Allosteric HIV-1 integrase (IN) inhibitors, or ALLINIs, are a new class of antiviral agents that bind at the dimer interface of the IN, away from the enzymatic catalytic site and block viral replication by triggering an aberrant multimerization of the viral enzyme. To further our understanding of the important binding features of multi-substituted quinoline-based ALLINIs, we have examined the IN multimerization and antiviral properties of substitution patterns at the 6 or 8 position. We found that the binding properties of these ALLINIs are negatively impacted by the presence of bulky substitutions at these positions. In addition, we have observed that the addition of bromine at either the 6 (6-bromo) or 8 (8-bromo) position conferred better antiviral properties. Finally, we found a significant loss of potency with the 6-bromo when tested with the ALLINI-resistant IN A128T mutant virus, while the 8-bromo analog retained full effectiveness.

A new series of 2,5 and 1,5-regioisomers of the tetrazolyl group viz., 3-[(5-benzyl/benzylthio-2H-tetrazol-2-yl) methyl]-2-chloro-6-substituted quinoline 6h-q and 3-[(5-benzyl/benzylthio-1H-tetrazol-1-yl) methyl]-2-chloro-6-substituted quinolines 7h-q were synthesized. Docking studies of all these compounds with DNA as target using PDB: 1AU5 and 453D revealed that the compounds 6h and 6i act as covalent cross linker on the DNA helix of the former and intercalate the latter both with higher C score values. Another set of docking studies in the active pocket of dihydrofolate reductase and N-myristoyl transferase as targets to assess antifungal activity revealed that compounds 6k, 6l, 6p and 7q (with bromo and fluro substituents) showcases different binding modes and hydrogen bonding. Further, the compounds were screened for anticancer activity (primary cytotoxicity) against NCI-60 Human tumor cell line at a single high dose (10-5 M) concentration assay. Among the tested compounds, 6h has shown 99.28% of GI against Melanoma (SK-MEL-5) and compound 6i has shown 97.56% of GI against Breast Cancer (T-47D). Further, in vitro antifungal assay against A. fumigatus and C. albicans for these compounds 6h-q and 7h-q revealed potential to moderate activities as compared to the standard.

F508del, the most frequent mutation in cystic fibrosis (CF), impairs the stability and folding of the CFTR chloride channel, thus resulting in intracellular retention and CFTR degradation. The F508del defect can be targeted with pharmacological correctors, such as VX-809 and VX-445, that stabilize CFTR and improve its trafficking to plasma membrane. Using a functional test to evaluate a panel of chemical compounds, we have identified tricyclic pyrrolo-quinolines as novel F508del correctors with high efficacy on primary airway epithelial cells from CF patients. The most effective compound, PP028, showed synergy when combined with VX-809 and VX-661 but not with VX-445. By testing the ability of correctors to stabilize CFTR fragments of different length, we found that VX-809 is effective on the amino-terminal portion of the protein that includes the first membrane-spanning domain (amino acids 1-387). Instead, PP028 and VX-445 only show a stabilizing effect when the second membrane-spanning domain is included (amino acids 1-1181). Our results indicate that tricyclic pyrrolo-quinolines are a novel class of CFTR correctors that, similarly to VX-445, interact with CFTR at a site different from that of VX-809. Tricyclic pirrolo-quinolines may represent novel CFTR correctors suitable for combinatorial pharmacological treatments to treat the basic defect in CF.

