Synthesis of new 4-(E)-alkenylpyrrolo[1,2-a]quinoxalines as antileishmanial agents by Suzuki-Miyaura cross-coupling reactions

A series of new 4-(E)-alkenylpyrrolo[1,2-a]quinoxaline derivatives, structural analogues of alkaloid chimanine B, was synthesized in good yields using efficient palladium(0)-catalyzed Suzuki-Miyaura cross-coupling reactions. These new compounds were tested for in vitro antiparasitic activity upon Leishmania amazonensis and Leishmania infantum strains. Biological results showed activity against the promastigote forms of L. amazonensis and L. infantum with IC₅₀ ranging from 0.5 to 7 μM. From a Structure-Activity Relationships point of view, these pharmacological results mainly enlightened the importance of the 4-lateral C₆, C₇ or C₈ α-unsaturated trans-alkenyl chain of unsubstituted pyrrolo[1,2-a]quinoxaline moiety.     

Synthesis and preliminary evaluation of new ursolic and oleanolic acids derivatives as antileishmanial agents

A series of new ursolic and oleanolic acids derivatives was synthesized via ursolic or oleanolic acids, previously extracted from South American Ilex species. These new compounds were tested for in vitro antiparasitic activity on Leishmania amazonensis and Leishmania infantum strains. Some of these compounds showed activity against the promastigote forms of L. amazonensis or L. infantum, with IC₅₀ ranging from 5 to 12 μM. As expected, most of the compounds showed a significant level of cytotoxicity against monocytes (IC₅₀ = 2-50 μM). From a structure-activity relationships point of view, these pharmacological results enlightened mainly the importance of an acetylation at position 3 of the oleanolic acid skeleton in the activity against the L. amazonensis strain, and of a bis-(3-aminopropyl)piperazine moiety on the carboxylic function of ursolic acid against the L. infantum strain.     

New pyrazolopyrimidine derivatives as Leishmania amazonensis arginase inhibitors

Arginase performs the first enzymatic step in polyamine biosynthesis in Leishmania and represents a promising target for drug development. Polyamines in Leishmania are involved in trypanothione synthesis, which neutralize the oxidative burst of reactive oxygen species (ROS) and nitric oxide (NO) that are produced by host macrophages to kill the parasite. In an attempt to synthesize arginase inhibitors, six 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine derivatives with different substituents at the 4-position of the phenyl group were synthesized. All compounds were initially tested at 100 µM concentration against Leishmania amazonensis ARG (LaARG), showing inhibitory activity ranging from 36 to 74%. Two compounds, 1 (R=H) and 6 (R=CF₃), showed arginase inhibition >70% and IC₅₀ values of 12 µM and 47 µM, respectively. Thus, the kinetics of LaARG inhibition were analyzed for compounds 1 and 6 and revealed that these compounds inhibit the enzyme by an uncompetitive mechanism, showing K_is values, and dissociation constants for ternary complex enzyme-substrate-inhibitor, of 8.5 ± 0.9 µM and 29 ± 5 µM, respectively. Additionally, the molecular docking studies proposed that these two uncompetitive inhibitors interact with different LaARG binding sites, where compound 1 forms more H-bond interactions with the enzyme than compound 6. These compounds showed low activity against L. amazonensis free amastigotes obtained from mice lesions when assayed with as much as 30 µM. The maximum growth inhibition reached was between 20 and 30% after 48 h of incubation. These results suggest that this system can be promising for the design of potential antileishmanial compounds.     

Synthesis,biological evaluation,and docking studies of novel 5,6-diaryl-1,2,4-triazine thiazole derivatives as a new class of α-glucosidase inhibitors

A novel 5,6-diaryl-1,2,4-triazine thiazole derivatives (7a-7q) were synthesized and characterized by ¹H NMR and ¹³C NMR and evaluated for their α-glucosidase inhibitory activity. All tested compounds displayed good α-glucosidase inhibitory activity with IC₅₀ values ranging between 2.85 ± 0.13 and 14.19 ± 0.23 μM when compared to the standard drug acarbose (IC₅₀ = 817.38 ± 6.27 μM). Compound 7i (IC₅₀ = 2.85 ± 0.13 μM) exhibited the highest activity among this series of compounds. Molecular docking studies were carried out in order to investigate the binding mode of this class of compounds to α-glucosidase. This study showed that these 5,6-diaryl-1,2,4-triazine thiazole derivatives are a new class of α-glucosidase inhibitors.     

