Design, synthesis, biological evaluation and molecular docking studies of quinoline-anthranilic acid hybrids as potent anti-inflammatory drugs.

Despite the high global prevalence, rheumatoid arthritis lacks a satisfactory treatment. Hence, the present study is undertaken to design and synthesize novel anti-inflammatory compounds. For this, quinoline and anthranilic acid, two medicinally-privileged moieties, were linked by pharmacophore hybridization, and following their computational assessments, three hybrids 5a-c were synthesized in good over all yields. The in vitro and in vivo anti-inflammatory potential of these hybrids was determined by anti-denaturation and anti-proteinase, and carrageenan-induced paw edema models. The computational studies of these hybrids revealed their drug-likeness, optimum pharmacokinetics, and less toxicity. Moreover, they demonstrated high binding affinity (-9.4 to -10.6 kcal mol-1) and suitable binding interactions for TNF-α, FLAP, and COX-II. A three-step synthetic route resulted in the hybrids 5a-c with 83-86% yield of final step. At 50 µg mL-1, the antiprotease and anti-denaturation activity of compound 5b was significantly higher than 5a and 5c. Furthermore, 5b significantly reduced the edema in the right paw of the rats that received carrageenan. The results of this study indicate the medicinal worth of the novel hybrids in treating inflammatory disorders such as rheumatoid arthritis.

Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects.

We have previously reported the total synthesis and structure-activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARß/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARß/δ and partial PPARγ activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities.

PI3Kδ and mTOR dual inhibitors: Design, synthesis and anticancer evaluation of 3-substituted aminomethylquinoline analogues.

Phosphatidylinositide-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) have recently been identified as potential cancer targets. In our work, a new family of quinoline analogues was designed, developed, and evaluated as dual inhibitors of PI3Kδ/mTOR. The preliminary biological activity analysis led to the discovery of the lead compounds 5h and 5e. Compounds 5h and 5e exhibited excellent anti-tumor potency with IC50 of 0.26 µM and 0.34 µM against Ramos cells, respectively. Importantly, based on the enzymatic activity assay results, compounds 5h and 5e were identified as dual inhibitors of PI3Kδ and mTOR, with IC50 values of 0.042 µM and 0.056 µM for PI3Kδ and 0.059 µM and 0.073 µM for mTOR, respectively. Furthermore, these compounds showed superior selectivity for blocking PI3Kδ compared to other PI3K isoforms (α, ß, and γ), supporting the concept of developing inhibitors that specifically target PI3Kδ/mTOR. The most effective compound 5h was chosen for additional biological testing. At a low dose of 0.5 µM, a western blot investigation confirmed the anticancer effects by inhibiting the PAM cascade, which in turn reduced downstream biomarkers pAkt (Ser473), pAkt (Thr308), and pRPS6 (Ser235/236). Furthermore, it increased apoptosis at the early (10.03 times) and late (17.95 times) stages in the Annexin-V assay as compared to the standard. In addition, the expression of p53, caspase-3, caspase-9, and the Bax/BCl-2 ratio were all significantly increased by compound 5h in the ELISA assay. Based on these results, it appears that 5h may activate the intrinsic apoptosis pathway, which in turn triggers cell death. Furthermore, the anticancer effects could be attributed to the inhibition of PI3Kδ/mTOR, as shown by docking interactions. Lastly, it demonstrated improved in vitro metabolic stability and passed the in silico ADMET/drug-likeness test. This profile recommends 5h for future in vivo PK-PD and efficacy investigations in animal cancer models.

Discovery of a new class of potent pyrrolo[3,4-c]quinoline-1,3-diones based inhibitors of human dihydroorotate dehydrogenase: Synthesis, pharmacological and toxicological evaluation.

Twenty N-substituted pyrrolo[3,4-c]quinoline-1,3-diones 3a-t were synthesized by a cyclization reaction of Pfitzinger's quinoline ester precursor with the selected aromatic, heteroaromatic and aliphatic amines. The structures of all derivatives were confirmed by IR, 1H NMR, 13C NMR and HRMS spectra, while their purity was determined using HPLC techniques. Almost all compounds were identified as a new class ofpotent inhibitors against hDHODH among which 3a and 3t were the most active ones with the same IC50 values of 0.11 µM, about seven times better than reference drug leflunomide. These two derivatives also exhibited very low cytotoxic effects toward healthy HaCaT cells and the optimal lipophilic properties with logP value of 1.12 and 2.07 respectively, obtained experimentally at physiological pH. We further evaluated the comparative differences in toxicological impact of the three most active compounds 3a, 3n and 3t and reference drug leflunomide. The rats were divided into five groups and were treated intraperitoneally, control group (group I) with a single dose of leflunomide (20 mg/kg) group II and the other three groups, III, IV and V were treated with 3a, 3n and 3t (20 mg/kg bw) separately. The investigation was performed in liver, kidney and blood by examining serum biochemical parameters and parameters of oxidative stress.

