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Graphical abstract Highlights • New thiophene & annulated thiophene pyrazole hybrids were designed & synthesized. • All compounds were more COX-2 selective inhibitors than COX-1. • Several compounds showed promising in vivo anti-inflammatory activities. • These compounds were non-toxic and GI safe compared to the references. • Their docking and in silico chemo-informatic properties were acceptable. Abstract New thiophene and annulated thiophene pyrazole hybrids were synthesized and screened for their in vitro COX-1/COX-2 enzymatic inhibition and in vivo anti-inflammatory activities. All compounds were more COX-2 selective inhibitors than COX-1 with compound 13 exhibiting the highest COX-2 selectivity index. Compounds 3, 6a , 9 and 11 were the most promising in the acute anti-inflammatory assay while compounds 3 , 5, 6a, 6c, 9, 10, 11 and 13 exerted promising anti-inflammatory activity in the sub-acute anti-inflammatory assay. Compounds 3, 6a , 6c , 9 , 10 and 11 were evaluated for their ED 50 values and were more potent than diclofenac sodium while compounds 6a , 6c and 9 were of greater potency than celecoxib with compound 6a being the most potent showing ED 50 = 0.033 mmol/kg. These compounds were non-toxic and proved to be gastrointestinal safe compared to indomethacin, diclofenac sodium and celecoxib. Docking studies into COX-2 active site (PDB code 3LN1) revealed that compounds 3, 6a, 6c, 9, 10, 11 and 13 had binding modes and energies comparable to that of celecoxib. Compounds 3, 9, 10 and 11 complied with Lipinski's RO5 while compounds 6a and 6c showed one violation whereas compound 13 deviated by 2 violations. Compounds 6a, 6c and 13 showed 100% plasma protein binding (PPB) and showed no aqueous solubility while compounds 3, 10 and 11 demonstrated the best drug likeness model scores. Therefore, the thiophene analog 3 and the thienopyrimidine derivatives 10 and 11 are promising anti-inflammatory candidates that exert moderate selective COX-2 inhibition with acceptable physicochemical properties. [ABSTRACT FROM AUTHOR]

This study reports the synthesis of two series of new purine bioisosteres comprising a pyrazolo[3,4-d]pyrimidine scaffold linked to piperazine moiety through different amide linkages. The newly synthesized compounds were evaluated for anticancer activity against four cell lines ( MDA- MB-231, MCF-7, SF-268, B16F-10) and cyclooxygenase ( COX-2) protein expression inhibition in lipopolysaccharide ( LPS)-activated rat monocytes. The results revealed that most of the synthesized compounds showed moderate-to-high cytotoxic activity against at least one cell line, with compound 10b being the most active against all used cell lines ( IC50 values 5.5-11 μg/ ml) comparable to cisplatin. In addition, six of these compounds ( 7b, 10a-d, and 12c) demonstrated inhibition of LPS-induced COX-2 protein expression at low concentration (25 μg/ ml) as compared to the control non-stimulated cells and showed a COX-2 selectivity index range comparable to diclofenac sodium. The overall results indicate that many of these pyrazolopyrimidine derivatives possess in vitro anti-inflammatory and anticancer activities at varying doses, and the most active compounds will be subjected to in vivo pharmacological evaluation. [ABSTRACT FROM AUTHOR]

New purine-pyrazole hybrids combining thiazoles, thiazolidinones and rhodanines as 15-LOX inhibitors, anticancer and antioxidants. 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. [ABSTRACT FROM AUTHOR]

Synthesis of twenty nine new 1,2,4-triazoles and some derived thiazolothiadiazoles (structurally-relevant to some reported triazoles with anticancer and/or Cdc25A/B inhibitory activities) is described in this study. The obtained NCI's in vitro antitumor data revealed that five analogs ( 12 , 15 , 18 , 19 and 22 ) displayed considerable tumor percentage growth inhibitory activity (GI%), among which the analog 18 possessed a special antitumor potential and spectrum. Additionally, the same five analogs showed a marginal GI effect on the normal breast epithelial cell line MCF-10A indicating higher selectivity towards cancer cells. The same active analogs 12 , 15 , 18 , 19 and 22 were further assessed for their in vitro Cdc25A/B phosphatase inhibitory activity (a possible antitumor target), where 18 and 22 displayed a distinctive inhibitory affinity towards the Cdc25B isozyme (6.7 and 8.4 μM, respectively). Docking of 12 , 15 , 18 , 19 and 22 with the active site of human Cdc25B phosphatase enzyme demonstrated superior binding profile by the top-scoring analog 18 relative to a reported Cdc25 phosphatase ligand. In silico calculations of molecular properties revealed that all of the active compounds comply with Lipinski's RO5 and Veber's criteria for good bioavailability suggesting good drug-likeness upon oral administration with a predicted high safety profile. [ABSTRACT FROM AUTHOR]