Antiprotozoal activities of marine polyether triterpenoids

Chagas disease and leishmaniasis are tropical neglected diseases caused by kinetoplastids protozoan parasites of Trypanosoma and Leishmania genera, and a public health burden with high morbidity and mortality rates in developing countries. Among difficulties with their epidemiological control, a major problem is their limited and toxic treatments to attend the affected populations; therefore, new therapies are needed in order to find new active molecules. In this work, sixteen Laurencia oxasqualenoid metabolites, natural compounds 1–11 and semisynthetic derivatives 12–16, were tested against Leishmania amazonensis, Leishmania donovani and Trypanosoma cruzi. The results obtained point out that eight substances possess potent activities, with IC₅₀ values in the range of 5.40–46.45 µM. The antikinetoplastid action mode of the main metabolite dehydrothyrsiferol (1) was developed, also supported by AFM images.The semi-synthetic active compound 28-iodosaiyacenol B (15) showed an IC₅₀ 5.40 µM against Leishmania amazonensis, turned to be non-toxic against the murine macrophage cell line J774A.1 (CC₅₀ > 100). These values are comparable with the reference compound miltefosine IC₅₀ 6.48 ± 0.24 and CC₅₀ 72.19 ± 3.06 μM, suggesting that this substance could be scaffold for development of new antikinetoplastid drugs.     

2-Aryl-quinazolin-4(3H)-ones as an inhibitor of leishmania folate pathway: In vitro biological evaluation,mechanism studies and molecular docking

To identify new agents for the American Cutaneous Leishmaniasis treatment, a series of 2-aryl-quinazolin-4(3H)-ones were tested against L. mexicana, L. braziliensis and L. amazonensis parasites as potential inhibitor of folic metabolism pathway. In general, the L. braziliensis and L. mexicana promastigote parasites were more sensitive to the action of the quinazolinones than L. amazonensis. The most active derivatives showed low-micromolar EC₅₀ ranging from 4 to 10 μM, being 1.3 to 4 fold more potent than glucantime reference drug. A complete in vitro evaluation on intracellular amastigote, axenic amastigote and murine peritoneal macrophage were performed for the most active derivatives. The compounds 2j, 2h, 2t and 2u displayed acceptable responses against intracellular amastigote compared to reference drug, excellent antileishmanial activities against axenic amastigote (LD₅₀ ranging from 1 to 4 μM) and relative low toxicities on peritoneal macrophages. To validate the efficacy of these four derivatives, an in vitro evaluation was performed against an antimony-resistant amastigote strain; identifying to 2h and 2u as promising antileishmanial leads for further pharmacokinetics and in vivo studies. Experimental mechanism assays putted in evidences that the most active compounds act as folate inhibitor. A tentative molecular docking on pteridine reductase 1 (PTR1) enzyme showed that the most active quinazolinones 2j and 2t are located in almost identical place compared with methotrexate reference into active site.     

Synthesis and algicidal activity of new dichlorobenzylamine derivatives against harmful red tides

In the present study, we synthesized 65 dichlorobenzylamine derivatives and investigated their algicidal activity against harmful red tides. The 3,4-dichlorobenzylamine derivatives showed relatively high activity against Cochlodinium polykrikoides, Heterosigma akashiwo, Chattonella marina, and Heterocapsa circularisquama, and the synthesized compounds 27, 28, 33, 34, 35, and 36 showed the highest algicidal activity after 24 h at 0.1 ~ 1.0 μM LC₅₀ against the four harmful algae species. To verify the safety of the compounds, acute ecotoxicology tests using the water flea (Daphnia magna) and zebrafish (Danio rerio) were conducted, and the tests confirmed that compounds 33 and 34 were not harmful because the target organisms showed high survival rates at 15 μM. The results indicate that compounds 33 and 34 are suitable substances for use in controlling harmful algae species.     

Synthesis and antileishmanial evaluation of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazole derivatives

A series of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (4a–g) and 5-amino-1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (5a–g) were synthesized and evaluated in vitro against three Leishmania species: L. amazonensis, L. braziliensis and L. infantum (L. chagasi syn.). The cytotoxicity was assessed. Among the derivatives examined, six compounds emerged as the most active on promastigotes forms of L. amazonensis with IC₅₀ values ranging from 15 to 60 μM. The reference drug pentamidine presented IC₅₀ = 10 μM. However, these new compounds were less cytotoxic than pentamidine. Based on these results, the more promising derivative 5d was tested further in vivo. This compound showed inhibition of the progression of cutaneous lesions in CBA mice infected with L. amazonensis relative to an untreated control.     