Novel Tetracyclic Azaphenothiazines with the Quinoline Ring as New Anticancer and Antibacterial Derivatives of Chlorpromazine.

Phenothiazine derivatives are widely studied in various fields such as biology, chemistry, and medicine research because of their pharmaceutical effects. The first compound used successfully in the treatment of psychosis was a phenthiazine derivative, chlorpromazine. Apart from its activity in neurons, chlorpromazine has also been reported to display anticancer and antibacterial properties. In this study, we present the synthesis and research on the activity of A549, MDA, MiaPaCa, PC3, and HCT116 cancer cell lines and of S. aureus, S. epidermidis, E. coli, and P. aeruginosa bacterial strains against a series of new tetracyclic chlorpromazine analogues containing a quinoline scaffold in their structure instead of the benzene ring and various substituents at the thiazine nitrogen. The structure of these novel molecules has been determined by 1H NMR, 13C NMR, and HRMS spectral techniques. The seven most active of the twenty-four new chlorpromazine analogues tested were selected to study the mechanism of cytotoxic action. Their ability to induce apoptosis or necrosis in cancer cells was assessed by flow cytometry analysis. The results obtained confirmed the proapoptotic activity of selected compounds, especially in terms of inducing late apoptosis or necrosis in cancer cell lines A549, MiaPaCa-2, and HCT-116. Furthermore, studies on the induction of cell cycle arrest suggest that the new chlorpromazine analogues exert antiproliferative effects by inducing cell cycle arrest in the S phase and, consequently, apoptosis.

Synthesis and biological evaluation of carboxamide and quinoline derivatives as P2X7R antagonists.

P2X7 receptor (P2X7R) has a key role in different pathological conditions, importantly overexpressed and activated in cancers. We explored the structure activity relationship (SAR) of three novel pyrazines, quinoline-carboxamide and oxadiazole series. Their selective inhibitory potency in Ca2+ mobilization assay using h-P2X7R-MCF-7 cells improved with phenyl ring substitutions (-OCF3, -CF3, and -CH3) in carboxamide and oxadiazole derivatives, respectively. However, highly electronegative fluoro, chloro, and iodo substitutions enhanced affinity. 1e, 2f, 2e, 1d, 2 g and 3e were most potent and selective toward h-P2X7R (IC50 values 0.457, 0.566, 0.624, 0.682, 0.813 and 0.890 µM, respectively) and were inactive at h-P2X4R, h-P2X2R, r-P2Y6R, h-P2Y2R, t-P2Y1R expressed in MCF-7 and 1321N1 astrocytoma cells. Cell viability (MTT assay at 100 µM, cell line) for 3e was 62% (HEK-293T), 70% (1321N1 astrocytoma) and 85% (MCF-7). >75% cell viability was noted for 2 g and >80% for 2e and 1d in all non-transfected cell lines. Anti-proliferative effects, compared to control (Bz-ATP), of selective antagonists (10 µM) were 3e (11%) 1d, (19%) 1e, (70%, P = 0.005) and 2f, (24%), indicating involvement of P2X7R. Apoptotic cell death by flow cytometry showed 1e to be most promising, with 35% cell death (PI positive cells), followed by 2e (25%), 2f (20%), and 1d (19%), compared to control. Fluorescence microscopic analysis of apoptotic changes in P2X7R-transfected cell lines was established. 1e and 2f at 1X and 2X IC50 increased cellular shrinkage, nuclear condensation and PI/DAPI fluorescence. In-silico antagonist modeling predicted ligand receptor interactions, and all compounds obeyed Lipinski rules. These results suggest that pyrazine, quinoline-carboxamide and oxadiazole derivatives could be moderately potent P2X7R antagonists for in vivo studies and anti-cancer drug development.