Detecting aggregated amyloid peptides (Abeta plaques) presents targets for developing biomarkers of Alzheimer's disease (AD). Polymeric n-butyl-2-cyanoacrylate (PBCA) nanoparticles (NPs) were encapsulated with radiolabelled amyloid affinity (125)I-clioquinol (CQ, 5-chloro-7-iodo-8-hydroxyquinoline) as in vivo probes. (125)I-CQ-PBCA NPs crossed the BBB (2.3 +/- 0.9 ID/g) (P < .05) in the WT mouse (N = 210), compared to (125)I-CQ (1.0 +/- 0.4 ID/g). (125)I-CQ-PBCA NP brain uptake increased in AD transgenic mice (APP/PS1) versus WT (N = 38; 2.54 x 10(5) +/- 5.31 x 10(4) DLU/mm(2); versus 1.98 x 10(5) +/- 2.22 x 10(4) DLU/mm(2)) and in APP/PS1/Tau. Brain increases were in mice intracranially injected with aggregated Abeta(42) peptide (N = 17; 7.19 x 10(5) +/- 1.25 x 10(5) DLU/mm(2)), versus WT (6.07 x 10(5) +/- 7.47 x 10(4) DLU/mm(2)). Storage phosphor imaging and histopathological staining of the plaques, Fe(2+) and Cu(2+), validated results. (125)I-CQ-PBCA NPs have specificity for Abeta in vitro and in vivo and are promising as in vivo SPECT ((123)I), or PET ((124)I) amyloid imaging agents.

Within the context of our anthelmintic discovery program, we recently identified and evaluated a quinoline derivative, called ABX464 or obefazimod, as a nematocidal candidate; synthesised a series of analogues which were assessed for activity against the free-living nematode Caenorhabditis elegans; and predicted compound-target relationships by thermal proteome profiling (TPP) and in silico docking. Here, we logically extended this work and critically evaluated the anthelmintic activity of ABX464 analogues on Haemonchus contortus (barber's pole worm) - a highly pathogenic nematode of ruminant livestock. First, we tested a series of 44 analogues on H. contortus (larvae and adults) to investigate the nematocidal pharmacophore of ABX464, and identified one compound with greater potency than the parent compound and showed moderate activity against a select number of other parasitic nematodes (including Ancylostoma, Heligmosomoides and Strongyloides species). Using TPP and in silico modelling studies, we predicted protein HCON_00074590 (a predicted aldo-keto reductase) as a target candidate for ABX464 in H. contortus. Future work aims to optimise this compound as a nematocidal candidate and investigate its pharmacokinetic properties. Overall, this study presents a first step toward the development of a new nematocide.

We describe the design and synthesis of two isatin-tethered quinolines series (Q6a-h and Q8a-h), in connection with our research interest in developing novel isatin-bearing anti-tubercular candidates. In a previous study, a series of small molecules bearing a quinoline-3-carbohydrazone moiety was developed as anti-tubercular agents, and compound IV disclosed the highest potency with MIC value equal to 6.24 µg/mL. In the current work, we adopted the bioisosteric replacement approach to replace the 3,4,5-trimethoxy-benzylidene moiety in the lead compound IV with the isatin motif, a privileged scaffold in the TB drug discovery, to furnish the first series of target molecules Q6a-h. Thereafter, the isatin motif was N-substituted with either a methyl or benzyl group to furnish the second series Q8a-h. All of the designed quinoilne-isatin conjugates Q6a-h and Q8a-h were synthesized and then biologically assessed for anti-tubercular actions towards drug-susceptible, MDR, and XDR strains. Superiorly, the N-benzyl-bearing compound Q8b possessed the best activities against the examined M. tuberculosis strains with MICs equal 0.06, 0.24, and 1.95 µg/mL, respectively.

Fungal infections have emerged as a current serious global public health problem. The main problem involving these infections is the expansion of multidrug resistance. Therefore, the prospection of new compounds with efficacy antifungal becomes necessary. Thus, this study evaluated the antifungal profile and toxicological parameters of quinolines derivatives against Candida spp. and dermatophyte strains. As a result, a selective anti-dermatophytic action was demonstrated by compound 5 (geometric means (GM = 19.14 μg ml-1)). However, compounds 2 (GM = 50 μg ml-1) and 3 (GM = 47.19 μg ml-1) have presented only anti-Candida action. Compounds 3 and 5 did not present cytotoxic action. Compound 5 did not produce dermal and mucosal toxicity. In addition, this compound showed the absence of genotoxic potential, suggesting safety for topical and systemic use. Quinolines demonstrated a potent anti-dermatophytic and anti-yeast action. Moreover, compound 5 presented an excellent toxicological profile, acting as a strong candidate for the development of a new effective and safe compound against dermatophytosis of difficult treatment.

