Synthesis and biological evaluation of 6H-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones as antimitotic agents and inhibitors of tubulin polymerization

A series of 6H-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones have been synthesized and evaluated for their antiproliferative activities. Among them, compounds 2j and 4d displayed potent cytotoxic activities in vitro against HeLa cell line with IC₅₀ values of 0.07 and 0.06 μM, respectively. In general, the antiproliferative activities are correlated with the inhibitory effect on tubulin polymerization and binding property of the colchicine binding site. In addition, flow cytometry and immunofluorescence analysis revealed selected compounds caused G2/M phase arrest of the cell cycle and disruption of the mitotic spindle assembly, which had correlation with proliferation inhibitory activity.     

Synthesis and in vitro anticancer evaluation of some fused indazoles,quinazolines and quinolines as potential EGFR inhibitors

derivatives of benzo[g]indazole 5a, b, benzo[h]quinazoline 7, 12a-c, 13a-c and 15a-c and benzo[h]quinoline 17a-c and 19a-c were synthesized from 6-methoxy-3,4-dihydronaphthalen-1(2H)-one (1). Anticancer activity of all the synthesized compounds was evaluated against four cancerous cell lines; HepG2, MCF-7, HCT116 and Caco-2. MCF-7 cells emerged as the most sensitive cell line against the target compounds. All the examined compounds, except 5a and 5b, displayed potent to moderate anticancer activity against MCF-7 cells with an IC₅₀ values ranging from 7.21 to 21.55 µM. In particular, compounds 15c and 19b emerged as the most potent derivatives against EGFR-expressing MCF-7 cells with IC₅₀ values = 7.70 ± 0.39 and 7.21 ± 0.43 μM, respectively. Additionally, both compounds did not display any significant cytotoxicity towards normal BHK-21 fibroblast cells (IC₅₀ value > 200 µM), thereby providing a good safety profile as anticancer agents. Furthermore, compounds 15c and 19b displayed potent inhibitory activity towards EGFR in the sub-micromolar range (IC₅₀ = 0.13 ± 0.01 and 0.14 ± 0.01 μM, respectively), compared to that of Erlotinib (IC₅₀ = 0.11 ± 0.01 μM). Docking studies for 15c and 19b into EGFR active site was carried out to explore their potential binding modes. Therefore, compounds 15c and 19b can be considered as interesting candidates for further development of more potent anticancer agents.     

Antitubulin effects of aminobenzothiophene-substituted triethylated chromones

In the course of our continuing studies on the 2-(benzo[b]thiophene-3′-yl)-6,8,8-triethyldesmosdumotin B (TEDB-TB) series, we designed and synthesized nine amino-TEDB-TB derivatives to improve pharmaceutical properties, identify structure activity relationships, and discover novel antitubulin agents. Among all newly synthesized amino-TEDB-TBs, the 5′- and 6′-amino derivatives, 6 and 7, exhibited significant antiproliferative activity against five human tumor cell lines, including an MDR subline overexpressing P-gp. The IC₅₀ values of 0.50–1.01 µM were 3–6 times better than those of previously reported hydroxy-TEDB-TBs. Compounds 6 and 7 inhibited tubulin polymerization, induced both depolymerization of interphase microtubules and multiple spindle formations, and caused cell arrest at prometaphase. Among all compounds, compound 7 scored best pharmaceutically with LogP 2.11 and biologically with greater antiproliferative activity and induction of cell cycle arrest at prometaphase.     

