Expanding the anticancer potential of 1,2,3-triazoles via simultaneously targeting Cyclooxygenase-2, 15-lipoxygenase and tumor-associated carbonic anhydrases

Cancer is a multifactorial disorder involving multiplicity of interrelated signaling pathways and molecular targets. To that end, a multi-target design strategy was adopted to develop some 1,2,3-triazoles hybridized with some pharmacophoric anticancer fragments, as first-in-class simultaneous inhibitors of COX-2, 15-LOX and tumor associated carbonic anhydrase enzymes. Results revealed that compounds 5a, 5d, 8b and 8c were potent inhibitors of COX-2 and 15-LOX enzymes. COX-2 inhibitory activity was further demonstrated by the inhibition of the accumulation of 6-keto-PGF1α, a metabolite of COX-2 products in two cancer cell lines. The sulfonamide bearing derivatives 5d and 8c were effective nanomolar and submicromolar inhibitors of tumor associated hCA XII isoform, respectively. Strong to moderate inhibitory activities were observed in the in vitro antiproliferative assay on lung (A549), liver (HepG2) and breast (MCF7) cancer cell lines (IC50 2.37–28.5 μM) with high safety margins on WI-38 cells. A cytotoxic advantage of CA inhibition was observed as an increased activity against tumor cell lines expressing CA IX/XII. Further mechanistic clues for the anticancer activities of compound 5a and its sulfonamide analog 5d were derived from induction of cell cycle arrest at G2/M phase. They also triggered apoptosis via increasing expression levels of caspase-9 and Bax together with suppressing that of Bcl-2. The in vitro anti-tumor activity was reflected as reduced tumor size upon treatment with 8c in an in vivo cancer xenograft model. Docking experiments on the target enzymes supported their in vitro data and served as further molecular evidence. In silico calculations and ligand efficiency indices were promising. In light of these data, such series could offer new structural insights into the understanding and development of multi-target COX-2/15-LOX/hCA inhibitors for anticancer outcomes. © 2020 Elsevier Masson SA

Synthesis of Tetrahydrobenzothieno[ 2,3-d]pyrimidine and Tetrahydrobenzothieno[3,2-e]- [1,2,4]triazolo[4,3-c]pyrimidine Derivatives as Potential Antimicrobial Agents

Five series of tetrahydrobenzothieno[2,3-d]pyrimidine and tetrahydrobenzothienotriazolopyrimidine derivatives have been synthesized namely: 4-(substituted amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidines 4a–d, 4-substituted (methylidenehydrazino)-5,6,7,8-tetrahydro[1]benzothieno- [2,3-d]pyrimidines 6a–c, 4-(3,5-disubstituted pyrazol-1-yl)-5,6,7,8-tetrahydro- [1]benzothieno[2,3-d]pyrimidines 7a,b, 3-substituted-8,9,10,11-tetrahydro- [1]benzothieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidines 8a,b, N-(phenyl or 4-substituted phenyl)-2-(8,9,10,11-tetrahydro[1]benzothieno[3,2-e][1,2,4]- triazolo[4,3-c]pyrimidin-3-ylsulfanyl)acetamides 10a–c. Preliminary antimicrobial testing revealed that compounds 4a and 10b were the most active among the tested compounds against C. albicans showing IZ = 22 mm and MIC = MBC = 31.25 μg/ml, with no significant antibacterial activity. Compounds 6b and 6c showed the highest antibacterial activity against S. aureus (IZ = 21 mm, MIC = 62.5 μg/ml, MBC = 125 μg/ml for 6b; IZ = 21 mm, MIC = MBC = 125 μg/ml for 6c). Compounds 4c and 6c showed the highest antibacterial potency against P. aeruginosa among the tested compounds (IZ = 19–20 mm, MIC = MBC = 62.5 μg/ml). None of the tested compounds showed significant antibacterial activity against E. coli