Emergence of antimicrobial resistance to standard commercial drugs has become a critical public health concern worldwide. Hence, novel antimicrobials with improved biological activities are urgently needed. In this regard, a series of quinoline-stilbene derivatives were synthesized from substituted quinoline and benzyltriphenylphosphonium chloride using Wittig reaction. Furthermore, a novel pinacol of quinoline was synthesized by pinacolinazation of 2-methoxyquinoline-3-carbaldehyde which was achieved by aluminum powder-potassium hydroxide reagent combination at ambient temperature in methanol. The structures of the synthesized compounds were established based on their spectral data. The antibacterial activities of the synthesized compounds were evaluated in vitro by the paper disc diffusion method against two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) and two Gram-negative bacteria (Escherichia coli and Salmonella typhimurium). The best activity was displayed by compound 19 against E. coli with an inhibition zone of 16.0 ± 0.82 mm and 14.67 ± 0.94 mm at 500 and 250 μg/mL, respectively. This is close to ciprofloxacin which is used as a positive control. The results of in silico molecular docking evaluation of the compounds against E. coli DNA gyraseB were in good agreement with the in vitro antibacterial analysis. Compounds 19 (-6.9 kcal/mol) and 24 (-7.1 kcal/mol) showed the maximum binding affinity close to ciprofloxacin (-7.3 kcal/mol) used as positive control. Therefore, the antibacterial activity displayed by these compounds is encouraging for further investigation to improve the activities of quinoline-stilbenes by incorporating various bioisosteric groups in one or more positions of the phenyl nuclei for their potential pharmacological use. Findings of the DPPH radical scavenging assay indicated that some of the quinolone stilbenes and pinacol possess moderate antioxidant properties compared to ascorbic acid used as a natural antioxidant.

GlaxoSmithKline and Astex Pharmaceuticals recently disclosed the discovery of the potent H-PGDS inhibitor GSK2894631A 1a (IC50 = 9.9 nM) as part of a fragment-based drug discovery collaboration with Astex Pharmaceuticals. This molecule exhibited good murine pharmacokinetics, allowing it to be utilized to explore H-PGDS pharmacology in vivo. Yet, with prolonged dosing at higher concentrations, 1a induced CNS toxicity. Looking to attenuate brain penetration in this series, aza-quinolines, were prepared with the intent of increasing polar surface area. Nitrogen substitutions at the 6- and 8-positions of the quinoline were discovered to be tolerated by the enzyme. Subsequent structure activity studies in these aza-quinoline scaffolds led to the identification of 1,8-naphthyridine 1y (IC50 = 9.4 nM) as a potent peripherally restricted H-PGDS inhibitor. Compound 1y is efficacious in four in vivo inflammatory models and exhibits no CNS toxicity.

Phosphotungstic acid (H(3)PW(12)O(40)) was used as an efficient and recyclable catalyst for the synthesis of polysubstituted quinolines through the Friedländer condensation of 2-aminoarylketone with carbonyl compounds, which was achieved by conventional heating under solvent-free conditions.

4-Hydroxy-2-alkylquinolines produced by Pseudomonas aeruginosa can inhibit the growth of both metronidazole-sensitive and resistant strains of Helicobacter pylori in vitro. The MIC of one analogue, 4-hydroxy-2-heptylquinoline, was determined by agar plate incorporation as 0.1-0.5 mg/L which compares favourably with other anti-helicobacter agents.

The anti-cancer activity of the benzo[h]quinolines was evaluated on cultured human skin cancer (G361), lung cancer (H460), breast cancer (MCF7) and colon cancer (HCT116) cell lines. The inhibitory effect of these compounds on the cell growth was determined by the MTT assay. The compounds 3e, 3f, 3h and 3j showed potential cytotoxicity against these human cancer cell lines. Effect of active compounds on DNA oxidation and expression of apoptosis related gene was studied. We also developed a quantitative method to measure the activity of cyclin-dependent kinases-2 (CDK2) by western blotting in the presence of active compound. In addition, molecular docking revealed that benzo[h]quinolines can correctly dock into the hydrophobic pocket of the targets receptor protein aromatase and CDK2, while their bioavailability/drug-likeness was predicted to be acceptable but requires future optimization. These findings reveal that benzo[h]quinolines act as anti-cancer agents by inducing oxidative stress-mediated DNA damage.

