Iron mediated reductive cyclization/oxidation for the generation of chemically diverse scaffolds: An approach in drug discovery.

Chemically diverse scaffolds represent a main source of biologically important starting points in drug discovery. Herein, we report the development of such diverse scaffolds from nitroarene/ nitro(hetero)arenes using a key synthetic strategy. In a pilot-scale study, the synthesis of 10 diverse scaffolds was achieved. The 1,7-phenanthroline, thiazolo[5,4-f]quinoline, 2,3-dihydro-1H-pyrrolo[2,3-g]quinoline, pyrrolo[3,2-f]quinoline, 1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one, [1,2,5]oxadiazolo[3,4-h]quinoline, 7H-pyrido[2,3-c]carbazole, 3H-pyrazolo[4,3-f]quinoline, pyrido[3,2-f]quinoxaline were obtained from nitro hetero arenes in ethanol using iron-acetic acid treatment followed by reaction under oxygen atmosphere. This diverse library is compliant with the rule of five for drug-likeness. The mapping of chemical space represented by these scaffolds revealed a significant contribution to the underrepresented chemical diversity. Crucial to the development of this approach was the mapping of biological space covered by these scaffolds which revealed neurotropic and prophylactic anti-inflammatory activities. In vitro, neuro-biological assays revealed that compounds 14a and 15a showed excellent neurotropic potential and neurite growth compared to controls. Further, anti-inflammatory assays (in vitro and in vivo models) exhibited that Compound 16 showed significant anti-inflammatory activity by attenuating the LPS-induced TNF-α and CD68 levels by modulating the NFkB pathway. In addition, treatment with compound 16 significantly ameliorated the LPS-induced sepsis conditions, and pathological abnormalities (in lung and liver tissues) and improved the survival of the rats compared to LPS control. Owing to their chemical diversity along with bioactivities, it is envisaged that new quality pre-clinical candidates will be generated in the above therapeutic areas using identified leads.

Nitazoxanide potentiates linezolid against linezolid-resistant Staphylococcus aureus in vitro and in vivo.

BACKGROUND: Antimicrobial resistance is a growing menace, claiming millions of lives all over the world. In this context, drug repurposing is one approach gaining interest as a suitable alternative to conventional drug discovery and development. METHODS: Whole-cell assays were used to screen FDA-approved drugs to identify novel antimicrobial agents active against bacterial pathogens. Following identification of nitazoxanide, its various characteristics, such as antimicrobial activity against MDR isolates, time-kill kinetics, ability to synergize with approved drugs, antibiofilm activity and ability to generate resistance in Staphylococcus aureus, were determined, followed by determination of its in vivo potential against MDR S. aureus. RESULTS: Nitazoxanide demonstrated a potent in vitro antistaphylococcal profile, including equipotent activity against clinical drug-resistant S. aureus and Enterococcus spp. Nitazoxanide exhibited concentration-dependent killing, significantly eradicated preformed S. aureus biofilm and S. aureus did not generate resistance to it. Nitazoxanide strongly synergized with linezolid both in vitro and in vivo against linezolid-susceptible and -resistant S. aureus, displaying superior activity to untreated control and drug-alone treatment groups. CONCLUSIONS: Nitazoxanide can be utilized in combination with linezolid against infections caused by linezolid-resistant S. aureus as it exhibits strong synergism in vitro and in vivo.

Selectfluor-Mediated Synthesis of ß-Acyl Allyl Sulfones/ß-Acyl Allyl Benzotriazoles from Ketones/Acetylenes, Aryl Sulfinates/Benzotriazole, and DMSO as a Dual-Carbon Synthon.

A Selectfluor-mediated approach for the synthesis of ß-acyl allyl sulfones/ß-acyl allyl benzotriazoles with excellent atom economy from readily available acetophenones/aryl acetylenes, aryl sulfinates/benzotriazoles, and dimethyl sulfoxide (DMSO) is described. In this protocol, DMSO acts as a dual-carbon synthon, resulting in a transition-metal-free construction of two C-C and one C-S or two C-C and one C-N bonds in one pot. This approach is extended to generate chemically diverse compounds. Additionally, ß-acyl allyl sulfones/ß-acyl allyl benzotriazoles were prepared from acetylenes instead of acetophenones.