Synthesis and biological evaluation of imidazo[2,1-b]thiazole-benzimidazole conjugates as microtubule-targeting agents

A series of imidazo[2,1-b]thiazole-benzimidazole conjugates were synthesized and evaluated for their antiproliferative activity against four human cancer cell lines i.e.; HeLa (cervical), A549 (lung), MCF-7 (breast) and DU-145 (prostate) along with normal HEK-293 cell line. Amongst them, conjugate 6d displayed significant cytotoxicity against human lung cancer cell line, A549 with IC₅₀ value 1.08 µM. Further, cell cycle analysis revealed that this compound arrested the cell cycle at G2/M phase in A549 cells. Furthermore, the tubulin polymerization assay results suggest that this conjugate (6d) exhibits significant inhibitory effect on the tubulin assembly with an IC50 value of 1.68 µM. Moreover, the apoptotic inducing properties of compound 6d was confirmed by Hoechst staining, measurement of mitochondrial membrane potential (ΔΨm) and annexin V-FITC assay. Further, molecular docking studies revealed that compound 6d occupied the colchicine binding site.     

Synthesis,antimycobacterial activity and docking study of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives and related hydrazide-hydrazones

A new convenient method for preparation of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b–g and coumarin containing hydrazide-hydrazone analogues 4a–e was presented. The antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and cytotoxicity against the human embryonic kidney cell line HEK-293 were tested in vitro. All compounds demonstrated significant minimum inhibitory concentrations (MIC) ranging 0.28–1.69 μM, which were comparable to those of isoniazid. The cytotoxicity (IC₅₀ > 200 µM) to the “normal cell” model HEK-293T exhibited by 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b–e, was noticeably milder compared to that of their hydrazone analogues 4a–e (IC₅₀ 33–403 µM). Molecular docking studies on compounds 4a–e and 5b–g were also carried out to investigate their binding to the 2-trans-enoyl-ACP reductase (InhA) enzyme involved in M. tuberculosis cell wall biogenesis. The binding model suggested one or more hydrogen bonding and/or arene-H or arene-arene interactions between hydrazones or pyrazole-fused coumarin derivatives and InhA enzyme for all synthesized compounds.     

Design and synthesis of novel pyrrolo[2,3-b]pyridine derivatives targeting V600EBRAF

Several pyrrolo[2,3-b]pyridine-based B-RAF inhibitors are well known and some of them are currently FDA approved as anticancer agents. Based on the structure of these FDA approved ^V600EB-RAF inhibitors, two series of pyrrolo[2,3-b]pyridine scaffold were designed and synthesized in attempt to develop new potent ^V600EB-RAF inhibitors. The 38 synthesized compounds were biologically evaluated for their ^V600EB-RAF inhibitory effect at single dose (10 μM). Compounds with high percent inhibition were tested to determine their IC₅₀ over ^V600EB-RAF. Compounds 34e and 35 showed the highest inhibitory effect with IC₅₀ values of 0.085 µM and 0.080 µM, respectively. Headed for excessive biological evaluation, the synthesized derivatives were tested over sixty diverse human cancer cell lines. Only compound 35 emerged as a potent cytotoxic agent against different panel of human cancer cell lines.     

Design,synthesis, and structure-activity relationships of new benzofuro[3,2-b]pyridin-7-ols as DNA topoisomerase II inhibitors

Human DNA topoisomerases have become attractive targets for developing more effective anticancer drugs. In this study, a series of new benzofuro[3,2-b]pyridin-7-ols were designed and synthesized for the first time and screened for their topoisomerase I and II inhibitory and antiproliferative activity. Structure-activity relationships revealed the position of ortho- and para-hydroxyl group at 2-phenyl ring, and meta-hydroxyl group at 4-phenyl ring of benzofuro[3,2-b]pyridin-7-ol are important for potent and selective topo II inhibitory activity. Compound 11 showed the most selective and potent topo II inhibition (100% inhibition at 100?µM) and strongest antiproliferative activity (IC₅₀?=?0.86?µM) than all the positive controls in HeLa cell line.     

