Novel quinazolinone Derivatives: Design, synthesis and in vivo evaluation as potential agents targeting Alzheimer disease.

Since Alzheimer disease is one of the most prevalent types of dementia with a high mortality and disability rate, so development of multi-target drugs becomes the major strategy for battling AD. This study shows the development of a series of quinazolinone based derivatives as novel, multifunctional anti-AD drugs that exhibit both cholinesterase inhibitoryand anti-inflammatory properties. The preliminary results of the in vitro AChE inhibition activity showed that compounds 4b, 5a, 6f, 6h and 7b were better represented for further evaluation. Furthermore, in-vivo AChE inhibition activity and behavior Morris water maze test against donepezil as reference drug were evaluated. Additionally, hippocampal inflammatory markers; TNF-α, NFĸB, IL-1ß and IL-6 and antioxidant markers; SOD and MDA were assessed to evaluate the efficacy of quinazolinone derivatives against AD hallmarks. The results showed that 6f, 6h and 7b have promising anti-acetylcholinesterase, anti-inflammatory and antioxidant activities thus, have a significant effect in treatment of AD. Moreover, Histopathological examination revealed that 6f, 6h and 7b derivatives have neuroprotective effect against neuronal damage caused by induced scopolamine model in mice. Finally, the binding ability of the synthesized derivatives to the target, AChE was investigated through molecular docking which reflected significant interactions to the target based on their docking binding scores. Hence, the newly designed quinazolinone derivatives possess promising anti-acetylcholinesterase activity and challenging for the management of AD in the future.

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, synthesis and anti-Mycobacterium tuberculosis evaluation of new thiazolidin-4-one and thiazolo[3,2-a][1,3,5]triazine derivatives.

In response to the urgent need to encounter infection diseases, and upon increasing concerns about the devastating effects of tuberculosis (TB), the promising thiazolidin-4-one scaffold was used as a starting point to design and synthesize seventeen new compounds, relying on the pharmacophoric features of different anti-Mycobacterium tuberculosis and antibacterial active compounds. Thiazolidin-4-one was elaborated to result in bi-functioning formation, and further ring fusion into a thiazolo[3,2-a][1,3,5]triazine, which was hybridized with different heterocyclic rings and sulfonamide moieties. All the newly synthesized compounds were evaluated for their activity against drug sensitive (DS), multi-drug resistant (MDR) and extensive drug resistant (XDR) Mycobacterium tuberculosis (Mtb) strains. Additionally, their anti-bacterial activity against several bronchitis causing-bacteria (ATCC) and their antifungal activity were assessed. Several compounds showed promising results regarding all of the mentioned assays without any antifungal activities. Particularly, compound 3 showed a promising activity against the three Mtb strains (DS, MDR and XDR) with MIC of 2.49, 9.91 and 39.72 µM, respectively. Furthermore, compound 7c revealed antituberculosis activity with MIC of 2.28, 18.14 and 36.31 µM against DS, MDR and XDR strains, respectively. Both of compounds 3 and 7c surpassed azithromycin on several bronchitis causing-bacteria and showed enhanced inhibitory activity against Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA), with IC50 of 3.90 and 2.47 µM, respectively. The enzymatic activity was augmented by the binding characteristics of 3 and 7c in the InhA active site. Further investigations confirmed their safety on normal cell lines, and promising predicted ADME characteristics.

Design and synthesis of novel 4-fluorobenzamide-based derivatives as promising anti-inflammatory and analgesic agents with an enhanced gastric tolerability and COX-inhibitory activity.