Synthesis and evaluation of novel almazole D analogs as anticancer agents.

Novel almazole D-amide conjugates, esters, and N-alkylated analogs were synthesized and investigated for their anticancer activity against seven cancer cell lines. Among the series, compounds 5g and 5m showed significant anticancer activities against multiple cell lines with moderate selectivity indices. Compound 5g had IC50 values of 5.86 ± 0.31, 9.94 ± 0.06, 12.74 ± 0.12, and 9.40 ± 0.03 µM against the B16-F10, DU145, HeLa, and LC-540 cell lines, respectively, while compound 5m showed IC50 values of 6.35 ± 0.09, 9.17 ± 0.11, 9.00 ± 0.011, 19.65 ± 0.63, 8.13 ± 0.04, and 11.56 ± 0.01 µM against B16-F10, DU145, HeLa, HepG2, LC-540, and SK-BR-3 cells, respectively. Compared to almazole D, which only showed significant activity against B16-F10 cells (IC50 = 9.05 ± 0.008 µM), the synthesized analogs showed improved anticancer activity against multiple cell lines. The kinase inhibition assay coupled with the docking studies revealed that epidermal growth factor receptor (EGFR) kinase inhibition via interaction with amino acid residue T790 on the EGFR is one of the possible mechanisms by which 5g exerts its anticancer potential. The ADMET prediction and drug-likeness of the analogs project the synthesized analogs as promising agents, which can be further developed for application in cancer therapy.

Methylene-Tethered Arylsulfonation and Benzotriazolation of Aryl/Heteroaryl C-H Bonds with DMSO as a One-Carbon Surrogate.

The Selectfluor-mediated approach toward the synthesis of methylene-tethered arylsulfonation and benzotriazolation of imidazopyridines has been described. The reaction involves imidazopyridine, aryl sulfinate, or benzotriazole and dimethyl sulfoxide (DMSO) in the presence of Selectfluor, where DMSO acts as a one-carbon synthon. The protocol has been extended to the methylene-tethered arylsulfonation and benzotriazolation of ß-naphthols. The mechanistic insights show that the intermediate 3-((methylthio)methyl)-2-phenylimidazo[1,2-a]pyridine is generated from imidazopyridine, DMSO, and Selectfluor. The nucleophilic displacement by the aryl sulfinate salt or benzotriazole on the intermediate afforded the product.

3-Aryl-substituted imidazo[1,2-a]pyridines as antituberculosis agents.

Novel inhibitors are needed to tackle tuberculosis. Herein, we report the 3-aryl-substituted imidazo[1,2-a]pyridines as potent antituberculosis agents. A small library of 3-aryl-substituted imidazo[1,2-a]pyridines was synthesized using direct arylation, followed by nitro reduction and finally Pd-catalyzed C-N coupling reactions. The compounds thus obtained were evaluated against Mycobacterium tuberculosis H37Rv. Compound 26 was identified as an antituberculosis lead with a minimum inhibitory concentration of 2.3 µg/ml against M. tuberculosis H37Rv. This compound showed a selectivity index of 35. The docking of 26 in the active site of the M. tuberculosis cytochrome bc1 complex cytochrome b subunit (Mtb QcrB) revealed key π-π interactions of compound 26 with the Tyr389 and Trp312 residues of Mtb QcrB.

Synthesis and efficacy of pyrvinium-inspired analogs against tuberculosis and malaria pathogens.