The reaction of mercaptoacetic acid esters with pentachloro-2-nitro-1,3-butadiene provides the appropriate precursors for the synthesis of 2,3,4-trisubstituted benzo[h]quinolines. These heterocycles are easily accessible via a single-step reaction with naphthalen-1-amine or anthracen-1-amine as the precursor. Due to the steric bulk and high electron density ring, the ring closure of benzo[h]quinolines takes place exclusively. Such highly substituted annelated pyridine systems can be modified in subsequent, selective reactions to build up new N-heterocycles with promising microbiological properties. The antibacterial and antiproliferative assays against four mammalian cell lines demonstrate that some of the sulfur-substituted benzo[h]quinoline analogs display potent phenotypic bioactivities in the single-digit micromolar range.

KRAS is one of the most frequently mutated oncogenes in human cancer, yet remaining undruggable. To explore a new therapeutic strategy, a library of 5-methyl-indolo[3,2-c]quinoline derivatives (IQc) with a range of alkyldiamine side chains was designed to target DNA and RNA G-quadruplexes (G4) in the promoter and 5'-UTR mRNA of the KRAS gene. Biophysical experiments showed that di-substituted IQc compounds are potent and selective KRAS G4 stabilizers. They preferentially inhibit the proliferation of KRAS mutant cancer cell lines (0.22 < IC50 < 4.80 μM), down-regulate KRAS promoter activity in a luciferase reporter assay, and reduce both KRAS mRNA and p21(KRAS) steady-state levels in mutant KRAS colon cancer cell lines. Additionally, IQcs induce cancer cell death by apoptosis, explained in part by their capacity to repress KRAS expression. Overall, the results suggest that targeting mutant KRAS at the gene level with G4 binding small molecules is a promising anticancer strategy.

The synthesis and anti-inflammatory effects of certain pyrazolo[4,3-c]quinoline derivatives 2a⁻2r are described. The anti-inflammatory activities of these derivatives were evaluated by means of inhibiting nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Among them, 3-amino-4-(4-hydroxyphenylamino)-1H-pyrazolo[4,3-c]-quinoline (2i) and 4-(3-amino-1H-pyrazolo[4,3-c]quinolin-4-ylamino)benzoic acid (2m) exhibited significant inhibition of LPS-stimulated NO production with a potency approximately equal to that of the positive control, 1400 W. Important structure features were analyzed by quantitative structure⁻activity relationship (QSAR) analysis to give better insights into the structure determinants for predicting the inhibitory effects on the accumulation of nitric oxide for RAW 264.7 cells in response to LPS. In addition, our results indicated that their anti-inflammatory effects involve the inhibition of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) protein expression. Further studies on the structural optimization are ongoing.

Molecular docking studies of quinoline and 2-chloroquinoline substrates at the active site of toluene dioxygenase (TDO), were conducted using Autodock Vina, to identify novel edge-to-face interactions and to rationalize the observed stereoselective cis-dihydroxylation of carbocyclic rings and formation of isolable cis-dihydrodiol metabolites. These in silico docking results of quinoline and pyridine substrates, with TDO, also provided support for the postulated cis-dihydroxylation of electron-deficient pyridyl rings, to give transient cis-dihydrodiol intermediates and the derived hydroxyquinolines. 2-Chloroquinoline cis-dihydrodiol metabolites were used as precursors in the chemoenzymatic synthesis of enantiopure arene oxide and arene dioxide derivatives of quinoline, in the context of its possible mammalian metabolism and carcinogenicity.