Responding to the great demand of developing potent NSAIDs with an enhanced safety profile and reasonable selectivity, in the present study novel 4-fluorobenzamide derivatives were synthesized and screened for their anti-inflammatory and analgesic activities using carrageenan-induced rat paw edema method and acetic acid-induced abdominal writhing in mice, respectively. All the new target compounds except the carbamothioylhydrazine series (5a-d), and the 4-fluorophenyl thiadiazolo derivative 6b showed promising anti-inflammatory activity ranged between 53.43 and 92.36% inhibition of edema (at 3 h) compared to the reference standard indomethacin (65.64%). All the newly synthesized compounds showed potent analgesic activity ranged between 71 and 100 % writhing protection compared to indomethacin (74.06%). Moreover, the most active compounds; the ester hybrids 2a,b, the thioureido quinazolinones 4b,c, and the thiadiazole congener 6a, showed promising gastric tolerability with ulcer index ranged between 0 and 6.60 compared to indomethacin (12.13). The thioureido quinazolinone derivatives 4b,c showed the most potent anti-inflammatory and analgesic activities with a remarkable gastric tolerability compared to the other derivatives. The 4-chlorophenyl derivative 4b is considered the most promising analogue showing 92.36% inhibition of edema, 100% writhing protection in analgesia testing, and a COX-2 selectivity index of 5.75 which was better than that of indomethacin and celecoxib standards (selectivity index = 0.27 and 4.55; respectively). Moreover, it showed an ulcer index equals zero with gastric acidity and mucin levels comparable to that of the control group indicating its minor effect on gastric cell physiology and its high tolerability. Molecular docking studies predicted the binding pattern of the newly synthesized compounds in COX-1 and COX-2 enzymes confirming the ability of the most active candidates to satisfy the structural features required for binding and rationalized their selectivity based on their docking binding patterns and scores. Furthermore, the newly synthesized 4-fluorobenzamide derivatives possess promising predicted pharmacokinetic properties indicated by calculating their key physicochemical parameters and absorption percentages.

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.

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.

1,2,4-Trisubstituted imidazolinones with dual carbonic anhydrase and p38 mitogen-activated protein kinase inhibitory activity.

Various 1,2,4 trisubstituted imidazolin-5-one derivatives were synthesized and evaluated for their inhibitory activity against p38 mitogen-activated protein kinase (p38MAPK) and carbonic anhydrase (CA) enzymes aiming to explore potential dual inhibitors. Results revealed that compounds 3c, 3g, 3h, 4a, 6c and 6d were the most effective derivatives against p38αMAPK (IC50 = 0.14, 0.14, 0.056, 0.14, 0.13 and 0.14 µM, respectively) compared to sorafenib (IC50 = 1.58 µM) as standard drug. On the other hand, compound 4a revealed the best inhibitory activity against all the tested carbonic anhydrase isoforms CA I, II, IV and IX with Ki values of 95.0, 0.83, 6.90 and 12.4 nM, respectively compared to acetazolamide with Ki values 250, 12.1, 74 and 12.8 nM, respectively. Therefore, compound 4a can be considered as a potent dual p38αMAPK/CA inhibitor.

Synthesis, biological evaluation and molecular modeling study of new (1,2,4-triazole or 1,3,4-thiadiazole)-methylthio-derivatives of quinazolin-4(3H)-one as DHFR inhibitors.

A new series of 2-mercapto-quinazolin-4-one analogues was designed, synthesized and evaluated for their in vitro DHFR inhibition, antitumor and antimicrobial activity. Compound 17 proved to be the most active DHFR inhibitor with IC50 value of 0.01µM, eight fold more active than methotrexate (MTX). Compounds 16 and 24 showed antitumor activity against human Caco2 colon and MCF-7 breast tumor cell lines with IC50 values of 25.4 and 9.5µg/ml, respectively. Compounds 15, 20, 21 and 30 showed considerable activity against the Gram-positive bacteria Staphylococcus aureus while 24 and 30 proved active against Bacillus subtilis with a magnitude of potency comparable to the broad spectrum antibiotic Ciprofloxacin. Strong activity was observed for 13, 14, 19, 20 and 24 against Candida albicans and Aspergillus flavus. Compound 17 shared a similar molecular docking mode with MTX and made a critical hydrogen bond and arene-arene interactions via Ala9 and Phe34 amino acid residues, respectively.