Herein, we report the synthesis and evaluation of pyrvinium-based antimalarial and antitubercular compounds. Pyrvinium is an FDA approved drug for the treatment of pinworm infection, and it has been reported to have antiparasitic and antimicrobial activities. Pyrvinium contains quinoline core coupled with pyrrole. We replaced the pyrrole with various aryl or heteroaryl substituents to generate pyrvinium analogs. The profiling of these compounds against malaria parasite P. falciparum 3D7 revealed analogs with better antimalarial activity than pyrvinium pamoate. Compound 14 and 16 showed IC50 of 23 nM and 60 nM against P. falciparum 3D7, respectively. These compounds were also effective against drug-resistant malaria parasite P. falciparum Dd2 with IC50 of 53 nM and 97 nM, respectively. The cytotoxicity against CHO-K1, HEK and NRK-49F cells revealed better selectivity index for these new analogs compared to pyrvinium. Additionally, this series of compounds showed activity against M. tuberculosis H37Rv; particularly compounds 10, 13, 14 and 16 showed equipotent antitubercular activity to that of pyrvinium pamoate. The compounds 14 and 16 should be taken forward as leads for further optimization.

Synthesis of novel 4,5-dihydropyrrolo[1,2-a]quinoxalines, pyrrolo[1,2-a]quinoxalin]-2-ones and their antituberculosis and anticancer activity.

A facile strategy was developed for the synthesis of biologically important 4,5-dihydropyrrolo[1,2-a]quinoxalines and pyrrolo[1,2-a]quinoxalin]-2-ones by treating 2-(1H-pyrrol-1-yl)anilines with imidazo[1,2-a]pyridine-3-carbaldehyde or isatin, using amidosulfonic acid (NH3 SO3 ) as a solid catalyst in water at room temperature. The protocol has been extended to electrophile ninhydrin. The catalyst could be recycled for six times without the loss of activity. The compounds were evaluated for their antituberculosis, antibacterial, and anticancer activities. It is worth noting that compounds 3d and 3e demonstrated a minimum inhibitory concentration value of 6.25 µM against Mycobacterium tuberculosis H37Rv, whereas compounds 3d, 3g, 5d, 5e, and 5i showed a remarkable inhibition of A549, DU145, HeLa, HepG2, MCF-7, and B16-F10 cell lines, respectively. Staphylococcus aureus was inhibited by compounds 5b, 5e, 5d, 5g, and 5l at 32 µg/ml.

Strategies towards the synthesis of anti-tuberculosis drugs.

Antituberculosis drugs have captured the attention of the scientific community due to the emergence of drug resistance. Hence, the development of new analogs and new drugs which can treat drug-resistant tuberculosis is required. In this report, we reviewed the strategies towards the synthesis of antituberculosis drugs. These strategies include semisynthetic approaches, resolution based strategies, microbial transformations, solid phase synthesis, and asymmetric synthesis. As stereochemistry is an important hallmark of many drugs, the strategies based on asymmetric synthesis are described in detail. The emphasis on semisynthetic approaches is given for aminoglycoside antibiotics.

Transition metal-free functionalized hydration of alkynes: one-pot synthesis of fluorinated ß-keto-imidates using Selectfluor.

A transition metal-free, four-component one-pot synthesis of polyfunctionalized fluorinated ß-keto-imidates via the functionalized hydration of alkynes has been described. The intermediate 1,3-ketoamino moiety was obtained from easily accessible arylpropioladehyde and arlyhydroxylamine and was treated with Selectfluor delivering fluorinated ß-keto-imidates. A wide variety of functional groups are tolerated under mild reaction conditions and the product applicability is highlighted.

N,N-Diarylsulfonamide Reduces Proinflammatory Cytokine Interleukin-6 Levels in Cells through Nuclear Factor-κB Regulation.