Design,synthesis, docking study, α-glucosidase inhibition,and cytotoxic activities of acridine linked to thioacetamides as novel agents in treatment of type 2 diabetes

A novel series of acridine linked to thioacetamides 9a–o were synthesized and evaluated for their α-glucosidase inhibitory and cytotoxic activities. All the synthesized compounds exhibited excellent α-glucosidase inhibitory activity in the range of IC₅₀ = 80.0 ± 2.0–383.1 ± 2.0 µM against yeast α-glucosidase, when compared to the standard drug acarbose (IC₅₀ = 750.0 ± 1.5 µM). Among the synthesized compounds, 2-((6-chloro-2-methoxyacridin-9-yl)thio)-N-(p-tolyl) acetamide 9b displayed the highest α-glucosidase inhibitory activity (IC₅₀ = 80.0 ± 2.0 μM). The in vitro cytotoxic assay of compounds 9a–o against MCF-7 cell line revealed that only the compounds 9d, 9c, and 9n exhibited cytotoxic activity. Cytotoxic compounds 9d, 9c, and 9n did not show cytotoxic activity against the normal human cell lines HDF. Kinetic study revealed that the most potent compound 9b is a competitive inhibitor with a K_i of 85 μM. Furthermore, the interaction modes of the most potent compounds 9b and 9f with α-glucosidase were evaluated through the molecular docking studies.     

Discovery of new inhibitors against both NF-κB and osteoclastogenesis from in-house library with α, β-unsaturated-enone fragment

The α,β-unsaturated-enone contained natural products have been reported showing NF-κB inhibition effect. It is well known that NF-κB inhibitors can also be used to inhibit osteoclastogenesis. In a continual discovery new agents for anti-osteoclastogenesis, 8 different type compounds with α,β-unsaturated-enone fragments from our in-house library were evaluated for NF-κB inhibition and anti-osteoclastogenesis. Experimental results indicated five compounds exhibited inhibition of NF-κB signal pathway. Among them, one compound ((E)-2-(4-fluorobenzylidene)-3,4-dihydronaphthalen-1(2H)-one, 6a) simultaneously inhibits both osteoclastogenesis and NF-κB signal pathway. Furthermore, 12 compounds with similar scaffold with 6a were tested for anti-osteoclastogenesis. As a result, 9 compounds inhibited both NF-κB and osteoclastogenesis. Among them, compound 6b is the most potent inhibitor against NF-κB (IC₅₀ = 2.09 μM) and osteoclast differentiation (IC₅₀ = 0.86 μM). Further studies show that compound 6b blocks the phosphorylation of both p65 and IκBα, and suppresses NF-κB targeted gene expression without interfering MAPKs and PI3K/Akt signal transduction pathways. This study demonstrates that we can identify promising synthesized compounds with new scaffolds as therapeutic solutions against osteoclastogenesis inspired by the privileged fragment derived from natural leads.     

Antimicrobial effects of N-benzyloxycarbonyl-S-(2,4-dinitrophenyl) glutathione diesters against chloroquinine sensitive (NF54) and resistant (K1) strains of Plasmodium falciparum

N-Benzyloxycarbony-S-(2,4-dinitrophenyl)glutathione diesters have been investigated for antimalarial activity against chloroquinine sensitive (NF54) and resistant (K1) strains of P. falciparum. Both strains appear equally susceptible to inhibition by compounds 1–4, with an IC₅₀ ∼ 4.92–6.97 μM, consistent with the target of these compounds being the PfMRP transporter. Against the NF54 strain, diester derivatives containing ethyl side chains showed lower in vitro activity than those with methyl side chains 1–4, IC₅₀ ∼ 5.7–6.97 μM with the exception of compound 5 (IC₅₀ > 25 μM). The cytotoxicity of compounds with log P ∼ 3.9–5.8 were lower against the murine L6 cell line than compounds with a higher log P > 5.8 that were toxic. Overall the cytotoxicity of compounds 1–7 were lower against KB cells than against the L6 cell line with the exception of compound 4, which showed a higher relative toxicity.     