Discovering of new anticancer agents with potential activity against tubulin polymerisation is still a promising approach. Colchicine binding site inhibitors are the most relevant anti-tubulin polymerisation agents. Thus, new quinoline derivatives have been designed and synthesised to possess the same essential pharmacophoric features of colchicine binding site inhibitors. The synthesised compounds were tested in vitro against a panel of three human cancer cell lines (HepG-2, HCT-116, and MCF-7) using colchicine as a positive control. Comparing to colchicine (IC50 = 7.40, 9.32, and 10.41 µM against HepG-2, HCT-116, and MCF-7, respectively), compounds 20, 21, 22, 23, 24, 25, 26, and 28 exhibited superior cytotoxic activities with IC50 values ranging from 1.78 to 9.19 µM. In order to sightsee the proposed mechanism of anti-proliferative activity, the most active members were further evaluated in vitro for their inhibitory activities against tubulin polymerisation. Compounds 21 and 32 exhibited the highest tubulin polymerisation inhibitory effect with IC50 values of 9.11 and 10.5 nM, respectively. Such members showed activities higher than that of colchicine (IC50 = 10.6 nM) and CA-4 (IC50 = 13.2 nM). The impact of the most promising compound 25 on cell cycle distribution was assessed. The results revealed that compound 25 can arrest the cell cycle at G2/M phase. Annexin V and PI double staining assay was carried out to explore the apoptotic effect of the synthesised compounds. Compound 25 induced apoptotic effect on HepG-2 thirteen times more than the control cells. To examine the binding pattern of the target compounds against the tubulin heterodimers active site, molecular docking studies were carried out.

Neocryptolepine (5-methyl-5H-indolo[2,3-b] quinoline) analogs were synthesized and evaluated in vitro and in vivo for their effect versus Ehrlich ascites carcinoma (EAC). The analogs showed stronger cytotoxic activity against EAC cells than the reference drug. The in vivo evaluation of the target compounds against EAC-induced solid tumor in the female albino Swiss mice revealed a remarkable decrease in the tumor volume (TV) and hepatic lipid peroxidation. A noticeable increase of both superoxide dismutase (SOD) and catalase (CAT) levels was reported (p < 0.001), which set-forth proof of their antioxidant effect. In addition, the in vitro antioxidant activity of the neocryptolepine analogs was screened out using the DPPH method and showed promising activities activity. The histopathological investigations affirmed that the tested analogs have a remarkable curative effect on solid tumors with minimal side-effect on the liver. The study also includes illustrated mechanism of the antitumor activity at the cell level by flow cytometry. The cell cycle analysis showed that the neocryptolepine analogs extensively increase the aggregation of tumor cells in three phases of the cell cycle (G0/G1, S and G2/M) with the emergence of a hypo-diploid DNA content peak (sub-G1) in the cell cycle experiments, which is a clear-cut for the apoptotic cell population. Furthermore, the immunological study manifested a significant elevation in splenic lymphocyte count (p < 0.001) with the elevation of the responsiveness of lymphocytes to phytohemagglutinin (PHA). These results indicate that these naturally-based neocryptolepine alkaloids exhibit marked antitumor activity in vivo and represent an important lead in the development of natural-based anticancer drugs.

The pandemic that started in Wuhan (China) in 2019 has caused a large number of deaths, and infected people around the world due to the absence of effective therapy against coronavirus 2 of the severe acute respiratory syndrome (SARS-CoV-2). Viral maturation requires the activity of the main viral protease (Mpro), so its inhibition stops the progress of the disease. To evaluate possible inhibitors, a computational model of the SARS-CoV-2 enzyme Mpro was constructed in complex with 26 synthetic ligands derived from coumarins and quinolines. Analysis of simulations of molecular dynamics and molecular docking of the models show a high affinity for the enzyme (∆E binding between -5.1 and 7.1 kcal mol-1). The six compounds with the highest affinity show K d between 6.26 × 10-6 and 17.2 × 10-6, with binding affinity between -20 and -25 kcal mol-1, with ligand efficiency less than 0.3 associated with possible inhibitory candidates. In addition to the high affinity of these compounds for SARS-CoV-2 Mpro, low toxicity is expected considering the Lipinski, Veber and Pfizer rules. Therefore, this novel study provides candidate inhibitors that would allow experimental studies which can lead to the development of new treatments for SARS-CoV-2.

Microtubules have key roles in essential cellular processes such as mitosis, cell motion, and intracellular organelle transport. Increasing interest has been given to tubulin binding compounds after the introduction of taxanes into clinical oncology. The object of this study was synthesis and biological evaluation of novel 5,6,7-trimethoxy quinolines as tubulin inhibitors.