Search

New quinoline-pyridine hybrids were designed and synthesised as PIM-1/2 kinase inhibitors. Compounds 5b, 5c, 6e, 13a, 13c, and 14a showed in-vitro low cytotoxicity against normal human lung fibroblast Wi-38 cell line and potent in-vitro anticancer activity against myeloid leukaemia (NFS-60), liver (HepG-2), prostate (PC-3), and colon (Caco-2) cancer cell lines. In addition, 6e, 13a, and 13c significantly induced apoptosis with percentage more than 66%. Moreover, 6e, 13a, and 13c significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, 5c, 6e, and 14a showed potent in-vitro PIM-1 kinase inhibitory activity. While, 5b showed potent in-vitro PIM-2 kinase inhibitory activity. Kinetic studies using Lineweaver–Burk double-reciprocal plot indicated that 5b, 5c, 6e, and 14a behaved as competitive inhibitors while 13a behaved as both competitive and non-competitive inhibitor of PIM-1 kinase enzyme. Molecular docking studies indicated that, in-silico affinity came in coherence with the observed in-vitro inhibitory activities against PIM-1/2 kinases. [ABSTRACT FROM AUTHOR]

New spiro-piperidine derivatives were synthesised via the eco-friendly ionic liquids in a one-pot fashion. The in vitro antileishmanial activity against Leishmania major promastigote and amastigote forms highlighted promising antileishmanial activity for most of the derivatives, with superior activity compared to miltefosine. The most active compounds 8a and 9a exhibited sub-micromolar range of activity, with IC50 values of 0.89 µM and 0.50 µM, respectively, compared to 8.08 µM of miltefosine. Furthermore, the antileishmanial activity reversal of these compounds via folic and folinic acids displayed comparable results to the positive control trimethoprim. This emphasises that their antileishmanial activity is through the antifolate mechanism via targeting DHFR and PTR1. The most active compounds showed superior selectivity and safety profile compared to miltefosine against VERO cells. Moreover, the docking experiments of 8a and 9a against Lm-PTR1 rationalised the observed in vitro activities. Molecular dynamics simulations confirmed a stable and high potential binding to Lm-PTR1. [ABSTRACT FROM AUTHOR]

Fascin is an actin-bundling protein overexpressed in various invasive metastatic carcinomas through promoting cell migration and invasion. Therefore, blocking Fascin binding sites is considered a vital target for antimetastatic drugs. This inspired us to find new Fascin binding site blockers. First, we built an active compound set by collecting reported small molecules binding to Fascin's binding site 2. Consequently, a high-quality decoys set was generated employing DEKOIS 2.0 protocol to be applied in conducting the benchmarking analysis against the selected Fascin structures. Four docking programs, MOE, AutoDock Vina, VinaXB, and PLANTS were evaluated in the benchmarking study. All tools indicated better-than-random performance reflected by their pROC-AUC values against the Fascin crystal structure (PDB: ID 6I18). Interestingly, PLANTS exhibited the best screening performance and recognized potent actives at early enrichment. Accordingly, PLANTS was utilized in the prospective virtual screening effort for repurposing FDA-approved drugs (DrugBank database) and natural products (NANPDB). Further assessment via molecular dynamics simulations for 100 ns endorsed Remdesivir (DrugBank) and NANPDB3 (NANPDB) as potential binders to Fascin binding site 2. In conclusion, this study delivers a model for implementing a customized DEKOIS 2.0 benchmark set to enhance the VS success rate against new potential targets for cancer therapies. [ABSTRACT FROM AUTHOR]

A structure-guided modelling approach using COX-2 as a template was used to investigate the effect of replacing the chloro atom located at the chlorophenyl ring of amide-linked bipyrazole moieties, aiming at attaining better anti-inflammatory effect with a good safety profile. Bromo, fluoro, nitro, and methyl groups were revealed to be ideal candidates. Consequently, new bipyrazole derivatives were synthesised. The in vitro inhibitory COX-1/COX-2 activity of the synthesised compounds exhibited promising selectivity. The fluoro and methyl derivatives were the most active candidates. The in vivo formalin-induced paw edoema model confirmed the anti-inflammatory activity of the synthesised compounds. All the tested derivatives had a good ulcerogenic safety profile except for the methyl substituted compound. In silico molecular dynamics simulations of the fluoro and methyl poses complexed with COX-2 for 50 ns indicated stable binding to COX-2. Generally, our approach delivers a fruitful matrix for the development of further amide-linked bipyrazole anti-inflammatory candidates. [ABSTRACT FROM AUTHOR]