Insight on Some Newly Synthesized Trisubstituted Imidazolinones as VEGFR-2 Inhibitors.

Two series of ten new 1,2,4-trisubstituted imidazolin-5-ones were synthesized and screened against MCF-7 breast cancer and A549 lung cancer cell lines to test their potential in vitro anticancer activity. The results revealed preferential activity of the tested compounds toward MCF-7 cell lines compared to A549 cell lines. The most promising ten compounds (3a, 3c, 3f, 3g, 3h, 3i, 3j, 6a, 6f, and 6i) were subjected to VEGFR-2 enzyme inhibitory activity testing to further explore their mechanism of action. The tested compounds showed remarkable enzyme inhibition in micromolar concentrations ranging from 0.07 to 0.36 µM, compared with Sorafenib and Sunitinib with IC50 values of 0.06 and 0.12 µM, respectively. The most promising candidate, 3j, was further evaluated for its cell cycle phases, apoptotic induction ability, as well as its antiproliferative activity and inhibitory potential for endothelial cell migration, analyzed by a cell scratch assay. Furthermore, in silico studies were also performed to identify and detect the stability of the binding poses.

Discovery of a new potent oxindole multi-kinase inhibitor among a series of designed 3-alkenyl-oxindoles with ancillary carbonic anhydrase inhibitory activity as antiproliferative agents.

An optimization strategy was adopted for designing and synthesizing new series of 2-oxindole conjugates. Selected compounds were evaluated for their antiproliferative effect in vitro against NCI-60 cell lines panel, inhibitory effect on carbonic anhydrase (CA) isoforms (hCAI, II, IX and XII), and protein kinases. Compounds 5 and 7 showed promising inhibitory effects on hCA XII, whereas compound 4d was the most potent inhibitor with low nanomolar CA inhibition against all tested isoforms. These results were rationalized by using molecular docking. Despite its lack of CA inhibitory activity, compound 15c was the most active antiproliferative candidate against most of the 60 cell lines with mean growth inhibition 61.83% and with IC50 values of 4.39, 1.06, and 0.34 nM against MCT-7, DU 145, and HCT-116 cell lines, respectively. To uncover the mechanism of action behind its antiproliferative activity, compound 15c was assessed against a panel of protein kinases (RET, KIT, cMet, VEGFR1,2, FGFR1, PDFGR and BRAF) showing % inhibition of 74%, 31%, 62%, 40%, 73%, 74%, 59%, and 69%, respectively, and IC50 of 1.287, 0.117 and 1.185 µM against FGFR1, VEGFR, and RET kinases, respectively. These results were also explained through molecular docking.

Insights into targeting SARS-CoV-2: design, synthesis, in silico studies and antiviral evaluation of new dimethylxanthine derivatives.

Aiming to achieve efficient activity against severe acute respiratory syndrome coronavirus (SARS-CoV-2), the expansion of the structure- and ligand-based drug design approaches was adopted, which has been recently reported by our research group. Purine ring is a corner stone in the development of SARS-CoV-2 main protease (Mpro) inhibitors. The privileged purine scaffold was elaborated to achieve additional affinity based on hybridization and fragment-based approaches. Thus, the characteristic pharmacophoric features that are required for the inhibition of Mpro and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 were utilized along with the crystal structure information of both targets. The designed pathways involved rationalized hybridization with large sulfonamide moieties and a carboxamide fragment for the synthesis of ten new dimethylxanthine derivatives. The synthesis was performed under diverse conditions to afford N-alkylated xanthine derivatives, and cyclization afforded tricyclic compounds. Molecular modeling simulations were used to confirm and gain insights into the binding interactions at both targets' active sites. The merit of designed compounds and the in silico studies resulted in the selection of three compounds that were evaluated in vitro to estimate their antiviral activity against SARS-CoV-2 (compounds 5, 9a and 19 with IC50 values of 38.39, 8.86 and 16.01 µM, respectively). Furthermore, oral toxicity of the selected antiviral candidates was predicted, in addition to cytotoxicity investigations. Compound 9a showed IC50 values of 8.06 and 3.22 µM against Mpro and RdRp of SARS-CoV-2, respectively, in addition to promising molecular dynamics stability in both target active sites. The current findings encourage further specificity evaluations of the promising compounds for confirming their specific protein targeting.

