for treatment of inflammation. Results/methodology: The target compounds were designed to hybridize benzothiophene scaffold or its bioisostere benzofuran with various anti-inflammatory pharmacophore hetercycles through different atoms spacers. Compounds 4a, 4c, 4d, 5b, 7a, showed significant in vitro LOX inhibitory activity higher than that of meclofenamate sodium. Compounds 4b, 4e, 4f, 5a exhibited significant in vitro COX-2 inhibition higher than celecoxib and in vitro LOX inhibitory activity twice that of reference. These compounds elicited significant in vivo anti-inflammatory activities higher than celecoxib in formalin-induced paw edema test. Compound 4e exhibited gastrointestinal safety profile as celecoxib. The results were also consistent with the docking studies., Conclusion: Compound 4e could be considered as structural lead for the development of a new class of anti-inflammatory agents with better safety profile.

A series of novel quinoline-2-carboxamides 15-28 was synthesized and evaluated in vitro as dual COXs/LOX inhibitors. Compounds 19 and 27 exhibited the highest potency and selectivity for COX-2 inhibitory activity (IC 50  = 1.21 and 1.13 μM, respectively; selectivity index (COX-1/COX-2) = 6.52 and 7.61, respectively) in comparison to the reference drug celecoxib (COX-2 IC 50  = 0.88 μM; selectivity index (COX-1/COX-2) = 8.31). The anti-inflammatory activity of the newly synthesized compounds was further assessed in vivo using carrageenan induced paw edema assay. Interestingly, the in vitro results of COXs inhibitory assay were consistent with that of the in vivo assay where compounds 19 and 27 showed the highest anti-inflammatory activity with edema inhibition percentages of 59.38% and 65.03%, respectively compared to celecoxib (71.21%) after 5 h. Moreover, it was found that compounds 19 and 27 have a superior gastric safety profile comparable to indomethacin. The molecular docking study of compounds 19 and 27 into COX-2 active site suggested that these hits assumed binding pattern and interactions similar to that of bromocelecoxib (S-58) as a cocrystallized ligand explaining their remarkable COX-2 inhibitory activity and selectivity. Taken together, these results indicated that these derivatives are good leads for subsequent development into potential anti-inflammatory agents with least gastric damage., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

A new series of 11-keto-β-boswellic acid and 3-O-acetyl-11-keto-β-boswellic acid analogs (5, 7, 8, 10, 13, 18a-d, 27a-c, 28a-d) were synthesized by modification of hydroxyl and acid functional moieties of boswellic acids. The structures of these analogs were confirmed by spectral data analysis ( 1 H, 13 C NMR and mass). Compounds 18b, 27a and 8 showed potent 5-lipoxygenase enzyme inhibitory activity (IC 50 : 19.53, 20.31 and 44.14μg/mL). The computational studies revealed that selectivity of AKBA is due to its fitment into the 5-LOX receptor, which is missing for the other enzymes like 12-LOX, COX-1 and COX-2. Our study found potentiating effects of 2-formyl and 3-keto substituents in reviving inactive AKBA analogues possessing essential COOH group at 4th position., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A total of 48 analogues of the natural product myxochelin A were prepared and evaluated for their inhibitory effects on human 5-lipoxygenase in both cell-free and cell-based assays. Structure-activity relationship analysis revealed that the secondary alcohol function and only chiral center of myxochelin A is not required for biological activity. By expanding the diaminoalkane linker of the two aromatic residues it was possible to generate a myxochelin derivative with superior activity against 5-lipoxygenase in intact cells., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The arachidonic acid cascade is a key player in inflammation, and numerous well-established drugs interfere with this pathway. Previous studies have suggested that simultaneous inhibition of 5-lipoxygenase (5-LO) and soluble epoxide hydrolase (sEH) results in synergistic anti-inflammatory effects. In this study, a novel prototype of a dual 5-LO/sEH inhibitor KM55 was rationally designed and synthesized. KM55 was evaluated in enzyme activity assays with recombinant enzymes. Furthermore, activity of KM55 in human whole blood and endothelial cells was investigated. KM55 potently inhibited both enzymes in vitro and attenuated the formation of leukotrienes in human whole blood. KM55 was also tested in a cell function-based assay. The compound significantly inhibited the LPS-induced adhesion of leukocytes to endothelial cells by blocking leukocyte activation.

The biosynthesis of leukotrienes in one of the arachidonic acid pathways and PGE 2 in the other by 5-LOX and mPGES1 respectively, play pivotal roles in augmenting inflammatory responses. PGE 2 is known to participate in cancer pathological processes as well. Isocoumarins are natural compounds with a wide range of biological activities. In this study, 3-aryl isocoumarin derivatives are synthesized and tested against 5-LOX enzyme in vitro and PGE 2 production in HeLa cells. Most of the compounds show high activity, and 1c is identified as a dual inhibitor with an IC 50 of 4.6 ± 0.26 μM and 6.3 ± 0.13 μM against 5-LOX and PGE 2 production respectively. Another compound 7f, exhibits an IC 50 of 12.4 ± 0.14 μM against 5-LOX. Further investigations reveal that the mechanism of action of 1c and 7f against 5-LOX is mixed and competitive modes of action respectively. Thunberginol A (7c) exhibits IC 50 of 15.8 ± 0.03 μM against PGE 2 production. 1c and 7c inhibit the mRNA expression of mPGES1 and COX-2. The study has identified a novel scaffold, 1c with a dual inhibitory activity which can be further optimized to compete against Licofelone which is under clinical trials (with IC 50 of 6.0 μM for mPGES1 & 0.2 μM for 5-LOX). To conclude, 3-aryl isocoumarin derivatives appears as promising tools to fight against inflammatory diseases as well as cancer., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Two new series of N-substituted indole derivatives 4a-l and 5a-h were synthesized. Their chemical structures were confirmed using spectroscopic tools including IR, (1)H NMR, (13)C NMR mass spectroscopy and elemental analyses. The results showed no significant cytotoxic activity on either cancer or normal human cells. Anti-inflammatory activity for all target compounds was evaluated in vitro. Compounds 5a-h were found to have better anti-inflammatory activity than 4a-l. The inhibitory activity of COX-2 and 5-LOX were tested for 5a-h. Three compounds, 5c, 5d and 5f showed excellent COX-2 inhibitory activity with IC50 ranging from 0.98 to 1.23 μM compared to the reference celecoxib (1.54 μM). These compounds had a reasonable selectivity index between 7.03 and 8.05. Additionally, p-methylbenzoyl derivative 5g (IC50 = 5.78 μM) had superior 5-LOX inhibitory activity, higher than quercetin. 5e was close to quercetin in its LOX inhibitory activity. Compounds 5a-h were docked inside the active site of COX-2 and 5-LOX enzymes., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)