Promising inhibitory activities of the parasite multiplication were obtained upon evaluation of in vivo anti-malarial activities of new pyrazolylpyrazoline derivatives against Plasmodium berghei infected mice. Further evaluation of 5b and 6a against chloroquine-resistant strain (RKL9) of P. falciparum showed higher potency than chloroquine. In vitro antileishmanial activity testing against Leishmania aethiopica promastigote and amastigote forms indicated that 5b, 6a and 7b possessed promising activity compared to miltefosine and amphotericin B deoxycholate. Moreover, antileishmanial activity reversal of the active compounds via folic and folinic acids showed comparable results to the positive control trimethoprim, indicating an antifolate mechanism via targeting leishmanial DHFR and PTR1. The compounds were nontoxic at 125, 250 and 500mg/kg. In addition, docking of the most active compound against putative malarial target Pf-DHFR-TS and leishmanial PTR1 rationalised the observed activities. Molecular dynamics simulations confirmed a stable and high potential binding of 7a against leishmanial PTR1. [ABSTRACT FROM AUTHOR]

The novel coronavirus disease COVID-19, caused by the virus SARS CoV-2, has exerted a significant unprecedented economic and medical crisis, in addition to its impact on the daily life and health care systems all over the world. Regrettably, no vaccines or drugs are currently available for this new critical emerging human disease. Joining the global fight against COVID-19, in this study we aim at identifying a potential novel inhibitor for SARS COV-2 2′-O-methyltransferase (nsp16) which is one of the most attractive targets in the virus life cycle, responsible for the viral RNA protection via a cap formation process. Firstly, nsp16 enzyme bound to Sinefungin was retrieved from the protein data bank (PDB ID: 6WKQ), then, a 3D pharmacophore model was constructed to be applied to screen 48 Million drug-like compounds of the Zinc database. This resulted in only 24 compounds which were subsequently docked into the enzyme. The best four score-ordered hits from the docking outcome exhibited better scores compared to Sinefungin. Finally, three molecular dynamics (MD) simulation experiments for 150 ns were carried out as a refinement step for our proposed approach. The MD and MM-PBSA outputs revealed compound 11 as the best potential nsp16 inhibitor herein identified, as it displayed a better stability and average binding free energy for the ligand-enzyme complex compared to Sinefungin. [ABSTRACT FROM AUTHOR]

In the designed compounds, either a biarylamide or biarylurea moiety or an N-substituted piperazine motif was linked to position 1 of the phthalazine core. The anti-proliferative activity of the synthesised compounds revealed that eight compounds (6b, 6e, 7b, 13a, 13c, 16a, 16d and 17a) exhibited excellent broad spectrum cytotoxic activity in NCI 5-log dose assays against the full 60 cell panel with GI50 values ranging from 0.15 to 8.41 µM. Moreover, the enzymatic assessment of the synthesised compounds against VEGFR-2 tyrosine kinase showed the significant inhibitory activities of the biarylureas (12b, 12c and 13c) with IC50s of 4.4, 2.7 and 2.5 μM, respectively, and with 79.83, 72.58 and 71.6% inhibition of HUVEC at 10 μM, respectively. Additionally, compounds (7b, 13c and 16a) were found to induce cell cycle arrest at S phase boundary. Compound 7b triggered a concurrent increase in cleaved caspase-3 expression level, indicating the apoptotic-induced cell death. [ABSTRACT FROM AUTHOR]

A new series of quinoline-based benzenesulfonamides (QBS) were developed as potential carbonic anhydrase inhibitors (CAIs). The target QBS CAIs is based on the 4-anilinoquinoline scaffold where the primary sulphonamide functionality was grafted at C4 of the anilino moiety as a zinc anchoring group (QBS 13a–c); thereafter, the sulphonamide group was switched to ortho- and meta-positions to afford regioisomers 9a–d and 11a–g. Moreover, a linker elongation approach was adopted where the amino linker was replaced by a hydrazide one to afford QBS 16. All the described QBS have been synthesized and investigated for their CA inhibitory action against hCA I, II, IX and XII. In general, para-sulphonamide derivatives 13a–c displayed the best inhibitory activity against both cancer-related isoforms hCA IX (KIs = 25.8, 5.5 and 18.6 nM, respectively) and hCA XII (KIs = 9.8, 13.2 and 8.7 nM, respectively), beside the excellent hCA IX inhibitory activity exerted by meta-sulphonamide derivative 11c (KI = 8.4 nM). The most promising QBS were further evaluated for their anticancer and pro-apoptotic activities on two cancer cell lines (MDA-MB-231 and MCF-7). In addition, molecular docking simulation studies were applied to justify the acquired CA inhibitory action of the target QBS. [ABSTRACT FROM AUTHOR]