A new series of pyrazole derivatives were synthesized by hybridization with five-membered heterocyclic moieties such as thiazoles, thiazolidinones, 1,3,4-thiadiazoles and pyrazolines. The compounds were evaluated for their in vivo antimalarial activity against Plasmodium berghei infected mice and the most active derivatives were further examined for their in vitro antimalarial activity against chloroquine resistant (RKL9) strain of Plasmodium falciparum . Compounds 2c , 2d , 4b , 4c , 4d , 5a , 6c , 8c and 9b had more than 90% parasite suppression activity of that found with the antimalarial reference standard drug, chloroquine phosphate and had lower IC 50 values than chloroquine. Compounds 4b and 9b were the most active derivatives, and their activities were 5-fold higher than chloroquine. All the newly synthesized compounds were evaluated for their in vitro antileishmanial activity against Leishmania aethiopica promastigotes and amastigote. The results showed that compounds 2c , 2d , 3d , 4b , 4c , 4d and 5a had lower or similar IC 50 values than the reference standard drugs, amphotericin B and miltefosine. Compound 3d had the highest antileishmanial activity. Collectively, compounds 2c , 2d , 4b , 4c, 4d and 5a exhibited dual activity against malaria and leishmaniasis and were safe and well tolerated by the experimental animals orally up to 300 mg/kg and parenterally up to 100 mg/kg. [ABSTRACT FROM AUTHOR]

A series of new oxadiazoline-substituted naphthalenyl acetates 3a – e and oxadiazoline-substituted 4-methoxynaphthalenyl acetates 7b – e were synthesized and tested by the National Cancer Institute (NCI) for their in vitro anticancer activity. The two derivatives bearing acetoxy groups at the 1 and 3 positions of the phenyl ring 3c and 7c were the most active showing significant anticancer activity against all tested cancer cell lines, with GI 50 values ranging from 0.175 to 3.91 μM, and 0.306–11.7 μM, respectively. The selectivity of compound 3c was greater for non-solid tumor cell lines. Computational prediction of molecular and pharmacokinetic properties revealed that both compounds are safe and compound 7c had a good drug-likeness score. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis of two groups of structure hybrids comprising basically the antipyrine moiety attached to either polysubstituted thiazole or 2,5-disubstituted-1,3,4-thiadiazole counterparts through various linkages is described. Twelve out of the newly synthesized compounds were evaluated for their anti-inflammatory activity using two different screening protocols; namely, the formalin-induced paw edema and the turpentine oil-induced granuloma pouch bioassays, using diclofenac Na as a reference standard. The ulcerogenic effects and acute toxicity (ALD50) values of these compounds were also determined. Meanwhile, the analgesic activity of the same compounds was evaluated using the rat tail withdrawal technique. Additionally, the synthesized compounds were evaluated for their in vitro antimicrobial activity. In general, compounds belonging to the thiazolylantipyrine series exhibited better biological activities than their thiadiazolyl structure variants. Collectively, compounds 6, 10, 26, and 27 proved to display distinctive anti-inflammatory and analgesic profiles with a fast onset of action. All of the tested compounds revealed super GI safety profile and are well tolerated by the experimental animals with high safety margin (ALD50 >3.0g/kg). Meanwhile, compounds 7, 10, 11, and 23 are considered to be the most active broad spectrum antimicrobial members in this study. Compound 10 could be identified as the most biologically active member within this study with an interesting dual anti-inflammatory analgesic and antibacterial profile. [Copyright &y& Elsevier]

[Display omitted] • New 5-(2,6-dichlorophenyl)-3-oxo-2,3-dihydro-5 H -thiazolo[3,2- a ]pyrimidine-7-carboxylic acids (4 – 20) were synthesized. • Derivatives 8 and 9 demonstrated > 70 % p38α MAPK inhibition. • 8 and 9 displayed strong antitumor activities against cancer cells more than 5-FU. • Both 8 and 9 showed DNA damaging activity having LOD in the nanomolar range. • Molecular docking and in silico studies were investigated. In pursuit of discovering novel scaffolds that demonstrate potential inhibitory activity against p38α MAPK and possess strong antitumor effects, we herein report the design and synthesis of new series of 17 final target 5-(2,6-dichlorophenyl)-3-oxo-2,3-dihydro-5 H -thiazolo[3,2- a ]pyrimidine-7-carboxylic acids (4 – 20). Chemical characterization of the compounds was performed using FT-IR, NMR, elemental analyses and mass spectra of some representative examples. With many compounds showing potential inhibitory activity against p38α MAPK, two derivatives, 8 and 9 , demonstrated the highest activity (>70 % inhibition) among the series. Derivative 9 displayed IC 50 value nearly 2.5 folds more potent than 8. As anticipated, they both showed explicit interactions inside the kinase active site with the key binding amino acid residues. Screening both compounds for cytotoxic effects, they exhibited strong antitumor activities against lung (A549), breast (MCF-7 and MDA MB-231), colon (HCT-116) and liver (Hep-G2) cancers more potent than reference 5-FU. Their noticeable strong antitumor activity pointed out to the possibility of an augmented DNA binding mechanism of antitumor action besides their kinase inhibition. Both 8 and 9 exhibited strong ctDNA damaging effects in nanomolar range. Further mechanistic antitumor studies revealed ability of compounds 8 and 9 to arrest cell cycle in MCF-7 cells at S phase, while in HCT-116 treated cells at G0-G1 and G2/M phases. They also displayed apoptotic induction effects in both MCF-7 and HCT-116 with total cell deaths more than control untreated cells in reference to 5-FU. Finally, the compounds were tested for their anti-migratory potential utilizing wound healing assay. They induced a significant decrease in wound closure percentage after 24 h treatment in the examined cancer cells when compared to untreated control MCF-7 and HCT-116 cells better than 5-FU. In silico computation of physicochemical parameters revealed the drug-like properties of 8 and 9 with no violation to Lipinski's rule of five as well as their tolerable ADMET parameters, thus suggesting their utilization as potential future drug leads amenable for further optimization and development. [ABSTRACT FROM AUTHOR]