The arylsulfonamides were synthesized from aryl sulfonyl chloride and aromatic amines in dichloromethane in the presence of pyridine. The aryne chemistry was used to prepare diarylsulfonamide from arylsulfonamides and O-silylaryl triflate with CsF in acetonitrile at room temperature for 30 min. The synthesized compounds were evaluated for cytotoxicity followed by the cytokine/inflammatory marker's inhibition capability and its mechanism of action in RAW-264.7 cells. Elevated interleukin-6 (IL-6) levels have been reported in inflammatory conditions and inflammation-associated disorders. Hence, reducing the IL-6 levels in inflammatory conditions can serve as an attractive therapeutic target in dealing the inflammation. Among 42 compounds, seven compounds showed significant inhibition of IL-6 levels in lipopolysaccharide (LPS) challenged RAW-264.7 cells at 12.5 µM concentration. Further, investigation revealed that the IC50 value of these compounds for reducing IL-6 levels was found to be in the range of 2.6 to 9.7 µM. The promising compounds 5y (IC50 of 2.6 µM) and 5n (IC50 of 4.1 µM) along with other derivatives fulfil drug-likeness parameters laid down by Lipinski's rule of five. Further, RT-qPCR and Western-blot analysis revealed that treatment with 5n significantly reduced the expression of pro-inflammatory, inflammatory and macrophage marker's expression (IL-1ß, CCL2, COX2 and CD68) compared to LPS control. The mechanistic evaluation showed that 5n exhibited anti-inflammatory properties by modulating the nuclear factor-κB (NF-κB) activation. The identified compound can be a promising candidate for further discovery efforts to generate a preclinical candidate effective in inflammation.

Methyl 3-[(1,1-dioxo-1λ(6),2-benzothiazol-3-yl)amino]-5-nitrothiophene-2-carboxyl-ate.

The title nitro-thio-phene compound, C(13)H(9)N(3)O(6)S(2), crystallizes with two independent mol-ecules in the asymmetric unit; the mol-ecular structure of each is stabilized by an intra-molecular N-H⋯O hydrogen bond. The two mol-ecules adopt flattened but slightly different conformations, viz. the dihedral angle between the thio-phene ring and the essentailly planar 1,2-benzisothia-zole fragment (r.m.s. deviations = 0.0227 and 0.0108 Å, respectively) is 15.62 (11)° in one mol-ecule and 5.46 (11)° in the other. In the crystal, mol-ecules are arranged into layers parallel to (-111) with weak C(ar)-H⋯O inter-actions formed within the layer. N-H⋯O hydrogen bonds also occur. There are π-π stacking inter-actions between the mol-ecules in neighbouring layers, the distance between the centroids of the 1,2-benzisothia-zole benzene rings being 3.8660 (16) Å. Moreover, dipolar S=O⋯C=O inter-actions with an O⋯C distance of 2.893 (3) Šare observed between the symmetry-independent mol-ecules in different layers. The title compound showed weak inhibition of HLE (human leukocyte elastase).

Pyrvinium pamoate potentiates levofloxacin against levofloxacin-resistant Staphylococcus aureus.

Background: Drug repurposing is a viable approach to expediting the tedious conventional drug discovery process, given rapidly increasing bacterial resistance. In this context, we have repurposed pyrvinium pamoate (PP) for its antibacterial activity against Staphylococcus aureus. Methods: US FDA-approved non-antibiotics were screened against clinically relevant bacterial pathogens to identify antibacterials. The hits were further evaluated utilizing a variety of preclinical parameters, following which in vivo efficacy was estimated in isolation and in combination in a murine neutropenic thigh infection model. Result: The screening identified PP exhibiting potent activity against S. aureus along with concentration-dependent killing. PP also showed a post-antibiotic effect of >22 h and significantly eradicated preformed S. aureus biofilms and intracellular S. aureus at 1× and 5× MIC, respectively. PP synergized with levofloxacin both in vitro and in vivo, resulting in ∼1.5 and ∼0.5 log10 CFU/g reduction against susceptible and resistant S. aureus infections, respectively, as compared with untreated control. Conclusion: Pyrvinium potentiates levofloxacin against levofloxacin-resistant S. aureus.

Treatment of drug-resistant bacterial infections urgently requires novel antibiotic combinations that can help in reducing the dose of antibiotic required as well as decreasing the emergence of resistance. In this context, pyrvinium pamoate is active as an antibacterial against clinically drug-resistant Staphylococcus aureus and combines well with levofloxacin against levofloxacin-resistant S. aureus. Given the paucity of available treatments for multidrug-resistant S. aureus, this is a very welcome new addition to the antibiotic arsenal.

A new screening assay for allosteric inhibitors of cSrc.