• New pyrazolo[3,4-d]pyrimidines and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidines were designed and synthesized. • In vitro COX-1/COX-2 inhibitory assay. • In vivo formalin paw edema and cotton pellets induced granuloma assays. • Docking experiments rationalized in vitro COX-2 inhibitory activity. • In silico pharmacokinetics and drug-likeness predictions recommended acceptable profiles. New pyrazolo[3,4- d ]pyrimidinone and pyrazolo[4,3-e][1,2,4]triazolo[4,3- a ]pyrimidinone derivatives were synthesized. They have been evaluated for their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay. Moreover, compounds with promising in vitro activity and COX-1/COX-2 selectivity indices were subjected for in vivo anti-inflammatory testing using formalin induced paw edema and cotton-pellet induced granuloma assays for acute and chronic models, respectively. Compounds (2c, 3i, 6a, 8 and 12) showed promising COX-2 inhibitory activity and high selectivity compared to celecoxib. Most of the compounds exhibited potential anti-inflammatory activity for both in vivo acute and chronic models. Almost all compounds displayed safe gastrointestinal profile and low ulcerogenic potential guided by histopathological examination. Furthermore, molecular docking experiments rationalized the observed i n vitro anti-inflammatory activity of selected candidates. In silico predictions of the pharmacokinetic and drug-likeness properties recommended accepted profiles of the majority of compounds. In conclusion, this work provides an extension of the chemical space of pyrazolopyrimidinone and pyrazolotriazolopyrimidinone chemotypes for the anti-inflammatory activity. [ABSTRACT FROM AUTHOR]

New quinoline compounds comprising pyrazole scaffold through different amide linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory activity. Eight compounds ( 5c , 11b,c , 12c , 14a,b , 20a and 21a ) were found to exhibit promising anti-inflammatory profiles in acute and sub-acute inflammatory models. They were screened for their ulcerogenic activity and none of them showed significant ulcerogenic activity comparable to the reference drug celecoxib and are well tolerated by experimental animals with high safety margin (ALD 50  > 0.3 g/kg). Compounds 5c , 11b,c , 12c , 14a,b , 20a and 21a showed significant in vitro LOX inhibitory activity higher than that of zileuton. In vitro COX-1/COX-2 inhibition study revealed that compounds 12c , 14a,b and 20a showed higher selectivity towards COX-2 than COX-1. Among the tested compounds, 12c , 14a and 14b showed the highest inhibitory activity against COX-2 with an IC 50 values of 0.1, 0.11 and 0.11 μM respectively. The docking experiments attempted to postulate the binding mode for the most active compounds in the binding site of COX-2 enzymes and confirmed the high selectivity binding towards COX-2 enzyme over COX-1. [ABSTRACT FROM AUTHOR]

New functionalized acrylamide derivatives bearing sulfisoxazole moiety were synthesized and evaluated for their in vitro antimicrobial activities. In vivo pharmacokinetic study was carried out. Molecular modeling studies indicated that these compounds were able to inhibit the microbial dihydropteroate synthase enzyme (DHPS). • Acrylamide derivatives bearing sulfisoxazole moiety were synthesized. • Target compounds were evaluated in vitro as antimicrobial agents. • DHPS is confirmed to be a putative target for these compounds. • Docking experiments against DHPS rationalized the observed activities. • 99mTc-5g complex could be used as a diagnostic radio imaging material. New functionalized acrylamide derivatives bearing sulfisoxazole moiety were designed to target bacterial dihydropteroate synthase (DHPS). The in vitro antimicrobial activities of these compounds were assessed. The E -configuration of compound 5b was proved by single crystal X-ray analysis. Compounds 5g and 5h displayed double the activity of ampicillin against B. subtilis. Also, 5h was two times more active than gentamycin against E. coli. Interestingly, compounds 5f-g , 7c , 8a, 8c exhibited two folds the potency of amphotericin B against S. racemosum while 5h displayed three folds the activity of amphotericin B against S. racemosum. Most of the synthesized compounds showed superior activities to the parent sulfisoxazole and were non-toxic to normal cells. DHPS is confirmed to be a putative target for our compounds via antagonizing their antibacterial activity by the folate precursor (p -aminobenzoic acid) and product (methionine) on E. coli ATCC 25922. Docking experiments against DHPS rationalized the observed antibacterial activity. Additionally, compound 5g was evaluated as a selective targeting vector for 99mTc that showed a remarkable uptake and targeting ability towards the infection site that was induced in mice. [ABSTRACT FROM AUTHOR]

New thienopyrimidinone and triazolothienopyrimidinone derivatives have been synthesized. These compounds were subjected to anti-inflammatory and antimicrobial activity screening aiming to identify new candidates that have dual anti-inflammatory and antimicrobial activities. Compounds 5 , 7 and 10a showed minimal ulcerogenic effect and high selectivity towards human recombinant COX-2 over COX-1 enzyme. Their docking outcome correlated with their biological activity and assured the high selectivity binding towards COX-2. In addition, they could act safely up to 80 mg/kg orally or 40 mg/kg parentrally. The antimicrobial screening showed that compound 10a displayed distinctive inhibitory effect on the growth of Escherichia coli comparable to that of ampicillin. Moreover, compounds 5 , 7 , 9 and 12a possessed 50% of the inhibitory activity of ampicillin against E. coli. Thus, compounds 5 , 7 and 10a represent promising dual acting anti-inflammatory and antimicrobial agents. This work provides rewarding template enriching the chemical space for dual anti-inflammatory anti-microbial activities. [ABSTRACT FROM AUTHOR]