Design,synthesis and biological evaluation of fused naphthofuro[3,2-c] quinoline-6,7,12-triones and pyrano[3,2-c]quinoline-6,7,8,13-tetraones derivatives as ERK inhibitors with efficacy in BRAF-mutant melanoma

Approximately 60% of human cancers exhibit enhanced activity of ERK1 and ERK2, reflecting their multiple roles in tumor initiation and progression. Acquired drug resistance, especially mechanisms associated with the reactivation of the MAPK (RAF/MEK/ERK) pathway represent a major challenge to current treatments of melanoma and several other cancers. Recently, targeting ERK has evolved as a potentially attractive strategy to overcome this resistance. Herein, we report the design and synthesis of novel series of fused naphthofuro[3,2-c]quinoline-6,7,12-triones 3a-f and pyrano[3,2-c]quinoline-6,7,8,13-tetraones 5a,b and 6, as potential ERK inhibitors. New inhibitors were synthesized and identified by different spectroscopic techniques and X-ray crystallography. They were evaluated for their ability to inhibit ERK1/2 in an in vitro radioactive kinase assay. 3b and 6 inhibited ERK1 with IC50s of 0.5 and 0.19 µM, and inhibited ERK2 with IC50s of 0.6 and 0.16 µM respectively. Kinetic mechanism studies revealed that the inhibitors are ATP-competitive inhibitors where 6 inhibited ERK2 with a K_i of 0.09 µM. Six of the new inhibitors were tested for their in vitro anticancer activity against the NCI-60 panel of tumor cell lines. Compound 3b and 6 were the most potent against most of the human tumor cell lines tested. Moreover, 3b and 6 inhibited the proliferation of the BRAF mutant A375 melanoma cells with IC50s of 3.7 and 0.13 µM, respectively. In addition, they suppressed anchorage-dependent colony formation. Treatment of the A375 cell line with 3b and 6 inhibited the phosphorylation of ERK substrates p-90RSK and ELK-1 and induced apoptosis in a dose dependent manner. Finally, a molecular docking study showed the potential binding mode of 3b and 6 within the ATP catalytic binding site of ERK2.     

Synthesis,anticancer assessment on human breast,liver and colon carcinoma cell lines and molecular modeling study using novel pyrazolo[4,3-c]pyridine derivatives

The key intermediate 3-aminopyrazolo[4,3-c]pyridine-4,6-dione (2) is considered as a precursor for some novel pyrazolo[4,3-c]pyridines 4a-c, arylhydrazopyrazolo[4,3-c]pyridines 8a-e, pyrazolo[4,5,1-ij][1,6]naphthyridines 11a-e and pyrido[4′,3′:3,4]pyrazolo[1,5-a]-pyrimidines 15a-d through Knovenegal condensation, coupling reaction and Michael addition. Some of the newly synthesized pyrazolo[4,3-c]pyridine derivatives were investigated for anticancer activity. The results of the cytotoxic activity revealed that compound 6b was the most active compound against the breast and liver carcinoma cell lines which gives IC₅₀ values of 1.937 and 3.695 µg/mL, respectively compared to reference drug (doxorubicin) with IC₅₀ values of 2.527 and 4.749 µg/ml, respectively. Moreover, compound 6c was potent compound against the colon carcinoma cell line which gives the value of IC₅₀ = 2.914 µg/ml compared to doxorubicin with IC₅₀ value of 3.641 µg/ml. Some selected of the novel synthesized compounds were docked inside the active site of ERK2 enzyme and were found display a suitable binding with the active site amino acids according to their bond lengths, angles and conformational energy.     