Design, synthesis, and biological evaluation of novel quinoline derivatives as small molecule mutant EGFR inhibitors targeting resistance in NSCLC: In vitro screening and ADME predictions.

Here in, we report the design, synthesis and in vitro anticancer activity of a novel series of 24 quinoline analogues of substituted amide and sulphonamide derivatives. The anticancer activity of the synthesised compounds was evaluated against the HCC827, H1975 (L858R/T790 M), A549 (WT EGFR), A-549 and BEAS-2B cell lines. The majority of quinoline compounds demonstrated a significant cytotoxic effect. Compound 21 was found to be the most potent, with IC50 values of 0.010 µM, 0.21 µM, 0.99 µM and 2.99 µM as compared to Osimertinib with IC50 values with of 0.0042 µM, 0.04 µM, 0.92 µM and 2.67 µM. Compound 21 exhibited promising inhibitory enzymatic activity against the EGFR L858R/T790 M with IC50 value of 138 nM, comparable to Osimertinib's 110 nM. Employing a Western blot assay on the phosphorylation of EGFR and the signalling pathways transmission in HCC827 cells, the anticancer activity of the synthesised compounds 18 and 21 was evaluated in terms of its mechanism of action. All the compounds were subjected to a comparative molecular docking study against various EGFR enzyme types, including the wild-type (PDB: 4I23) and T790 M mutant (PDB: 2JIV) enzymes. Furthermore, compounds were examined at the allosteric binding site of the EGFR enzyme with the L858R/T790 M/C797S mutation (PDB ID: 5D41). The MD simulation study was also performed for EGFR-compound 21 complex which indicates the stability compound 21 in both ATP and allosteric site of enzyme. Further, in silico ADME prediction studies of all derivatives were found promising, signifying the drug like properties.

Synthesis of Selenyl-Substituted Quinoline Derivatives via Substrate-Controlled Three-Component Domino Reactions.

A simple and efficient method for the preparation of selenyl-substituted quinoline derivatives through a CSp3-H selenylation of in situ-generated 3-acetyl quinoline has been developed. This protocol is easy to handle, scalable, and good functional group tolerant, providing a rapid method to 3-selenoacetyl quinoline and 3-diselenoacetyl quinoline derivatives.

Synthesis of Copper Oxide-Based Nanoformulations of Etoricoxib and Montelukast and Their Evaluation through Analgesic, Anti-Inflammatory, Anti-Pyretic, and Acute Toxicity Activities.

Copper oxide nanoparticles (CuO NPs) were synthesized through the coprecipitation method and used as nanocarriers for etoricoxib (selective COX-2 inhibitor drug) and montelukast (leukotriene product inhibitor drug) in combination therapy. The CuO NPs, free drugs, and nanoformulations were investigated through UV/Vis spectroscopy, FTIR spectroscopy, XRD, SEM, and DLS. SEM imaging showed agglomerated nanorods of CuO NPs of about 87 nm size. The CE1, CE2, and CE6 nanoformulations were investigated through DLS, and their particle sizes were 271, 258, and 254 nm, respectively. The nanoformulations were evaluated through in vitro anti-inflammatory activity, in vivo anti-inflammatory activity, in vivo analgesic activity, in vivo anti-pyretic activity, and in vivo acute toxicity activity. In vivo activities were performed on albino mice. BSA denaturation was highly inhibited by CE1, CE2, and CE6 as compared to other nanoformulations in the in vitro anti-inflammatory activity. The in vivo bioactivities showed that low doses (5 mg/kg) of nanoformulations were more potent than high doses (10 and 20 mg/kg) of free drugs in the inhibition of pain, fever, and inflammation. Lastly, CE2 was more potent than that of other nanoformulations.

Design, synthesis and anticancer evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety as novel multi-target TKIs.

Giving the fact that the disorders of multiple receptor tyrosine kinases (RTKs) are characteristics of various cancers, we assumed that developing novel multi-target drugs might have an advantage in treating the complex cancers. Taking the multi-target c-Met inhibitor Foretinib as the leading compound, we discovered a novel series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety with the help of molecular docking. Among them, the most promising compound 33 showed a prominent activity against Hela (IC50 = 0.21 µM), A549 (IC50 = 0.39 µM), and MCF-7 (IC50 = 0.33 µM), which were 3.28-4.82 times more active than that of Foretinib. Additionally, compound 33 dose dependently induced apoptosis by arresting A549 cells at G1 phase. Enzymatic assays and docking analyses were further confirmed that compound 33 was a multi-target inhibitor with the strong potencies against c-Met (IC50 = 11.77 nM), MEK1 (IC50 = 10.71 nM), and Flt-3 (IC50 = 22.36 nM). In the A549 cells mediated xenograft mouse model, compound 33 inhibited the tumor growth (TGI = 64%) without obvious toxicity, establishing compound 33 as a promising candidate for cancer therapy.

