Design, synthesis, and biological evaluation of some new 2-phenyl-3,6-pyridazinedione derivatives as PDE-5 inhibitors.

Various 2-phenyl-3,6-pyridazinedione derivatives 4a-j, 5a-c, 6a,b, 7a-c, 8, 9, 10a-d, and 11a-d, were effectivelysynthesized, and tested for their potential inhibition of phosphodiesterase enzyme at 10 µM. Then fourteen compounds exhibiting the highest inhibition 4b, 4d, 4e, 4g, 4h, 4i, 5a, 6a,b, 7c, 10a,b, 11a, and 11d were selected for screening their PDE-5 inhibition, where compounds 4b,g,h, and 11a revealed promising PDE-5 inhibition having IC50 values = 25, 53, 22, and 42 nM, respectively in comparison with Sildenafil (IC50 = 16 nM). Additionally, these four most active compounds were safe to normal fibroblast cell line WI-38. Moreover, 4f, 4h, 4j, 10d, and 11d had almost the same anti-proliferative effect against the aortic cell line as Sildenafil. Furthermore, molecular docking illustrated that the binding of the target compounds with the key amino acids in the binding site of PDE-5 (PDB 2H42) was like to that of the cocrystallized ligand Sildenafil. Additionally, molecular dynamics simulation for the most active compound 4h revealed high stability of the 4h -PDE5 complex explaining its promising activity as a PDE-5 inhibitor. Therefore, the 2-phenyl-3,6-pyridazinedione scaffold can be considered an important core for designing more promising PDE-5 inhibitors.

Exploration of thiazolidine-2,4-diones as tyrosine kinase inhibitors: Design, synthesis, ADMET, docking, and antiproliferative evaluations.

As dual EGFR and VEGFR-2 inhibitors, 22 innovative thiazolidine-2,4-diones were modeled, constructed, and measured for their anticancer performance versus four human neoplasms HCT-116, MCF-7, A549, and HepG2. Molecular docking and MD simulation were performed to inspect the binding technique of the proffered congeners with the EGFR and VEGFR-2 receptors. Evidence realized thanks to the docking inquests was vastly consistent together with that detected through the biological screening. Structures 14a and 14g emerged as the most active compounds toward HCT116 (IC50 = 6.01 and 7.44 µM), MCF-7 (IC50 = 5.77 and 7.23 µM), A549 (IC50 = 5.35 and 5.47 µM) and HepG2 (IC50 = 3.55 and 3.85 µM) tumefaction cells. Compounds 14a and 14g exhibited higher events than sorafenib (IC50 = 5.05, 5.58, 4.04, and 4.00 µM) against HepG2 instead subordinate incidents concerning A549, MCF-7, and HCT116, parallelly. Nevertheless, these compounds signified weightier performance than erlotinib (IC50 = 13.91, 8.20, 5.49, 7.73, and µM), with respect to the four cell lines. Compounds having the best activity against the four cell lines, 12a-f, 13a-d, and 14a-g were chosen to appraise their in vitro VEGFR-2 and EGFRT790M inhibiting activities. The best results were for compounds 14a and 14g compared to sorafenib and erlotinib, respectively, with IC50 values of 0.74 and 0.78 µM and 0.12 and 0.14 µM, respectively. Moreover, 13d, 14a, and 14g showed an adequate in silico calculated ADMET profile. The current investigation presents novel candidates for future optimization to construct mightier and eclectic binary VEGFR-2/EGFRT790M restrainers with higher antitumor effects.

New quinazolinone-based derivatives as DHFR/EGFR-TK inhibitors: Synthesis, molecular modeling simulations, and anticancer activity.

