1. Eicosanoids like leukotrienes and prostaglandins that produced within the arachidonic acid cascade are involved in the pathogenesis of pain, acute and chronic inflammatory diseases. A promising approach for an effective anti-inflammatory therapy is the development of inhibitors targeting more than one enzyme of this cascade. Aiming to develop balanced COX/LOX inhibitors; 4-aminosalicylate based thiazolinones having different substituents at the 5th position of the 4-thiazolinone ring (2-22) were designed, synthesized, characterized and evaluated in vitro and in vivo for their anti-inflammatory activity. Most of the investigated compounds showed high COX-2 inhibitory potencies (IC₅₀ 39-200 nM) with selectivity indexes (30-84). Two compounds, 19 and 21, (IC₅₀ = 41 and 44 nM), are equipotent to celecoxib (IC₅₀ = 49 nM), while compound 22 (IC₅₀ = 39 nM) was the most potent. For 15-LOX, compounds 5, 11, 19, 21 and 22 revealed higher potency (IC₅₀ 1.5-2.2 µM) than zileuton (IC₅₀ 15 µM). Thus, compounds 5, 11, 19, 21 and 22 are potent dual inhibitors of COX-2 and 15-LOX. In vivo anti-inflammatory testing of these compounds revealed that, compounds 5 and 21 had an anti-inflammatory activity similar to indomethacin and celecoxib (% inhibition of oedema = 60 ± 9) and higher than diclofenac potassium (% inhibition = 52 ± 29), while compound 22 (% inhibition = 63 ± 5) was more active than the reference drugs. The results showed that the activity is controlled by the bulkiness and lipophilicity of the substituent at the 5th position. The cytotoxicity results revealed that all compounds are not cytotoxic, additionally, in an experimental model of ulcerogenic effect, the most active compounds 21 and 22 showed better safety profile than indomethacin. Further, at the active sites of the COX-1, COX-2 and 15-LOX co-crystal, 19, 21, and 22 showed high binding forces in free binding energy study, which is consistent with in vitro and in vivo results. In conclusion, these compounds are good candidates for further biological investigation as potential anti-inflammatory drugs with dual balanced inhibition of COX and 15-LOX and good safety profile.

A potential microtubule destabilizing series of new thirty-five Pyrrol-2-one, Pyridazin-3(2H)-one and Pyridazin-3
(2H)-one/oxime derivatives has been synthesized and tested for their antiproliferative activity against a panel of
60 human cancer cell lines. Compounds IVc, IVg and IVf showed a broad spectrum of growth inhibitory activity
against cancer cell lines representing renal, cancer of lung, colon, central nervous system, ovary, and kidney.
Among them, compound IVg was found to have broad spectrum anti-tumor activity against the tested nine tumor
subpanels with selectivity ratios ranging between 0.21 and 3.77 at the GI50 level. In vitro assaying revealed
tubulin polymerization inhibition by all active compounds IVc, IVg and IVf. The results of the docking study
revealed nice fitting of compounds IVc, IVf, and IVg into CA-4 binding site in tubulin. The three compounds
exhibited high binding affinities (ΔGb = - 12.49 to -12.99 kcal/mol) toward tubulin compared to CA-4 (- 8.87
kcal/mol). Investigation of the binding modes of the three compounds IVc, IVf, and IVg revealed that they
interacted mainly hydrophobically with tubulin and similar binding orientations to that of CA-4. These observations
suggest that tubulin is a possible target for these compounds.

A series of novel piperine–resveratrol hybrids 5a–h was designed, synthesized, and structurally elucidated
by IR, and 1H, 13C, and 19F NMR. Antiproliferative activities of 5a–h were evaluated by NCI against sixty
cancer cell lines. Compound 5b, possessing resveratrol pharmacophoric phenolic moieties, showed
a complete cell death against leukemia HL-60 (TB) and Breast cancer MDA-MB-468 with growth
inhibition percentage of
0.49 and
2.83, respectively. In addition, 5b recorded significant activity
against the other cancer cell lines with growth inhibition percentage between 80 to 95. New 5a–h
hybrids were evaluated for their inhibitory activities against Sirt-1 and Sirt-2 as molecular targets for their
antiproliferative action. Results showed that compounds 5a–h were more potent inhibitors of Sirt-2 than
Sirt-1 at 5 mm and 50 mm. Compound 5b showed the strongest inhibition of Sirt-2 (78  3% and 26  3%
inhibition at 50 mM and 5 mM, respectively). Investigation of intermolecular interaction via Hirschfeld
surface analysis indicates that these close contacts are mainly ascribed to the O–H/O hydrogen
bonding. To get insights into the Sirt-2 inhibitory mechanism, a docking study was performed where 5b
was found to fit nicely inside both extended C-pocket and selectivity pocket and could compete with
the substrate acyl-Lys. Another possible binding pattern showed that 5b could act by partial occlusion of
the NAD+ C-pocket. Collectively, these findings would contribute significantly to better understanding
the Sirt-2 inhibitory mechanism in order to develop a new generation of refined and selective Sirt-2
inhibitors.

A novel series of 19 quinoline/1,2,4-triazole hybrid 6a-i and 7a-j was synthesized and evaluated in vitro as dual COX-2/5-LOX inhibitors. Compounds 6e, 6i , and 7e displayed the highest potency and selectivity for inhibiting COX-2 activity (IC 50 = 7.25, 8.13, and 8.48 nM, respectively; selectivity index (COX-1/COX- 2) = 44.89, 30.30, and 33.47, respectively) in comparison to celecoxib (COX-2 IC 50 = 42.60 nM; selectivity index (SI) = 8.05). The anti-inflammatory activity of the newly synthesized compounds was further examined in vivo using a carrageenan induced paw edema assay. Interestingly, the in vitro findings of the COX inhibitory assay were consistent with the in vivo assay. Moreover, 6e, 6i , and 7e showed a substantial reduction in serum concentrations of PGE 2 , TNF- α, IL-6. Molecular docking analysis of compounds 6e , 6 f, 6i, 7e , and 7f revealed high binding affinities toward COX-2 compared to COX-1, which was matched with the experimental results. In addition, these compounds exhibited different binding orientations into the active site of COX-2, which were dependent on the type of substitutions on N4 of the triazole ring. Among the tested derivatives, compounds 6e, 6i and 7e which showed high selectivity to COX-2, exhibited hydrogen bonding interactions with key amino acids in COX-2 such as Arg120, Arg513, and/or Glu524. In addition, the tested compounds also showed multiple hydrogen bonds with the Arg101, Val110, Arg138 or His130 in 5-LOX. These findings show, taken together, that those derivatives are good leads to potential anti-inflammatory agents with lowest gastric damage.