A novel synthetic compound, (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-iminothiazolidin-4-one (MHY773) inhibits mushroom tyrosinase

As part of continued efforts for the development of new tyrosinase inhibitors, (Z)-5-(substituted benzylidene)-2-iminothiazolidin-4-one derivatives (1a – 1l) were rationally synthesized and evaluated for their inhibitory potential in vitro. These compounds were designed and synthesized based on the structural attributes of a β-phenyl-α,β-unsaturated carbonyl scaffold template. Among these compounds, (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-iminothiazolidin-4-one (1e, MHY773) exhibited the greatest tyrosinase inhibition (IC₅₀ = 2.87 μM and 8.06 μM for monophenolase and diphenolase), and outperformed the positive control, kojic acid (IC₅₀ = 15.59 and 31.61 μM). The kinetic and docking studies demonstrated that MHY773 interacted with active site of tyrosinase. Moreover, a melanin quantification assay demonstrated that MHY773 attenuates α-melanocyte-stimulating hormone (α-MSH) and 3-isobutyl-1-methylxanthine (IBMX)-induced melanin contents in B16F10 melanoma cells. Taken together, these data suggest that MHY773 suppressed the melanin production via the inhibition of tyrosinase activity. MHY773 is a promising for the development of effective pharmacological and cosmetic agents for skin-whitening.     

Structure–activity relationship studies on 1-heteroaryl-3-phenoxypropan-2-ones acting as inhibitors of cytosolic phospholipase A2α and fatty acid amide hydrolase: replacement of the activated ketone group by other serine traps

Cytosolic phospholipase A₂α (cPLA₂α) and fatty acid amide hydrolase (FAAH) are serine hydrolases. cPLA₂α is involved in the generation of pro-inflammatory lipid mediators, FAAH terminates the anti-inflammatory effects of endocannabinoids. Therefore, inhibitors of these enzymes may represent new drug candidates for the treatment of inflammation. We have reported that certain 1-heteroarylpropan-2-ones are potent inhibitors of cPLA₂α and FAAH. The serine reactive ketone group of these compounds, which is crucial for enzyme inhibition, is readily metabolized resulting in inactive alcohol derivatives. In order to obtain metabolically more stable inhibitors, we replaced this moiety by α-ketoheterocyle, cyanamide and nitrile serine traps. Investigations on activity and metabolic stability of these substances revealed that in all cases an increased metabolic stability was accompanied by a loss of inhibitory potency against cPLA₂α and FAAH, respectively.     

Synthesis, α-amylase inhibitory potential and molecular docking study of indole derivatives

In search of potent α-amylase inhibitor we have synthesized eighteen indole analogs (1–18), characterized by NMR and HR-EIMS and screened for α-amylase inhibitory activity. All analogs exhibited a variable degree of α-amylase inhibition with IC₅₀ values ranging between 2.031 ± 0.11 and 2.633 ± 0.05 μM when compared with standard acarbose having IC₅₀ values 1.927 ± 0.17 μM. All compounds showed good α-amylase inhibition. Compound 14 was found to be the most potent analog among the series. Structure-activity relationship has been established for all compounds mainly based on bringing about the difference of substituents on phenyl ring. To understand the binding interaction of the most active analogs molecular docking study was performed.     

Design and synthesis of new phthalazine-based derivatives as potential EGFR inhibitors for the treatment of hepatocellular carcinoma

Searching for new leads in the battle of cancer will never ends, we herein disclose the design and synthesis of new phthalazine derivatives and their in vitro and in vivo testing for their antiproliferative activity. Phthalazine was selected as a privilege moiety that is incorporated in a big number of anticancer drugs in clinical use or that are still under clinical or preclinical studies. We utilized the drug extension strategy to tailor the designed compounds to fit the EGFR hydrophobic sub pocket and cleft region. The designed phthalazine derivatives was synthesized by linking phthalazine moiety with 1,3,4-oxadiazole-thione and 1,2,4-triazole-thione. Alkylation and glycosylation of the new heterocyclic systems were successfully performed to be used in the drug extension. Coupling of some phthalazine derivatives with different amino acids was also performed to improve the drug selectivity.The synthesized compounds were tested for their antiproliferative activity against cancer cells both in vivo and in vitro. The in vitro activity against hepatocellular carcinoma (HepG2 cell line) ranged from 5.7 µg/mL to 43.4 µg/mL. Compounds 31a and 16 were the most active with an IC₅₀ 5.7 µg/mL and 7.09 µg/mL, respectively compared to the standard compound doxorubicin (4.0 µg/mL). In vivo, compounds 10 and 16 showed IC₅₀ values 7.25 μg/mL and 7.5 μg/mL, respectively compared to the standard compound cisplatin (IC₅₀ 9.0 μg/mL). In silico, testing of the phthalazine derivatives showed that they are good inhibitors for EGFR. The docking studies substantiated compounds 4, 10, 16 and 31a as new lead compounds and identified Arg841 as a key residue in the cleft region for binding stronger inhibitors.     