Synthesis and cytokinin activity of N-acylaminodeazapurines

Three 7-acylaminoimidazo[4,5-b]pyridines, namely 7-pentanoylaminoimidazo[4,5-b]pyridine (1), 7-benzoylaminoimidazo[4,5-b]pyridine(2), and 7-(2-furoylamino)imidazo[4,5-b]pyridine(3), six 4-acylaminoimidazo[4,5-c]pyridines, namely 4-propionylaminoimidazo[4,5-c]pyridine(4), 4-butyryl-aminoimidazo[4,5-c]pyridine(5), 4-pentanoylaminoimidazo[4,5-c]pyridine(6) 4-hexanoylaminoimidazo[4,5-c]pyridine(7),4-benzoylaminoimidazo[4,5-c]pyridine(8), and 4-(2-furoylamino)imidazo[4,5-c]-pyridine(9), and seven 7-acylaminoimidazo[4,5-c]pyridines, namely 7-propionylaminoimidazo[4,5-c]-pyridine(10), 7-butyrylaminoimidazo[4,5-c]pyridine(11), 7-pentanoylaminoimidazo[4,5-c]pyridine(12), 7-hexanoylaminoimidazo[4,5-c]pyridine(13), 7-benzoylaminoimidazo[4,5-c]pyridine(14), 7-phenylacetylaminoimidazo[4,5-c]pyridine(15), and 7-(2-furoylamino)imidazo[4,5-c]pyridine(16) were synthesized and tested for their cytokinin activity with the tobacco callus bioassay. 2 showed a cytokinin activity at 1 × 10⁻⁸ M and gave a callus yield about 72% of that produced by kinetin at 1 × 10⁻⁶ M. 1, 3 and 8 showed the optimum growth responses in the range of 10⁻⁷−10⁻⁶ M. 4, 5, 7, 9–16 were slightly active. These results support previous reports that a nitrogen atom at the 3-position in the purine ring plays an important role in conferring high cytokinin activity.     

Design,synthesis and anticancer evaluation of thieno[2,3-d]pyrimidine derivatives as dual EGFR/HER2 inhibitors and apoptosis inducers

Deregulation of many kinases is directly linked to cancer development and the tyrosine kinase family is one of the most important targets in current cancer therapy regimens. In this study, we have designed and synthesized a series of thieno[2,3-d]pyrimidine derivatives as an EGFR and HER2 tyrosine kinase inhibitors. All the synthesized compounds were evaluated in vitro for their inhibitory activities against EGFR^WT; and the most active compounds that showed promising IC₅₀ values against EGFR^WT were tested in vitro for their inhibitory activities against mutant EGFR^T790M and HER2 kinases. Moreover, the antitumor activities of these compounds were tested against four cancer cell lines (HepG2, HCT-116, MCF-7 and A431). Compounds 13g, 13h and 13k exhibited the highest activities against the examined cell lines with IC₅₀ values ranging from 7.592 ± 0.32 to 16.006 ± 0.58 µM comparable to that of erlotinib (IC₅₀ ranging from 4.99 ± 0.09 to 13.914 ± 0.36 µM). Furthermore, the most potent antitumor agent (13k) was selected for further studies to determine its effect on the cell cycle progression and apoptosis in MCF-7 cell line. The results indicated that this compound arrests G₂/M phase of the cell cycle and it is a good apoptotic agent. Finally, molecular docking studies showed a good binding pattern of the synthesized compounds with the prospective target, EGFR^WT and EGFR^T790M.     

Synthesis and cytotoxic activity of 5,6-heteroaromatically annulated pyridine-2,4-diamines

A series of 5,6-heteroaromatically annulated pyridine-2,4-diamines have been synthesized and their in vitro cytotoxic activities evaluated against six human cancer cell lines. Benzo[g] annulated pyrido[2,3-b]indolediamines 7a–b and 8 showed relatively high cytotoxic activity as well as most of the diamines with pyrrolo[2,3-b]pyridine 17, thieno[2,3-b]pyridine and furo[2,3-b]pyridine 26–28, 1,8-naphthyridine 32 and 34 and benzo[h]quinoline 37 skeletons. Surprisingly, pyrido[2,3-b]indolediamines 13 and 14 without benzo[g] annulation were inactive. None of the new compounds were as potent as ellipticine, the reference compound.     