New 2-mercapto-quinazolin-4-one analogs were synthesized and tested for their in vitro anticancer activity, dihydrofolate reductase (DHFR) inhibition, and epidermal growth factor tyrosine kinase (EGFR-TK) inhibition activities. Compound 24, which is characterized by a 2-benzyl-thio function, showed broad-spectrum anticancer activity with high safety profile and selectivity index. The concentrations of 24 causing 50% growth inhibition (GI50 ) and total cell growth inhibition (TGI) and its lethal concentration 50 (LC50 ) were 15.1, 52.5, and 91.2 µM, respectively, using 5-fluorouracil as a positive control. Also, it showed EGFR-TK inhibitory activity with IC50 = 13.40 nM compared to gefitinib (IC50 = 18.14 nM) and DHFR inhibitory potency with 0.30 µM compared to methotrexate (MTX; IC50 = 0.08 µM). In addition, compound 24 caused cell cycle arrest and apoptosis on COLO-205 colon cancer cells. Compounds 37, 21, and 54 showed remarkable DHFR inhibitory activity with IC50 values of 0.03, 0.08, and 0.08 µM, respectively. The inhibitory properties of these compounds are due to an electron-withdrawing group on the quinazolinone ring, except for compound 54. In a molecular modeling study, compound 24 showed the same binding mode as gefitinib as it interacted with the amino acid Lys745 via π-π interaction. Compound 37 showed a similar binding mode as MTX through the binding interaction with Lys68, Asn64 via hydrogen bond acceptor, and Phe31 via arene-arene interaction. The obtained model and substitution pattern could be used for further development.

Design and synthesis of some new 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines as multi tyrosine kinase inhibitors.

The present study involves design and synthesis of five series of 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines 9a-l, 11a-e, 13a-c, 14a-f and 15a-e. Candidates 9a-l and 11a-e were evaluated for their EGFR and HER2 inhibitory activity compared to Lapatinib. Compounds 9b, 9d, 9f, 11b and 11c were further screened for their in vitro cytotoxicity against two human breast cancer cell lines: AU-565 and MDA-MB-231 in addition to normal breast cell line MCF10A. Compound 9d revealed a remarkable cytotoxic efficacy against AU-565 cell line (IC50 = 1.54 µM) relative to Lapatinib (IC50 = 0.48 µM), whereas compounds 9d and 11c showed a superior cytotoxicity towards MDA-MB-231 (IC50 = 2.67 and 1.75 µM, respectively) in comparison to Lapatinib (IC50 = 9.29 µM). Moreover, compounds 13a-c, 13a-c, 14a-f and 15a-e were tested for their VEGFR-2 inhibitory activity compared to Sorafenib. Compounds 13a, 14c and 14e exhibited remarkable inhibition (IC50 = 79.80, 50.22 and 78.02 nM, respectively) relative to Sorafenib (IC50 = 51.87 nM). In vitro cytotoxicity of these compounds against HepG2, HCT-116 and normal cell (WISH) revealed a superior cytotoxicity against HepG2, HCT-116 especially 13a (IC50 = 17.51 and 5.56 µM, respectively) and 14c (IC50 = 10.40 and 3.37 µM, respectively) compared to Sorafenib (IC50 = 19.33 and 6.82 µM, respectively). Compounds 9d, 11c and 14c were subjected to cell cycle analysis and apoptotic assay. Molecular docking and ADME prediction studies were fulfilled to illustrate the interaction of the potent derivatives with the hot spots of the active site of EGFR, HER2 and VEGFR-2 along with prediction of their pharmacokinetic and physicochemical properties.

Synthesis, molecular modelling and QSAR study of new N-phenylacetamide-2-oxoindole benzensulfonamide conjugates as carbonic anhydrase inhibitors with antiproliferative activity.

In continuation of our previous studies to optimise potent carbonic anhydrase inhibitors, two new series of isatin N-phenylacetamide based sulphonamides were synthesised and screened for their human (h) carbonic anhydrase (EC 4.2.1.1) inhibitory activities against four isoforms hCA I, hCA II, hCA IX and hCA XII. The indole-2,3-dione derivative 2h showed the most effective inhibition profile against hCAI and hCA II (KI = 45.10, 5.87 nM) compared to acetazolamide (AAZ) as standard inhibitor. Moreover, 2h showed appreciable inhibition activity against the tumour-associated hCA XII, similar to AAZ showing KI of 7.91 and 5.70 nM, respectively. The analogs 3c and 3d showed good cytotoxicity effects, and 3c revealed promising selectivity towards lung cell line A549. Molecular docking was carried out for 2h and 3c to predict their binding conformations and affinities towards the hCA I, II, IX and XII isoforms.

Synthesis, in vitro anticancer activity and in silico studies of certain pyrazole-based derivatives as potential inhibitors of cyclin dependent kinases (CDKs).