Targeting kinases outside the highly conserved ATP pocket is thought to be a promising strategy for overcoming bottlenecks in kinase inhibitor research, such as limited selectivity and drug resistance. Here we report the development and application of a direct binding assay to detect small molecules that stabilize the inactive conformation of the tyrosine kinase cSrc. Protein X-ray crystallography validated the assay results and confirmed an exclusively allosteric binding mode.

Synthesis and biological evaluation of 7-substituted-1-(3-bromophenylamino)isoquinoline-4-carbonitriles as inhibitors of myosin light chain kinase and epidermal growth factor receptor.

Here we present the synthesis and biological activity of a series of 7-substituted-1-(3-bromophenylamino)isoquinoline-4-carbonitriles as inhibitors of myosin light chain kinase (MLCK) and the epidermal growth factor receptor kinase (EGFR). The inhibitory effect of these molecules was found to be dependent on the nature of the substituents at the 7-position of the isoquinoline scaffold.

Catalyst- and Additive-Free Approach to Constructing Benzo-oxazine, Benzo-oxazepine, and Benzo-oxazocine: O Atom Transfer and C═O, C-N, and C-O Bond Formation at Room Temperature.

An exclusive synthesis of benzo-oxazine, benzo-oxazepine, and benzo-oxazocine from aryl propanal and 2-(hydroxyamino)phenyl alcohol under metal-free conditions is described. O atom transfer and formation of new C═O, C-N, and C-O bonds occur at room temperature to form six-, seven-, and eight-membered heterocycles under one-pot reaction conditions without using an external oxidant and base. The photophysical properties are studied using ultraviolet-visible absorption and photoluminescence. The mechanistic elucidation is well supported by control experiment and literature precedents.

Characterization of irreversible kinase inhibitors by directly detecting covalent bond formation: a tool for dissecting kinase drug resistance.

Targeting protein kinases in cancer therapy with irreversible small-molecule inhibitors is moving to the forefront of kinase-inhibitor research and is thought to be an effective means of overcoming mutation-associated drug resistance in epidermal growth factor receptor kinase (EGFR). We generated a detection technique that allows direct measurements of covalent bond formation without relying on kinase activity, thereby allowing the straightforward investigation of the influence of steric clashes on covalent inhibitors in different resistant kinase mutants. The obtained results are discussed together with structural biology and biochemical studies of catalytic activity in both wild-type and gatekeeper mutated kinase variants to draw conclusions about the impact of steric hindrance and increased catalytic activity in drug-resistant kinase variants.

Catalyst-Free Regioselective [3+2] Cycloadditions of α,ß-unsaturated N-arylnitrones with Alkenes to Access Functionalized Isoxazolidines: A DFT Study.

The catalyst-free regioselective [3+2]-cycloaddition of α,ß-unsaturated N-arylnitrones with alkenes are developed. The series of synthetically important functionalized isoxazolidines are prepared in good to excellent yields by step economic pathway under ligand and transition-metal-free conditions. The regioselective cycloaddition pathway supported by control experiment and computational study.

Novel 1,3,4-oxadiazoles as antitubercular agents with limited activity against drug-resistant tuberculosis.

AIM: In recent times, heterocyclic chemotypes are being explored for the development of new antimycobacterials that target the drug-resistant tuberculosis. Here, we are disclosing the 5-substitued 2-mercapto-1,3,4-oxadiazoles as potent antitubercular agents. METHODOLOGY: A small library of 2-mercapto-1,3,4-oxadiazoles was synthesized using various acids. The compounds were evaluated for antituberculosis activity against M. tuberculosis H37Rv. RESULTS: Compound 8j was identified as antitubercular lead with MIC of 0.6 µg/ml against M. tuberculosis H37Rv. This compound was nontoxic to CHO-K1 cells and showed selectivity index of 39. Of note, 8j showed antitubercular activity against pre-extensively drug-resistant clinical isolate of Mycobacterium with MIC of 2 µg/ml. CONCLUSION: This study provides potent antitubercular agent which can be further optimized to discover novel antibiotics.