All new oxadiazoline-substituted naphthalenyl acetates (III), (V) are tested for their in vitro anticancer activity. [ABSTRACT FROM AUTHOR]

The introduction of new COX-2 inhibitors with high efficacy and enhanced safety profile would be a great achievement in the development of anti-inflammatory drugs. This study was designed to screen and assess the anti-inflammatory and analgesic activities as well as some of the expected side effects of some pyrazole derivatives, newly synthesized as potential COX-2 inhibitors at the Faculty of Pharmacy, Alexandria University and compared to indomethacin and celecoxib. Twelve compounds were screened for their anti-inflammatory activity using carrageenan-induced paw oedema and cotton pellet granuloma tests. On the basis of their apparent anti-inflammatory activity, four compounds with different substitutions were selected for the evaluation of their analgesic activity using the formalin-induced hyperalgesia and hot-plate tests. Compound AD 532, ((4-(3-(4-Methylphenyl)-4-cyano-1H-pyrazol-1-yl)benzenesulfonamide)), showed very promising results. In the single-dose and subchronic toxicity studies, compound AD 532 showed no ulcerogenic effect and produced minimal effects on renal function. Furthermore, compound AD 532 was a less potent inhibitor of COX-2 in vitro than celecoxib, which may indicate lower potential cardiovascular toxicity. It is concluded that compound AD 532 appears to be a promising and safe option for the management of chronic inflammatory conditions. This study recommends more in-depth investigation into the therapeutic effects and toxicity profile of this compound including its cardiovascular toxicity. [ABSTRACT FROM AUTHOR]

[Display omitted] • New thienopyrimidines and thienotriazolopyrimidines were potent cytotoxic agents. • 9b, 11b and 12 were EGFR inhibitors while 3b and 9d were ARO inhibitors. • Compound 9d downregulated HSP27 and p-ERK whereas, 11b downregulated p-AKT. • All tested compounds 2d, 3c, 5c, 9d, 11b and 12 were apoptotic inducers via caspase-9 activation. • Docking studies within EGFR and ARO revealed encouraging results. An array of newly synthesized thieno[3,2- d ]pyrimidine-based derivatives and thienotriazolopyrimidines hybridized with some pharmacophoric anticancer fragments were designed, synthesized and assessed for their in vitro antiproliferative activity against MCF-7 and MDA-MB-231 breast cancer cell lines using erlotinib and pictilisib as reference standards in the MTT assay. In general, many compounds were endowed with considerable antiproliferative activity (IC 50 = 0.43–1.31 µM). Some of the tested compounds, namely 3c, 5b, 5c, 9d, 10, 11b and 13 displayed remarkable antiproliferative activity against both cell lines. Meanwhile, compounds 2c-e, 3b, 4a, 5a, 9c and 15b showed noticeable selectivity against MCF-7 cells while compounds 2b, 3a, 4b, 6a-c, 7, 8, 9b and 12 exhibited considerable selectivity against MDA-MB-231 cells. Further mechanistic evidences for their anticancer activities were provided by screening the most potent compounds against MCF-7 and/or MDA-MB-231 cells for EGFR and ARO inhibitory activities using erlotinib and letrozole as reference standards respectively. Results proved that, in general, tested compounds were better EGFRIs than ARIs. In addition, significant overexpression in caspase-9 level in treated MCF-7 breast cell line samples was observed for all tested compounds with the 4-fluorophenylhydrazone derivative 2d exhibiting the highest activation. In treated MDA-MB-231 breast cell line samples, 11b was found to highly induce caspase-9 level thereby inducing apoptosis. Cell cycle analysis and Annexin V-FITC/PI assay were also assessed for active compounds where results indicated that all tested compounds induced preG1 apoptosis and cell cycle arrest at G2/M phase. Compound 9d , as an inhibitor of ARO, was observed to downregulate the downstream signaling proteins HSP27 and p-ERK in MCF-7 cells. Furthermore, compound 11b downregulated EGFR expression as well as the downstream signaling protein p-AKT. Docking experiments on EGFR and ARO enzymes supported their in vitro results. Thus, the thienotriazolopyrimidines 11b and 12 showing good EGFR inhibition and the thieno[3,2- d ]-pyrimidine derivatives 3b and 9d, eliciting the best ARO inhibition activity, can be considered as new candidates as anti-breast cancer agents that necessitate further development. [ABSTRACT FROM AUTHOR]