Design and synthesis of ciprofloxacin-sulfonamide hybrids to manipulate ciprofloxacin pharmacological qualities: Potency and side effects.

Fluoroquinolones are a class of antibacterial agents used clinically to treat a wide array of bacterial infections. Although being potent, susceptibility to CNS side effects limits their use. It was observed that improvements in absorption, activity and side effects were achieved via modifications at the N atom of the C7 of the side chain. To meet the increasing demand for development of new antibacterial agents, nineteen novel ciprofloxacin-sulfonamide hybrid molecules were designed, synthesized and characterized by IR, 1H NMR and 13C NMR as potential antibacterial agents with dual DNA gyrase/topoisomerase IV inhibitory activity. Most of the synthesized compounds showed significant antibacterial activity that was revealed by testing their inhibitory activity against DNA gyrase, DNA topoisomerase IV as well as their minimum inhibitory concentration against Staphylococcus aureus. Six ciprofloxacin-sulfonamide hybrids (3f, 5d, 7a, 7d, 7e and 9b) showed potent inhibitory activity against DNA topoisomerase IV, compared to ciprofloxacin (IC50: 0.55 µM), with IC50 range: 0.23-0.44 µM. DNA gyrase was also efficiently inhibited by five ciprofloxacin-sulfonamide hybrids (3f, 5d, 5e, 7a and 7d) with IC50 range: 0.43-1.1 µM (IC50 of ciprofloxacin: 0.83 µM). Compounds 3a and 3b showed a marked improvement in the antibacterial activity over ciprofloxacin against both Gram-positive and Gram-negative pathogens, namely, Staphylococcus aureus Newman and Escherichia coli ATCC8739, with MIC = 0.324 and 0.422 µM, respectively, that is 4.2-fold and 3.2-fold lower than ciprofloxacin (MIC = 1.359 µM) against the Gram-positive Staphylococcus aureus, and MIC = 0.025 and 0.013 µM, respectively, that is 10.2-fold and 19.6-fold lower than ciprofloxacin (MIC = 0.255 µM) against the Gram-negative Escherichia coli ATCC8739. Also, the most active compounds showed lower CNS and convulsive side effects compared to ciprofloxacin with a concomitant decrease in GABA expression.

Design and synthesis of novel benzimidazole derivatives as potential Pseudomonas aeruginosa anti-biofilm agents inhibiting LasR: Evidence from comprehensive molecular dynamics simulation and in vitro investigation.

Quorum sensing (QS) inhibition is one of the potential methods to target bacterial infection. In this study, comprehensive molecular dynamics simulation (MDS) experiments were conducted on the LasR structure to understand its structural dynamic behavior either in its ligand-free form or in its ligand-bound form (i.e. agonist or antagonist). The results revealed that LasR structure is significantly unstable in its ligand-free and antagonist-bound forms and such structural instability led eventually to complete dissociation of the functioning LasR dimeric form. Accordingly, twenty-eight benzimidazole derivatives were designed, synthesized as potential LasR antagonists, and characterized in vitro as QS inhibitors. Compounds 3d and 7f disclosed the highest percentage inhibition in biofilm formation, pyocyanin, and rhamnolipids production in Pseudomonas aeruginosa (71.70%, 68.70%, 54.00%) and (68.90%, 68.00%, 51.80%), respectively. MDS experiments revealed that these compounds as inhibitors, particularly, 3d, 7f, 8a, and 9g induce LasR structure instability and complete dissociation of its functioning dimeric form similarly to the previously reported inhibitor bromophenethyl-2-nitrobenzamide (BPNB). Furthermore, gene expression assays as another mechanism targeting quorum sensing genes to prove the inhibitory activity of these compounds on virulence factors, revealed that a number of the synthesized compounds were able to downregulate lasR (e.g. 3d and 7f by 61.70% and 26.00%, respectively) and rhlR (e.g. 7f by 16.30%) expressions. The results presented here provide a functional model for LasR that could guide future design of LasR inhibitors.