The development of new COX-2 inhibitors with analgesic and anti-inflammatory efficacy as well as minimal gastrointestinal, renal and cardiovascular toxicity, is of vital importance to patients suffering from chronic course pain and inflammatory conditions. This study aims at evaluating the therapeutic activity and adverse drug reactions associated with the use of the newly synthesized pyrazole derivative, compound AD732, E -4-[3-(4- methylphenyl)-5- hydroxyliminomethyl - 1H - pyrazol -1- yl ]benzenesulfonamide, as compared to indomethacin and celecoxib as standard agents. Anti-inflammatory activity was assessed using carrageenan-induced rat paw edema and cotton pellet granuloma tests; formalin-induced hyperalgesia and hot plate tests were done to study analgesic activity. In vitro tests to determine COX-1/COX-2 selectivity and assessment of renal and gastric toxicity upon acute exposure to AD732 were also conducted. Compound AD732 exhibited promising results; higher anti-inflammatory and analgesic effects compared to standard agents, coupled with the absence of ulcerogenic effects and minimal detrimental effects on renal function. Additionally, compound AD732 was a less potent inhibitor of COX-2 in vitro than celecoxib, which may indicate lower potential cardiovascular toxicity. It may be concluded that compound AD732 appears to be a safer and more effective molecule with promising potential for the management of pain and inflammation. [Display omitted] [ABSTRACT FROM AUTHOR]

• New conjugates of aryl sulfonyl hydrazone and 1,3-diaryl pyrazole were designed and synthesized. • They showed promising inhibition against NDM-1, IMP-1 and AIM-1 MBLs. • They exhibited promising ex vivo antibacterial activity against resistant clinical isolates of K. pneumoniae. • They were able to re-sensitize resistant K. pneumoniae (K5) towards meropenem and cefalexin. • The docking experiments on NDM-1 and IMP-1 rationalized the observed in vitro MBLs inhibition activity. Based on a structure-guided approach, aryl sulfonyl hydrazones conjugated with 1,3-diaryl pyrazoles were designed to target metallo-β-lactamases (MBLs), using Klebsiella pneumoniae NDM-1 as a model. The in vitro MBLs inhibition showed remarkable inhibition constant for most of the designed compounds at a low micromolar range (1.5–16.4 µM) against NDM-1 , IMP-1 and AIM-1 MBLs. Furthermore, all compounds showed promising antibacterial activity against (K+, K1-K9) resistant clinical isolates of K. pneumoniae and were able to re-sensitize resistant K. pneumoniae (K5) strain towards meropenem and cefalexin. Besides, in vivo toxicity testing exhibited that the most active compound was non-toxic and well tolerated by the experimental animals orally up to 350 mg/kg and up to 125 mg/kg parenterally. The docking experiments on NDM-1 and IMP-1 rationalized the observed in vitro MBLs inhibition activity. Generally, this work presents a fruitful matrix to extend the chemical space for MBLs inhibition. This aids in tackling drug-resistance issues in antibacterial treatment. [ABSTRACT FROM AUTHOR]

• Hybrids from tetrahydro-1H-pyrazolo[3,4- b quinolines were designed and prepared. • The compounds were tested for their dual activity as AChE / COX-2 inhibitors. • All compounds showed activities comparable to or significantly higher than tacrine. • Most of the compounds showed activities comparable to celecoxib. • All compounds showed a safe hepatic profile via hepatotoxicity testing. New tetrahydro-1 H -pyrazolo[3,4- b quinoline derivatives were designed, synthesized and characterized as dual anticholinestrase and cyclooxygenase-2 inhibitors. The in vitro and in vivo anti-cholinesterase evaluation exhibited promising activities with lower hepatotoxicity for many candidates compared to tacrine as a reference. Furthermore, their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay demonstrated superior activity to celecoxib with higher selectivity indices for some compounds. In addition, some candidates showed extended anti-inflammatory activity by inhibiting COX-2 protein induction. Besides, in silico docking experiments of the active compounds against h AChE rationalized the observed in vitro AChE inhibitory activity. In conclusion, this work provides an extension of the chemical space of tetrahydro-1 H -pyrazolo[3,4- b quinoline chemotype for the anticholinestrase and anti-inflammatory activity. This would aid to minimize the possible neuroinflammation linked to the pathogenesis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]