New diphenyl-1H-pyrazoles were synthesized and screened for CDK2 inhibition where 8d, 9b, 9c, and 9e exhibited promising activity (IC50 = 51.21, 41.36, 29.31, and 40.54 nM respectively) compared to R-Roscovitine (IC50 = 43.25 nM). Furthermore, preliminary anti-proliferative activity screening of some selected compounds on 60 cancer cell lines was performed at the (NCI/USA). Compounds 8a-c displayed promising growth inhibitory activity (mean %GI; 73.74, 94.32 and 74.19, respectively). Additionally, they were further selected by the NCI for five-dose assay, exhibiting pronounced activity against almost the full panel (GI50 ranges; 0.181-5.19, 1.07-4.12 and 1.07-4.82 µM, respectively) and (Full panel GI50 (MG-MID); 2.838, 2.306 and 2.770 µM, respectively). Screening the synthesized compounds 8a-c for inhibition of CDK isoforms revealed that compound 8a exhibited nearly equal inhibition to all the tested CDK isoforms, while compound 8b inhibits CDK4/D1 preferentially than the other isoforms and compound 8c inhibits CDK1, CDK2 and CDK4 more than CDK7. Flow cytometry cell cycle assay of 8a-c on Non-small cell lung carcinoma (NSCL HOP-92) cell line revealed S phase arrest by 8a and G1/S phase arrest by 8b and 8c. Apoptotic induction in HOP-92 cell line was also observed upon treatment with compounds 8a-c. Docking to CDK2 ATP binding site revealed similar interactions as the co-crystallized ligand R-Roscovitine (PDB code; 3ddq). These findings present compounds 8a-c as promising anti-proliferative agents.

Design, synthesis and in silico insights of new 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives with potent anticancer and multi-kinase inhibitory activities.

Aiming to obtain an efficient anti-proliferative activity, structure- and ligand-based drug design approaches were expanded and utilized to design and refine a small compound library. Subsequently, thirty-two 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives were selected for synthesis based on the characteristic pharmacophoric features required for PI3K and B-Raf oncogenes inhibition. All the synthesized compounds were evaluated for their in vitro anticancer activity. Compounds 17 and 22c displayed an acceptable potent activity according to the DTP-NCI and were further evaluated in the NCI five doses assay. To validate our design, compounds with the highest mean growth inhibition percent were screened against the target PI3Kα and B-RafV600E to confirm their multi-kinase activity. The tested compounds showed promising multi-kinase activity. Compounds 17 and 22c anticancer effectiveness and multi-kinase activity against PI3Kα and B-RafV600E were consolidated by the inhibition of B-RafWT, EGFR and VEGFR-2 with IC50 in the sub-micromolar range. Further investigations on the most potent compounds 17 and 22c were carried out by studying their safety on normal cell line, in silico profiling and predicted ADME characteristics.

3-Methyl-imidazo[2,1-b]thiazole derivatives as a new class of antifolates: Synthesis, in vitro/in vivo bio-evaluation and molecular modeling simulations.

Inhibiting the Dihydrofolate reductase (DHFR) enzyme has been validated in multiple clinical manifestations related to bacterial infection, malaria, and multiple types of cancer. Herein, novel series of 3-methyl-imidazo[2,1-b] thiazole-based analogs were synthesized and biologically evaluated for their in vitro inhibitory profile towards DHFR. Compounds 22 and 23 exhibited potent inhibitory profile targeting DHFR (IC50 0.079 and 0.085 µM, respectively comparable to MTX IC50 0.087 µM). Compounds 22 and 23 showed promising cytotoxicity against MCF7 breast cancer cell lines inducing cell cycle arrest and apoptosis. Furthermore, Compound 23 showed its potential to reduce body weight and tumor volume significantly, using Ehrlich ascites carcinoma (EAC) solid tumor animal model of breast cancer, compared to control-treated groups. Further, molecular modeling simulations validated the potential of 22 and 23 to have high affinity binding towards Arg22 and Phe31 residues via π-π interaction and hydrogen bonding within DHFR binding pocket. Computer-assisted ADMET study suggested that the newly synthesized analogs could have high penetration to the blood brain barrier (BBB), better intestinal absorption, non-inhibitors of CYP2D6, adequate plasma protein binding and good passive oral absorption. The obtained model and pattern of substitution could be used for further development of DHFR inhibitors.