Synthesis and computational studies of novel fused pyrimidinones as a promising scaffold with analgesic, anti-inflammatory and COX inhibitory potential.

Addressing the global need for the development of safe and potent NSAIDs, new series of oxadiazolo and thiadiazolo fused pyrmidinones were synthesized and initially tested for their analgesic activity. All tested compounds showed promising analgesic activity compared with the reference standard indomethacin. Moreover, anti-inflammatory activity evaluation, ulcerogenic liability, and in vitro COX-1, COX-2 enzyme inhibition assays were also performed for the most active derivatives. The methoxyphenyl piperazinyl derivative 3d showed analgesic activity surpassing indomethacin with protection of 100%, and 83%; respectively. Also 3d showed good anti-inflammatory activity with relatively lower ulcer index compared with other tested compounds, and potent COX-1 and COX-2 inhibitory activity with IC50 = 0.140, 0.007 µm, respectively, and with a selectivity index of 20.00 which was better than the reference standards and the other tested congeners. Additionally, compounds 3b, 3g and 3h revealed moderate selectivity (SI = 3.53, 3.70 and 5.87, respectively). Moreover, in silico physicochemical parameters revealed that the new fused pyrimidinones demonstrated promising pharmacokinetic properties. Furthermore, computational studies in form of 2D-quantitative structure-activity relationship (2D-QSAR) and 3D-pharmacophore confirmed the potential analgesic properties of the new target compounds.

Bacterial virulence factors: a target for heterocyclic compounds to combat bacterial resistance.

Antibiotic resistance is one of the most important challenges of the 21st century. However, the growing understanding of bacterial pathogenesis and cell-to-cell communication has revealed many potential strategies for the discovery of drugs that can be used for the treatment of bacterial infections. Interfering with bacterial virulence and/or quorum sensing could be a particularly interesting approach, because it is believed to exert less selective pressure on the bacterial resistance than with traditional strategies, geared toward killing bacteria or preventing their growth. Here, we discuss the mechanism of bacterial virulence, presenting promising strategies and recently synthesized heterocyclic compounds to combat future bacterial infections.

Mechanistic selectivity investigation and 2D-QSAR study of some new antiproliferative pyrazoles and pyrazolopyridines as potential CDK2 inhibitors.

Novel series of diphenyl-1H-pyrazoles (4a-g) and pyrazolo[3,4-b]pyridines (5a-g and 7a-i) were synthesized and evaluated for their antiproliferative activity against breast cancer cell line (MCF7) and Hepatocellular carcinoma cell line (HepG2). The highest MCF7 growth inhibition activity was attained via compounds 4f and 7e (IC50 = 1.29 and 0.93 µM, respectively), while compounds 5b and 7f were the most active ones against HepG2 (IC50 = 1.57 and 1.33 µM, respectively) compared to doxorubicin (IC50 = 1.88 and 7.30 µM, respectively). Cell cycle analysis showed arrest at S and G2-M phases in MCF7 cells treated with 4f and 7e, and at G2-M and G1/S phases in HepG2 cells treated with 5b and 7f, respectively. Apoptotic effect of compounds 4f, 5b, 7e, and 7f was indicated via their pre-G1 early and late apoptotic effects and augmented levels of caspase-9/MCF7 and caspase-3/HepG2. A worthy safety profile was assessed for compounds 4f and 7e on MCF10A and compounds 5b and 7f on THLE2 treated normal cells. Furthermore, compounds 4f, 5b and 7f displayed a promising selective profile for CDK2 inhibition vs. CDK1, CDK4, and CDK7 isoforms as proved from their selectivity index. Docking in CDK2 ATP binding site, co-crystallized with R-Roscovitine, demonstrated analogous interactions and comparable binding energy with the native ligand. 2D QSAR sighted the possible structural features governing the CDK2 inhibition activity elicited by the studied pyrazolo[3,4-b]pyridines. These findings present compounds 4f, 5b, and 7f as selective CDK2 inhibitors with promising antiproliferative activity against MCF7 and HepG2 cancer cells.