Investigation of the Anticancer Effect of α-Aminophosphonates and Arylidine Derivatives of 3-Acetyl-1-aminoquinolin-2(1H)-one on the DMBA Model of Breast Cancer in Albino Rats with In Silico Prediction of Their Thymidylate Synthase Inhibitory Effect.

Breast cancer is a major cause of death in women worldwide. In this study, 60 female rats were classified into 6 groups; negative control, α-aminophosphonates, arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one, DMBA, DMBA & α-aminophosphonates, and DMBA & arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one. New α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one were synthesized and elucidated by different spectroscopic and elemental analysis. Histopathological examination showed marked proliferation of cancer cells in the DMBA group. Treatment with α-aminophosphonates mainly decreased tumor mass. Bcl2 expression increased in DMBA-administered rats and then declined in the treated groups, mostly with α-aminophosphonates. The level of CA15-3 markedly declined in DMBA groups treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one. Gene expression of GST-P, PCNA, PDK, and PIK3CA decreased in the DMBA group treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one, whereas PIK3R1 and BAX increased in the DMBA group treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one. The molecular docking postulated that the investigated compounds can inhibt the Thymidylate synthase TM due to high hydrophobicity charachter.

A Review of Modifications of Quinoline Antimalarials: Mefloquine and (hydroxy)Chloroquine.

Late-stage modification of drug molecules is a fast method to introduce diversity into the already biologically active scaffold. A notable number of analogs of mefloquine, chloroquine, and hydroxychloroquine have been synthesized, starting from the readily available active pharmaceutical ingredient (API). In the current review, all the modifications sites and reactivity types are summarized and provide insight into the chemistry of these molecules. The approaches include the introduction of simple groups and functionalities. Coupling to other drugs, polymers, or carriers afforded hybrid compounds or conjugates with either easily hydrolyzable or more chemically inert bonds. The utility of some of the compounds was tested in antiprotozoal, antibacterial, and antiproliferative assays, as well as in enantiodifferentiation experiments.

Synthesis, Nanoformulations, and In Vitro Anticancer Activity of N-Substituted Side Chain Neocryptolepine Scaffolds.

The naturally occurring neocryptolepine (5-Methylindolo [2,3-b]quinoline) and its analogs exhibited prominent anticancer and antimalarial activity. However, the main problem of this class of compounds is their poor aqueous solubility, hampering their bioavailability and preventing their clinical development. To overcome the problem of insolubility and to improve the physicochemical and the pharmacological properties of 5-Methylindolo [2,3-b]quinoline compounds, this work was designed to encapsulate such efficient medical compounds into mesoporous silica oxide nanoemulsion (SiO2NPs). Thus, in this study, SiO2NPs was loaded with three different concentrations (0.2 g, 0.3, and 0.6 g) of 7b (denoted as NPA). The findings illustrated that the nanoparticles were formed with a spherical shape and exhibited small size (less than 500 nm) using a high concentration of the synthesized chemical compound (NPA, 0.6 g) and good stabilization against agglomeration (more than -30 mv). In addition, NPA-loaded SiO2NPs had no phase separation as observed by our naked eyes even after 30 days. The findings also revealed that the fabricated SiO2NPs could sustain the release of NPA at two different pH levels, 4.5 and 7.4. Additionally, the cell viability of the produced nanoemulsion system loaded with different concentrations of NPA was greater than SiO2NPs without loading, affirming that NPA had a positive impact on increasing the safety and cell viability of the whole nanoemulsion. Based on these obtained promising data, it can be considered that the prepared NPA-loaded SiO2NPs seem to have the potential for use as an effective anticancer drug nanosystem.

Synthesis and Preliminary Evaluation of the Cytotoxicity of Potential Metabolites of Quinoline Glycoconjugates.