Synthesis of benzo[d]imidazo[2,1-b]thiazole-chalcone conjugates as microtubule targeting and apoptosis inducing agents

A series of benzo[d]imidazo[2,1-b]thiazole-chalcone conjugates (5a-aa) were designed, synthesized and evaluated for their cytotoxic potency against a panel of human cancer cell lines like lung (A-549), breast (MDA MB-231), prostrate (DU-145) and colon cancer (HT-29). Preliminary results revealed that some of these conjugates like 5d and 5u exhibited significant antiproliferative effect against human breast cancer (MDA MB-231) with IC₅₀ values of 1.3 and 1.2 µM respectively. To investigate the mechanistic aspects underlying the activity, the detailed biological studies of these promising conjugates (5d and 5u) were carried out on the MDA MB-231 cancer cells. Flow cytometric analysis revealed that these conjugates induce cell-cycle arrest in the G2/M phase. The tubulin polymerization assay suggests that these conjugates effectively inhibit microtubule assembly. In addition, morphological changes, reactive oxygen species (ROS) detection by 2′, 7′–dichlorofluorescin diacetate (DCFDA) and annexin V–FITC/PI assays indicate that 5d and 5u induces apoptosis. Furthermore, in silico computational studies, including molecular docking studies have been carried out to rationalise the binding modes of these conjugates with the tubulin protein.     

Anti-proliferative potential of triphenyl substituted pyrimidines against MDA-MB-231, HCT-116 and HT-29 cancer cell lines

A series of triphenyl substituted pyrimidines as analogous of colchicine and combretastatin A-4 was synthesized and evaluated for the antiproliferative potential. The compounds were screened against MDA-MB-231, HCT-116 and HT-29 cell lines using MTT assay. Most of the compounds displayed antiproliferative activity in low to sub micro molar concentration. Amongst the synthesized derivatives, compounds HK-2, HK-10 and HK-13 were found to be effective against all the three cancer cell lines. HK-2 exhibited IC₅₀ values of 3.39 µM, 4.78 µM and 4.23 µM, HK-10 showed IC₅₀ values of 0.81 µM, 5.89 µM, 4.96 µM and HK-13 showed IC₅₀ values 3.24 µM, 4.93 µM and 4.73 µM against MDA-MB-231, HCT-116 and HT-29 cancer cell lines, respectively. HK-10 was found to be the most potent compound in the series with IC₅₀ values of 0.81 µM against MDA-MB-231. In the cell cycle analysis, HK-2 and HK-10 showed cell arrest at G2/M phase of the cell cycle while HK-13 inhibited cell growth at the G1/G0 phase. All the three compounds showed cell death induced through apoptosis. In the docking studies, HK-2, HK-10 and HK-13 were found to fit well in the colchicine binding site of the tubulin. Some of the compounds in the current series were found to be promising against all the three cancer cell lines and may act as potent leads for further development.     

Dual EGFR/HER2 inhibitors and apoptosis inducers: New benzo[g]quinazoline derivatives bearing benzenesulfonamide as anticancer and radiosensitizers

Dual targeting of EGFR and HER2 is a proven anticancer strategy for the treatment of solid tumors. An array of new N-substituted-2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio) acetamides 5–18 were designed and synthesized from the starting compound 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4. The targeted compounds were screened for their cytotoxic activity against MDA-MB-231 breast cancer cell line. The IC₅₀ of all the compounds were in the range of 0.36–40.90 µM. The percentage inhibition towards EGFR was measured and found to be in the range of 63.00–16.90 %. The most potent compounds 5, 9, 15, 17 and 18 were further screened for their activity against both EGFR and HER2 receptors. The compounds showed IC₅₀ in the range of 0.64–1.81 µM for EGFR and 1.13–2.21 µM for HER2, in comparison to erlotinib, the reference drug. Compound 17, the most potent towards EGFR in this series, undergoes cell cycle analysis and was found to arrest the cycle at the G2/M phase. Measurement of the cytotoxicity of compound 17 against normal breast cell line showed mild cytotoxic activity. The most potent compounds were subjected to a single dose of 8 Gy of γ-radiation and the cytotoxicity of the tested compounds was found to increase after irradiation, thus proving the synergistic effect of γ-irradiation. Molecular docking was adopted for all the synthesized compounds to confirm their mechanism of action.     