Three New 2,2′-Difurylketone Derivatives and Two New Chromones from the Rehmanniae Radix Praeparata

Rehmanniae Radix Praeparata is the processed products of the root of Rehmannia glutinosa. It has been used as a Traditional Chinese Medicine for thousands of years, and it has been found to possess widely pharmacological activities. In this study, three new 2,2′-difurylketone derivatives (rehmanniaeketone A–C) and two new chromones [3,8-dihydroxy-2-(2-hydroxyethyl)chromone and 3,8-dihydroxy-2-[(2-O-α-D-galactopyranosyloxy)ethyl]chromone] were isolated from the Rehmanniae Radix Praeparata. Furthermore all of the compounds were subjected to cytotoxic testing against the human lung carcinoma A549 cells. The cytotoxic results showed that rehmanniaeketone B and rehmanniaeketone C exhibited more stronger inhibition effects on the cell activity of A549 cells with the IC₅₀ 5.23 μM and 2.05 μM than other compounds. And 3,8-dihydroxy-2-(2-hydroxyethyl)chromone exhibited moderately inhibitory activity with the IC₅₀ 61 μM. Rehmanniaeketone A and 3,8-dihydroxy-2-[(2-O-α-D-galactopyranosyloxy]chromone showed no inhibitory effects.     

Synthesis and QSAR study of novel α-methylene-γ-butyrolactone derivatives as antifungal agents

Thirty-six new α-benzylidene-γ-lactone compounds based α-methylene-γ-butyrolactone substructure were prepared and characterized by spectroscopic analysis. All compounds were evaluated for antifungal activities in vitro against six plant pathogenic fungi and the half maximal inhibitory concentration (IC₅₀) against Botrytis cinerea and Colletotrichum lagenarium were investigated. Compounds 5c-3 and 5c-5 with the halogen atom exhibited excellent fungicidal activity against B. cinerea (IC₅₀ = 22.91, 18.89 μM). The structure-activity relationships (SARs) analysis indicated that the derivatives with electron-withdrawing substituents at the meta- or para-positions improves the activity. Via the heuristic method, the generated quantitative structure-activity relationship (QSAR) model (R² = 0.961) revealed a strong correlation of antifungal activity against B. cinerea with molecular structures of these compounds. Meanwhile, the cytotoxicity of 20 representative derivatives was tested in the human tumor cells line (HepG2) and the hepatic L02 cells line, the result indicated that the synthesized compounds showed significant inhibitory activity and limited selectivity. Compound 5c-5 has the highest fungicidal activity with IC₅₀ = 18.89 μM (against B. cinerea.) but low cytotoxicity with IC₅₀ = 35.4 μM (against HepG2 cell line) and IC₅₀ = 68.8 μM (against Hepatic L02 cell line). These encouraging results can be providing an alternative, promising use of α-benzylidene-γ-lactone through the design and exploration of eco-friendly fungicides with low toxicity and high efficiency.     

Anisakis simplex s.l.: Larvicidal activity of various monoterpenic derivatives of natural origin against L3 larvae in vitro and in vivo

This paper describes the activity against Anisakis simplex s.l. L₃ larvae of six monoterpenic derivatives obtained from different essential oils, (α-pinene, β-pinene, ocimene, myrcene, geranyl acetate, and cineole). In in vitro assays, α-pinene, ocimene and cineole showed high activity at a concentration of 125 μg/mL (48 h) but only α-pinene and ocimene were active at 62.5 μg/mL. In in vivo assays, L₃ larvae and study compounds were simultaneously administered per os to Wistar rats. The most active compound was α-pinene, finding lesions in only 20% of treated rats versus 98% of controls. Further in vivo studies are required to investigate whether addition of these compounds to food could have a prophylactic effect, reducing the pathogenicity of A. simplex s.l. L₃ in humans, and to explore any possible synergy among compounds.