Design, synthesis, and pharmacological characterization of some 2-substituted-3-phenyl-quinazolin-4(3H)-one derivatives as phosphodiesterase inhibitors.

Some 3-phenyl-quinazolin-4(3H)-one-2-thioethers (3a-e, 5a,b, 7a-e, 9a-d, 10a-d, and 12) along with 2-aminoquinazoline derivatives 13a-c were prepared and screened for their in vitro phosphodiesterase (PDE) inhibitory activity. Some compounds such as 7d,e, 9a,b,d, 10a,d, and 13b exhibited promising activity as compared with the non-selective PDE inhibitor IBMX. This inhibitory activity was validated by molecular docking in the active site of PDE7A and PDE4 to investigate their selectivity. Furthermore, the most active compound 10d (IC50 = 1.15 µM) was tested in vivo using behavioral tests. Compound 10d was able to pass the blood-brain barrier and improve scopolamine-induced cognitive deficits. Therefore, this core can be considered as a promising scaffold for further optimization to obtain new compounds with better PDE7A selective inhibition.

Nanomolar potency of imidazo[2,1-b]thiazole analogs as indoleamine 2,3-dioxygenase inhibitors.

Novel series of imidazo[2,1-b]thiazole analogs were designed, synthesized, and biologically evaluated as indoleamine 2,3-dioxygenase (IDO1) inhibitors. Imidazo[2,1-b]thiazoles 6, 7, and 8 showed inhibitory profiles against IDO1 at IC50 values of 68.48, 82.39, and 48.48 nM, respectively, compared with IDO5L at IC50 67.40 nM. Benzo[d]imidazo[2,1-b]thiazoles 17, 20, and 22 showed promising IDO1 inhibition at IC50 values of 53.58, 53.16, and 57.95 nM, respectively. Compound 7 showed a growth-inhibitory profile at GI of 39.33% against the MCF7 breast cancer cell line, while 8 proved lethal to ACHN renal cancer cells. Cells treated with compounds 17 and 22 showed a typical apoptosis pattern of DNA fragments that reflected the G0/G1, S, and G2/M phases of the cell cycle, together with a pre-G1 phase corresponding to apoptotic cells, which indicates that cell growth arrest occurred at the S phase. Molecular modeling simulations validated the potential of benzo[d]imidazo[2,1-b]thiazole analogs to chelate iron(III) within the IDO1 binding pocket and, hence, to have a better binding affinity via hydrophobic-hydrophobic interactions.

Synthesis and selective inhibitory effects of some 2-oxindole benzenesulfonamide conjugates on human carbonic anhydrase isoforms CA I, CA II, CA IX and CAXII.

Three series of 2-oxindole benzenesulfonamide conjugates with different linkers were prepared by the condensation reaction of isatin derivatives 1a-e with different benzenesulfonamides. They were screened for their ability to inhibit human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, hCA II, hCA IX and hCA XII. Many compounds revealed promising activity and selectivity toward CAI, CAII and CAIX compared to acetazolamide (AAZ) especially compounds 2b (KI = 97.6, 8.0 nM against hCA I, hCA II, respectively) and 3a (KI = 90.2, 6.5 and 21.4 nM against hCA I, hCA II and hCA IX, respectively) relative to AAZ (KI = 250, 12 and 25 nM). Additionally, compound 4a revealed the highest activity against hCA II and hCA IX with KI of 3.0 and 13.9 nM, respectively. Docking of 2b, 3a and 4a into the active site of CA I, II, IX and XII revealed binding mode comparable to AAZ confirming the inhibition results.

Synthesis of some N-aroyl-2-oxindole benzenesulfonamide conjugates with carbonic anhydrase inhibitory activity.

Implication of carbonic anhydrases (CAs) in many physiological functions made them attractive therapeutic targets. Herein, we report the synthesis of three series of benzenesulfonamide-based compounds (5a-e, 9a-e and 10a-e) as potential ligands to four of the human CA isoforms (hCA I, hCA II, hCA IX and hCA XII). All synthesized compounds were evaluated for their CA inhibitory activity. Most of the compounds preferentially inhibited the tumor-associated isoforms IX and XII. Series 9a-e and 10a-e showed the highest activity. Of particular interest was compound 10a which demonstrated the highest activity among all compounds with Ki of 68.3 and 21.5 nM against hCA IX and hCA XII, respectively, in addition to its highest selectivity index. To get deep insight on the interaction of compound 10a with CA, docking experiment was run to study the binding interaction with key amino acids and zinc ion in the catalytic site of the four isoforms studied.