1,2,3-triazole tethered Indole-3-glyoxamide derivatives as multiple inhibitors of 5-LOX,COX-2 & tubulin: Their anti-proliferative & anti-inflammatory activity

To evaluate the role of COX-2 and 5-LOX as dual inhibitors in controlling the cancer cell proliferation, a set of two series having 42 compounds of 1, 2, 3-Tethered Indole-3-glyoxamide derivatives were synthesized by employing click chemistry approach and were also evaluated for their in vitro cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) inhibitory activities with in vivo anti-inflammatory and in vitro anti-proliferative potencies. Among the compounds tested, compounds 11q and 13s displayed excellent inhibition of COX-2 (IC₅₀ 0.12 µM) with good COX-2 selectivity index (COX-2/COX-1) of 0.058 and 0.046 respectively. Compounds 11q and 13s also demonstrated comparable 5-LOX inhibitory activity with IC₅₀ 7.73 and 7.43 µM respectively to that of standard Norhihydroguaiaretic acid (NDGA: IC₅₀ 7.31 µM). Among all the selected cell lines, prostate cancer cell line DU145 was found to be susceptible to this class of compounds. Among all the tested compounds, compounds 11g, 11i, 11k, 11q, 13r, 13s and 13u demonstrated excellent to moderate anti-proliferative activity with IC_50s ranging between 6.29 and 18.53 µM. Compounds 11q and 11g demonstrated better anti-proliferative activities against DU145 cancer cell line with IC₅₀ values 8.17 and 8.69 µM respectively when compared to the standard drug etoposide (VP16; IC₅₀ 9.80 µM). Compounds 11g, 11k, 11q, 13s and 13u showed good dual COX-2/5-LOX inhibitory potentials with excellent anti-proliferative activity. Results from carrageenan-induced hind paw edema demonstrated that compounds 11b, 11l, 11q and 13q exhibited significant anti-inflammatory activity with 69–77% inhibition at 3 h, 75–82% inhibition at 5 h when compared to the standard drug indomethacin (66.6% at 3 h and 77.94% at 5 h). Ulcerogenic study revealed that compounds 11q and 13q did not cause any gastric ulceration. In vitro tubulin assay resuted that compound 11q interfered with microtubulin dynamic and act as tubulin polymerization inhibitor. In silico molecular docking studies demonstrated that compounds 11q and 13s are occupying the colchicines binding site of tubulin polymer and 11q illustrated very good binding affinities towards COX-2 and 5-LOX.     

Thiohydantoin derivatives incorporating a pyrazole core: Design,synthesis and biological evaluation as dual inhibitors of topoisomerase-I and cycloxygenase-2 with anti-cancer and anti-inflammatory activities

A new series of hybrid structures 14a–l containing thiohydantoin as anti-cancer moiety and pyrazole core possessing SO₂Me pharmacophore as selective COX-2 moiety was designed and synthesized to be evaluated for both anti-inflammatory and anti-cancer activities. The synthesized compounds were evaluated for their COX inhibition, in vivo anti-inflammatory activity, ulcerogenic liability, in vitro cytotoxic activity and human topoisomerase-1 inhibition. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. Also, all derivatives were significantly less ulcerogenic (ulcer indexes = 2.64–3.87) than ibuprofen (ulcer index = 20.25) and were of acceptable ulcerogenicity when compared with the non-ulcerogenic reference drug celecoxib (ulcer index = 2.99). Regarding anti-cancer activity, most of the target derivatives showed activities against A-549, MCF-7 and HCT-116 cell lines (IC₅₀ = 5.32–17.90, 3.67–19.04 and 3.19–14.87 µM respectively) in comparison with doxorubicin (IC₅₀ = 0.20, 0.50 and 2.44 µM respectively). Compound 14a inhibited the human topoisomerase-1 with IC₅₀ = 29.7 µg/ml while 14b and 14c showed more potent inhibitory activity with IC₅₀ = 26.5 and 23.3 µg/ml. respectively in comparison with camptothecin (IC₅₀ = 20.2 µg/ml). Additionally, COX-2 and human topoisomerase-1 docking studies were carried out to explain the interaction of the synthesized hybrid structures 14a–l with the target enzymes.     