Anti-hepatitis-C virus activity and QSAR study of certain thiazolidinone and thiazolotriazine derivatives as potential NS5B polymerase inhibitors.

The present study reports on evaluation of anti-HCV activity and QSAR of certain arylidenethiazolidinone derivatives as potential inhibitors of HCV-NS5B polymerase. The pursued compounds involving, 5-aryliden-3-arylacetamidothiazolidin-2,4-diones 4-6(a-f), 5-arylidine-2-(N-arylacetamido)-iminothiazolidin-4-one (10) and their rigid counterparts 5-arylidinethiazolotriazines 13-15(a-f), were synthesized and their structures confirmed by spectral and elemental analyses. The results of NS5B polymerase inhibition assay revealed compound 4e, as the most active inhibitor (IC50 = 0.035 µM), which is four folds greater than that of the reference agent, VCH-759, (IC50 = 0.14 µM). Meanwhile, compounds 4b, 4c, 5a, and 5c, and 13b, 14e and 15c displayed equipotency to 2 folds higher activity than VCH-759 (IC50 values: 0.085, 0.14, 0.14, 0.10, 0.12, 0.09 and 0.07 µM, respectively). Assessment of the anti-HCV activity (GT1a) using human hepatoma cell line (Huh-7.5) illustrates superior activity of 4e (EC50 = 3.80 µM) relative to VCH-759 (EC50 = 5.29 µM). Cytotoxicity evaluation on, Transformed normal cell lines (Human Liver Epithelial-2, THLE-2 and Proximal Tubular Epithelial, RPTEC/TERT1), demonstrate enhanced safety profile of 4e (CC50 = 102.77, 161.37 µM, respectively) compared to VCH-759 (CC50 = 61.83, 81.28 µM, respectively). Molecular docking of the synthesized derivatives to NS5B polymerase allosteric site (PDB: 2HWH) showed similar binding modes to that of the co-crystallized ligand. Moreover, QSAR models were established for the studied thiazolidinones and thiazolotriazines to investigate the molecular characteristics contributing to the observed NS5B polymerase inhibition activity. The obtained results inspire further investigations of thiazolidinones and thiazolotriazine aiming at affording more potent, safe and orally active non-nucleoside NS5B polymerase inhibitors as anti-HCV drug candidates.

Construction of some cytotoxic agents with aurone and furoaurone scaffolds.

AIM: In spite of the availability of different chemotherapies for cancer treatment, there is still a need for new candidates with higher efficacy and lower toxicity. METHODOLOGY: Aurones 7a-f, 8a-f and furoaurones 13a-f, 16a-c were synthesized. Some compounds were selected by the National Cancer Institute, USA, for cytotoxicity screening. RESULTS & DISCUSSION: The furoaurone derivative, 13a was the most active one exhibiting promising growth inhibition against leukemia, K562 and melanoma, MDA-MB-435 cells at concentration of 10 µM. It induced apoptosis in both cell lines by activation of CASP3 and inhibition of CDK2. Additionally, 13a showed good selectivity over normal kidney and liver cells. Simulation docking study was undertaken to gain insight into the possible binding mode of 13a in the CDK2 enzyme. CONCLUSION: The furoaurone 13a can be considered as a scaffold for further optimization to obtain more active hits. Graphical abstract [Formula: see text].