Some 1,3,5-trisubstituted pyrazoline derivatives targeting breast cancer: Design, synthesis, cytotoxic activity, EGFR inhibition and molecular docking.

Different 1,3,5-trisubstituted pyrazoline derivatives 2a-c, 3-c, 4a-f, 6a-c, 7a-f and 8a-d were prepared via condensation reaction of the appropriate chalcone 1a-c or 5a-c with various hydrazine derivatives. All compounds were screened for their cytotoxicity against breast MCF-7 cancer cell line and the normal fibroblasts WI-38. Thirteen compounds 2a, 3a, 3c, 4a-d, 6c, 7d, 7e, 8b, 8d and 8f revealed promising cytotoxicity against MCF-7 compared to the reference standard staurosporine and they were safe to the normal fibroblasts WI-38. In addition, compounds 3c, 6c, 7d, 8b and 8d elicited higher cytotoxicity than erlotinib and exhibited promising EGFR inhibitory activity at submicromolar level comparable to that of erlotinib except for compound 8b that may exert its cytotoxicity via another mechanism besides EGFR inhibition. Molecular docking of 3c, 6c, 7d, 8b and 8d in the active site of EGFR confirmed the obtained results.

Synthesis of 1,2,4-triazolo[1,5-a]pyrimidine derivatives: Antimicrobial activity, DNA Gyrase inhibition and molecular docking.

A series of 1,2,4-triazolo[1,5-a]pyrimidine derivatives was designed, synthesized and screened for their antibacterial and antifungal activities as well as their safety profile. Compounds 2b, 3a, 6b, 8b, 8c, 8h, 9a,b, 10b, 11a,b and 12a,b showed high activity against Gram-positive and Gram-negative bacteria with MIC values ranging from 0.25 to 2.0 µg/mL. Many compounds were safe with no cytotoxicity against human embryonic kidney and red blood cells at concentration up to 32 µg/mL. Moreover, compound 9a showed the highest inhibitory activity against DNA Gyrase with IC50 = 0.68 µM compared to ciprofloxacin IC50 = 0.85 µM. Molecular docking at DNA Gyrase active site revealed binding mode and docking scores comparable to that of ciprofloxacin confirming their antibacterial activity via DNA Gyrase inhibition.

Design and synthesis of some barbituric and 1,3-dimethylbarbituric acid derivatives: A non-classical scaffold for potential PARP1 inhibitors.

Six series based on barbituric acid 5a-e, 10a-d; thiobarbituric acid 6a-e, 11a-d and 1,3-dimethylbarbituric acid 7a-e, 12a-d were prepared and screened for their in vitro PARP1 inhibition. They revealed promising inhibition at nanomolar level especially compounds 5c, 7b, 7d and 7e (IC50 = 30.51, 41.60, 41.53 and 36.33 nM) with higher potency than olaparib (IC50 = 43.59 nM). Moreover, compounds 5b, 5d, 7a, 12a and 12c exhibited good comparable activity (IC50 = 65.93, 58.90, 66.57, 45.40 and 50.62 nM, respectively). Furthermore, the most active compounds 5c, 7b, 7d, 7e, 12a and 12c against PARP1 in vitro were evaluated in the BRCA1 mutated triple negative breast cancer cell line MDA-MB-436 where 5c and 12c showed higher potency compared to olaparib and result in cell cycle arrest at G2/M phase. 5c and 12c showed apoptotic effects in MDA-MB-436 and potentiated the cytotoxicity of temozolomide in A549 human lung epithelial cancer cell line. Compounds 5c and 12c represent interesting starting points towards PARP1 inhibitors.

Synthesis and anti-proliferative activity of some new quinoline based 4,5-dihydropyrazoles and their thiazole hybrids as EGFR inhibitors.