The design of prodrugs is one of the important strategies for selective anti-cancer therapies. When designing prodrugs, attention is paid to the possibility of their targeting tumor-specific markers such as proteins responsible for glucose uptake. That is why glycoconjugation of biologically active compounds is a frequently used strategy. Glycoconjugates consisting of three basic building blocks: a sugar unit, a linker containing a 1,2,3-triazole ring, and an 8-hydroxyquinoline fragment was described earlier. It is not known whether their cytotoxicity is due to whole glycoconjugates action or their metabolites. To check the biological activity of products that can be released from glycoconjugates under the action of hydrolytic enzymes, the synthetically obtained potential metabolites were tested in vitro for the inhibition of proliferation of HCT-116, MCF-7, and NHDF-Neo cell lines using the MTT assay. Research shows that for the full activity of glycoconjugates, the presence of all three building blocks in the structure of a potential drug is necessary. For selected derivatives, additional tests of targeted drug delivery to tumor cells were carried out using polymer nanocarriers in which they are encapsulated. This approach significantly lowered the determined IC50 values of the tested compounds and improved their selectivity and effectiveness.

Toll-like receptor 7 and 8 imidazoquinoline-based agonist/antagonist pairs.

Toll-like receptors (TLRs) 7 and 8 are key targets in the development of immunomodulatory drugs for treating infectious disease, cancer, and autoimmune disorders. These receptors can adopt both agonist and antagonist binding conformations that switch the receptor signal on or off to the downstream production of cytokines. In this study, we examined the effect of simple isomeric substitutions to the C2-butyl group of two imidazoquinoline agonists and evaluated the activity of these analogs using both TLR7 and TLR8 reporter cells and cytokine induction assays. Results are presented showing the C2-isobutyl and C2-cyclopropylmethyl isomers are both mixed TLR7/8 competitive antagonists of the parent agonist [4-Amino-1-(4-(aminomethyl)benzyl)-2-butyl-7-methoxycarbonyl-1H-imidazo[4,5-c]quinoline], indicating the conformation of the dimeric receptor complex is highly sensitive to steric perturbations to the ligand binding pocket. This observation is consistent with prior work demonstrating TLR7 and TLR8 activity is directly correlated to C2-alkyl substitutions that project into a hydrophobic pocket at the dimer interface of the receptor. The close structural relationship of the agonist/antagonist pairs identified here highlights the importance of this pocket in tipping the balance between the agonist and antagonist binding states of the receptor which may have significant ramifications to the design of imidazoquinoline-based immunomodulatory agents.

Structural Basis of 2-Phenylamino-4-phenoxyquinoline Derivatives as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors.

New target molecules, namely, 2-phenylamino-4-phenoxyquinoline derivatives, were designed using a molecular hybridization approach, which was accomplished by fusing the pharmacophore structures of three currently available drugs: nevirapine, efavirenz, and rilpivirine. The discovery of disubstituted quinoline indicated that the pyridinylamino substituent at the 2-position of quinoline plays an important role in its inhibitory activity against HIV-1 RT. The highly potent HIV-1 RT inhibitors, namely, 4-(2',6'-dimethyl-4'-formylphenoxy)-2-(5″-cyanopyridin-2″ylamino)quinoline (6b) and 4-(2',6'-dimethyl-4'-cyanophenoxy)-2-(5″-cyanopyridin-2″ylamino)quinoline (6d) exhibited half-maximal inhibitory concentrations (IC50) of 1.93 and 1.22 µM, respectively, which are similar to that of nevirapine (IC50 = 1.05 µM). The molecular docking results for these two compounds showed that both compounds interacted with Lys101, His235, and Pro236 residues through hydrogen bonding and interacted with Tyr188, Trp229, and Tyr318 residues through π-π stacking in HIV-1 RT. Interestingly, 6b was highly cytotoxic against MOLT-3 (acute lymphoblastic leukemia), HeLA (cervical carcinoma), and HL-60 (promyeloblast) cells with IC50 values of 12.7 ± 1.1, 25.7 ± 0.8, and 20.5 ± 2.1 µM, respectively. However, 6b and 6d had very low and no cytotoxicity, respectively, to-ward normal embryonic lung (MRC-5) cells. Therefore, the synthesis and biological evaluation of 2-phenylamino-4-phenoxyquinoline derivatives can serve as an excellent basis for the development of highly effective anti-HIV-1 and anticancer agents in the near future.