Novel pyrimidine-pyridine hybrids: Synthesis,cyclooxygenase inhibition,anti-inflammatory activity and ulcerogenic liability

Some derivatives containing pyrido[2,3-d:6,5d′]dipyrimidine-4,5-diones (9a-f), tetrahydropyrido[2,3-d]pyrimidine-6-carbonitriles (11a-c) and 6-(4-acetylphenyl)-2-thioxo-2,3,5,6,7,8-hexahydro-1H-pyrimido[4,5-d]pyrimidin-4-one (12) were synthesized from 6-amino-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (8). The anti-inflammatory effect of these candidates was determined and the ulcer indices were calculated for active compounds. 7-Amino-5-(3,4,5-trimethoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrido[2,3-d] pyrimidine-6-carbonitrile (11c) exhibited better edema inhibition than celecoxib. Moreover, compounds 9b, 9d and 11c revealed better COX-2 inhibitory activity in a range (IC₅₀ = 0.25–0.89 µM) than celecoxib (IC₅₀ = 1.11 µM). Regarding ulcerogenic liability, all of the compounds under the study were less ulcerogenic than indomethacin. Molecular docking studies had been carried on active candidates 9d and 11c to explore action mode of these candidates as leads for discovering other anti-inflammatory agents.     

Design,synthesis and in vitro anti-tuberculosis activity of benzo[6,7]cyclohepta[1,2-b]pyridine-1,2,3-triazole derivatives

A series of novel benzo[6,7]cyclohepta[1,2-b]pyridine-1,2,3-triazole hybrids (7a–j & 8a–j) have been designed and synthesized in excellent yields by Huisgen’s [3+2] cyclo addition reaction of 3-(azidomethyl)-2-methyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine (5) with various alkynes 6 in presence of copper sulphate and sodium ascorbate and their structures were confirmed by IR, ¹H NMR, ¹³C NMR and HRMS. The newly synthesized compounds 7a–j & 8a–j were evaluated for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC 27294). Among the compounds tested, the compounds 7i and 8g displayed most potent activity with MIC value of 1.56?µg/mL with low cytotoxicity.     

3D-QSAR pharmacophore modelling,virtual screening and docking studies for lead discovery of a novel scaffold for VEGFR 2 inhibitors: Design,synthesis and biological evaluation

A series of novel 6,7-dihydro-5H-cyclopenta[d]pyrimidine derivatives was successfully designed, synthesized and evaluated as a new chemical scaffold with vascular endothelial growth factor receptor (VEGFR 2) inhibitory activity. Compounds 6c and 6b showed enzyme inhibition of 97% and 87% at 10 µM, respectively, and exhibited potent dose-related VEGFR 2 inhibition with IC₅₀ values of 0.85 µM and 2.26 µM, respectively. The design of the 6,7-dihydro-5H-cyclopenta[d]pyrimidine scaffold was implemented via consecutive molecular modelling protocols prior to the synthesis and biological evaluation of the derivatives. First, sorafenib was docked in the binding site of VEGFR 2 to study its binding orientation and affinity, followed by the generation of a valid 3D QSAR pharmacophore model for use in the virtual screening of different 3D databases. Structures with promising pharmacophore-based virtual screening results were refined using molecular docking studies in the binding site of VEGFR 2. A novel scaffold was designed by incorporating the results of the pharmacophore model generation and molecular docking studies. The new scaffold showed hydrophobic interactions with the kinase front pocket that may be attributed to increasing residence time in VEGFR 2, which is a key success factor for ligand optimization in drug discovery. Different derivatives of the novel scaffold were validated using docking studies and pharmacophore mapping, where they exhibited promising results as VEGFR 2 inhibitors to be synthesized and biologically evaluated. 6,7-dihydro-5H-cyclopenta[d]pyrimidine is a new scaffold that can be further optimized for the synthesis of promising VEGFR 2 inhibitors.