Quinoline derivatives 2, 3, quinolinyl based pyrazolines 4a,b, 5 and quinolinyl pyrazolinyl thiazole hybrids 6a-d, 7a-c and 8a-d were synthesized and screened for their anti-proliferative activity against MCF-7, HeLa and DLD1 cancer cell lines as well as normal fibroblast WI-38. Most of the tested compounds showed promising anticancer activity in addition to their safety towards the normal cell line. Eight compounds eliciting superior cytotoxicity against DLD1 and safe to the normal cell line 2, 3, 5, 6a, 6b, 7b, 7c and 8a were evaluated for their efficacy as EGFR inhibitors. They revealed inhibitory activity at nanomolar level especially compounds 6b, 2 and 7c with IC50 (31.80, 37.07 and 42.52 nM) in comparison to Gefitinib (IC50 = 29.16 nM).

Design and synthesis of 1,2,4-triazolo[1,5-a]pyrimidine derivatives as PDE 4B inhibitors endowed with bronchodilator activity.

A series of 1,2,4-triazolo[1,5-a]pyrimidine derivatives was designed, synthesized, and screened for their phosphodiesterase (PDE 4B) inhibitory activity and bronchodilation ability. Compound 7e showed 41.80% PDE 4B inhibition at 10 µM. Eight compounds were screened for their bronchodilator activity, where compounds 7f and 7e elicited promising bronchodilator activity with EC50 values of 18.6 and 57.1 µM, respectively, compared to theophylline (EC50 = 425 µM). Molecular docking at the PDE 4B active site revealed a binding mode and docking scores comparable to those of a reference ligand, consistent with their PDE 4B inhibition activity.

Design and synthesis of novel imidazo[4,5-b]pyridine based compounds as potent anticancer agents with CDK9 inhibitory activity.

New imidazo[4,5-b]pyridine derivatives were designed, synthesized and screened for their anticancer activity against breast (MCF-7) and colon (HCT116) cancer cell lines. Nine compounds (I, II, IIIa, IIIb, IV, VI, VIIa, VIII, IX) showed significant activity against MCF-7, while six compounds (I, VIIc, VIIe, VIIf, VIII, IX) elicited a remarkable activity against HCT116. Compounds showing significant anticancer activity revealed remarkable CDK9 inhibitory potential (IC50 = 0.63-1.32 µM) relative to sorafenib (IC50 = 0.76 µM). Moreover, a molecular docking study was performed to illustrate the binding mode of the most active compounds in the active site of CDK9 where it revealed superior binding affinity relative to the natural ligand (T3C).

Synthesis, antitumor activity evaluation, and DNA-binding study of coumarin-based agents.

A novel series of coumarin-thiadiazole heterocycle derivatives was synthesized by the nucleophilic substitution reaction. The synthesized compounds were structurally verified by IR, 1 H NMR, 13 C NMR, mass spectra, and elemental analyses. The antitumor activity of the synthesized compounds was evaluated through DNA binding assays and the 60-cell line panel according to the US NCI-DTP protocol or a selection of human tumor cell lines: breast cancer (MCF-7), liver cancer (HepG-2), and colorectal cancer (HCT-116). Most of the compounds had better DNA/ethidium bromide fluorescence quenching rather than methyl green displacement, suggesting superior DNA intercalation over DNA groove binding. Compounds 8 and 14b showed the best quenching effect with KSV = 4.27 × 105 M-1 . Moreover, the results for compounds 8, 4c, and 4e revealed a possible dual DNA binding mode with the intercalation to be superior, with KSV 4.27 × 105 , 3.96 × 105 , and 3.51 × 105 M-1 , respectively, compared to 42%, 45%, and 43% methyl green displacement, respectively. Out of the 60-cell line panel, the leukemia HL-60 cell line was the most susceptible to growth inhibition when treated with 14a, resulting in 61% growth, followed by the lung carcinoma cell line NCI-H522 showing 67% growth when treated with 9. Moreover, compound 10c had an IC50 value of 24.9 µg/mL against the HepG-2 cell line.

Synthesis and QSAR study of novel anti-inflammatory active mesalazine-metronidazole conjugates.

Novel, mesalazine, metronidazole conjugates 6a-e with amino acid linkers were synthesized utilizing benzotriazole chemistry. Biological data acquired for all the novel bis-conjugates showed (a) some bis-conjugates exhibit comparable anti-inflammatory activity with parent drugs and (b) the potent bis-conjugates show no visible stomach lesions. 3D-pharmacophore and 2D-QSAR modeling support the observed bio-properties.