4-Oxooctahydroquinoline-1(2H)-carboxamides as hepatitis B virus (HBV) capsid core protein assembly modulators.

Hepatitis B virus (HBV) core protein, the building block of the HBV capsid, plays multiple roles in viral replication, and is an attractive target for development of antiviral agents with a new mechanism of action. In addition to the heteroaryldihydropyrimidines (HAPs), sulfamoylbenzamides (SBAs), dibenzothiazepine derivatives (DBTs), and sulfamoylpyrrolamides (SPAs) that inhibit HBV replication by modulation of viral capsid assembly and are currently under clinical trials for the treatment of chronic hepatitis B (CHB), other chemical structures with activity to modulate HBV capsid assembly have also been explored. Here we describe our continued optimization of a benzamide originating from our high throughput screening. A new bicyclic carboxamide lead featuring an electron deficient non-planar core structure was discovered. Evaluations of its ADMET (absorption, distribution, metabolism, excretion and toxicity) and pharmacokinetic (PK) profiles demonstrate improved metabolic stability and good bioavailability.

Discovery of Quinoline-Derived Trifluoromethyl Alcohols as Antiepileptic and Analgesic Agents That Block Sodium Channels.

The discovery of novel analgesic agents with high potency, low toxicity and low addictive properties remain a priority. This study aims to identify the analgesic potential of quinoline derived α-trifluoromethylated alcohols (QTA) and their mechanism of action. We synthesized and characterized several compounds of QTAs and screened them for antiepileptic and analgesic activity using zebrafish larvae in high thorough-put behavior analyses system. Toxicity and behavioral screening of 9 compounds (C1-C9) identified four candidates (C2, C3, C7 and C9) with antiepileptic properties that induces specific and reversible reduction in photomotor activity. Importantly, compounds C2 and C3 relieved the thermal pain response in zebrafish larvae indicating analgesic property. Further, using novel in vivo CoroNa green assay, we show that compounds C2 and C3 block sodium channels and reduce inflammatory sodium signals released by peripheral nerve and tissue damage. Thus, we have identified novel QTA compounds with antiepileptic and analgesic properties which could alleviate neuropathic pain.

Design, synthesis, and characterization of novel aminoalcohol quinolines with strong in vitro antimalarial activity.

Malaria is the fifth most lethal parasitic infections in the world. Herein, five new series of aminoalcohol quinolines including fifty-two compounds were designed, synthesized and evaluated in vitro against Pf3D7 and PfW2 strains. Among them, fourteen displayed IC50 values below or near of 50.0 nM whatever the strain with selectivity index often superior to 100.17b was found as a promising antimalarial candidate with IC50 values of 14.9 nM and 11.0 nM against respectively Pf3D7 and PfW2 and a selectivity index higher than 770 whatever the cell line is. Further experiments were achieved to confirm the safety and to establish the preliminary ADMET profile of compound 17b before the in vivo study performed on a mouse model of P. berghei ANKA infection. The overall data of this study allowed to establish new structure-activity relationships and the development of novel agents with improved pharmacokinetic properties.

Design, synthesis, and biological evaluation of novel morpholinated isatin-quinoline hybrids as potent anti-breast cancer agents.

Keeping in view the emerging need for potent and safer anti-breast cancer agents as well as the pharmacological attributes of isatin, quinolone, and morpholine derivatives, novel hydrazine-linked morpholinated isatin-quinoline hybrids were designed, synthesized, and evaluated as anti-breast cancer agents. The synthesized hybrid compounds were preliminarily screened against two breast cancer cell lines (MCF-7 and MDA-MB-231). Almost all synthetics showed potent inhibitory potential against hormone-positive MCF-7 cells while being inactive against hormone-negative MDA-MB-231 cells. Potent compounds were further evaluated against the L929 (noncancerous skin fibroblast) cell line and found to be highly selective for MCF-7 cells over L929 cells. Cell cycle analysis confirmed that the most potent compound AS-4 (MCF-7: GI50 = 4.36 µM) causes mitotic arrest at the G2 /M phase. Due to higher selectivity toward estrogen receptor alpha (ERα)-dependent MCF-7 cells, various binding interactions of AS-4 with ERα are also streamlined, suggesting the capability of AS-4 to completely block ERα. Overall, the study suggests that AS-4 can act as a potential lead for further development of potent and safer anti-breast cancer agents.