Showing papers in "Medicinal Chemistry Research in 2019"

Sulfa drug analogs: new classes of N-sulfonyl aminated azines and their biological and preclinical importance in medicinal chemistry (2000–2018)

Abstract: N-sulfonylamino azinones has attracted the interest of numerous researchers and extensive investigations on their biological activities have been done. The present review provides an overview of the patents and reports filed during the last few years pertaining to the synthesis N-sulfonyl azinones as well as their biological and preclinical studies. A brief discussion on the significant biological findings is also provided. It has been established that N-sulfonylamino azinones is privileged heterocycles possessing diuretic, antihypertensive, anti-inflammatory, and anticancer and other biological activities. In particular, a new generation of competitive AMPA receptor antagonist based on N-sulfonylamino 1H-quinazoline-2,4-diones is promising useful in the treatment neurological disorders such as epilepsy and schizophrenia. The scope of these new advances has been also highlighted in this review.

Design, synthesis, biological evaluation and molecular modeling of new coumarin derivatives as potent anticancer agents

Abstract: A novel series of coumarin-pyridine/fused pyridine hybrids were designed and synthesized. Their anticancer activity was evaluated against human cancer cell lines MCF-7, HCT-116, HepG-2, and A549. Compounds 9, 10, and 11 showed the most potent growth inhibitory activities with IC50 values ranging from 1.1 to 2.4 μM, against MCF-7 cell line. Flow cytometric analysis revealed that these compounds induced cell cycle arrest in the G2/M phase followed by apoptotic cell death. Consistent with these results, the activity of caspase-3 in MCF-7 cells was tested. The results indicated that compounds 9, 10, and 11 increased caspase-3 activity significantly compared to control group. Moreover, their binding affinity for caspase-3 was confirmed by docking study. Taking all these data together, it is suggested that these coumarin derivatives may be potential antiproliferative agents.

Design, synthesis, and antihypertensive activity of new pyrimidine derivatives endowing new pharmacophores

Abstract: A new series of achiral pyrimidine derivatives based on nifedipine-like structure was designed and synthesized. These pyrimidyl derivatives contained hydrazine, hydrazones, acetohydrazide, differently substituted benzylidene functionalities, benzosulfohydrazine, various heterocycles such as pyrazole, pyrazolidinedione, thiazoline, and thiazolidinone rings, and fused ring systems such as triazolopyrimidine and pyrimidotriazine rings. Compounds 5a, 5b, 11b, 8b, 9b–d, and 15b showed a decrease in mean arterial rabbit blood pressure (MABP) ranging from 51.4 to 78.2 mmHg in rabbits in comparison with nifedipine-treated rabbits. Among these derivatives, compounds 5a, 5b, 9b, and 9c were found to exhibit calcium channel blockade activity on preparations of rabbit aortae. They exhibited relaxation in the range of 89.2% to 74.4% in comparison to nifedipine (57.6%) as well as a decrease in heart rate. Histopathological effect of compounds 5a,b on the expression of endothelial nitric oxide synthase (eNOS) was also examined on rat aorta. An intense expression of eNOS immune staining in aortic endothelium was seen for compound 5b indicating that it lowered blood pressure via activation of eNOS expression in aorta.

Advance in biological activities of natural guaiane-type sesquiterpenes

Abstract: Belonging to the terpenes family, sesquiterpenes represent a group of natural compounds with diverse skeletal types. Given their unique structural features and various functional groups, these compounds possess numerous biological activities and have received increasing interest in recent years. Guaiane-type sesquiterpenes are a special category of sesquiterpenes with various biological activities, such as antitumor, anti-inflammatory, and antibacterial. Mipsagargin, a prodrug of thapsigargin, could be used in the treatment of glioblastoma multiforme and hepatocellular carcinoma, and has completed the phase II clinical trials. Guaiane-type sesquiterpenes are not only abundant but also diverse, widely distributed, and complex, and have variable structures. To our knowledge, there is no review of guaiane-type sesquiterpenes in extant literature. This review summarizes the distribution of guaiane-type sesquiterpenes in plants, the possible biogenic pathways and chemical structures as well as the research progress on their biological activities from 1990 to 2018. Guaiane-type sesquiterpenes are present in approximately 70 genera of 30 plant families (e.g., Asteraceae, Lamiaceae, Thymelaeaceae, and Zingiberaceae); they can be classified into 12,6-guaianolides, 12,8-guaianolides, pseudoguaianolides, tricycle guaiane-type sesquiterpenes, dimers or trimers containing guaiane-type sesquiterpenes mother nuclei, variant guaiane-type sesquiterpenes, and other guaiane-type sesquiterpenes. Among them, 12,8-guaianolides exerted the broadest biological activity.

Synthesis, structural characterization, and cytotoxic evaluation of chalcone derivatives

Abstract: Chalcones containing amino or acetamide groups on ring A and electron donating/withdrawing groups on ring B have been shown to have great cytotoxic potential against human cancer cell lines. In this work, a series of twenty chalcones, including nine 1-(4′-aminophenyl)-3-(substituted aryl)-2-propen-1-ones (1–9), nine 1-(4′-acetamidophenyl)-3-(substituted aryl)-2-propen-1-ones (1a–9a), and two 1-(3′-methoxy-4′-hydroxyphenyl)-3-(substituted aryl)-2-propen-1-ones (10, 11), were synthesized and submitted for initial biological screening using HCT-116 cells. Among the evaluated compounds, chalcone 6a showed strong and selective activity against HCT-116 cells (IC50 = 2.37 ± 0.73 µM). The preliminary structure–activity relationship analysis indicated that the cytotoxic effect of these compounds might be attributed to the combined effect of two electron withdrawing groups: the nitro group (NO2) at the meta-position of ring B and the acetyl group at the para-position of ring A. Moreover, chalcone 6a was able to induce G2/M cell cycle arrest and apoptosis at a concentration of 10 µM after 24 h of incubation. These data reinforce that compound 6a could be a promising lead compound for the future exploration of selective anti-colon carcinoma cancer agents.

Comparative α-glucosidase and α-amylase inhibition studies of rhodanine–pyrazole conjugates and their simple rhodanine analogues

Abstract: Novel rhodanine–pyrazole conjugates (6a–i) and their simple rhodanine analogues (8a–e) were prepared and comparatively screened for their antidiabetic activities against enzymatic targets, α-glucosidase and α-amylase. As expected, the molecular hybrids exhibited significantly greater inhibitory activity against α-glucosidase (IC50 = 2.259 × 10−6–1.160 × 10−4 mol/L), relative to their simple rhodanine counterparts (IC50 = 3.056 × 10−4–9.494 × 10−4 mol/L). Amongst the screened derivatives compounds 6a and 6f displayed a 3-fold and 42-fold greater potency against α-glucosidase (IC50 = 2.854 × 10−5 and 2.259 × 10−6mol/L, respectively) compared to the standard drug, acarbose. The designed molecular conjugates displayed an improved binding affinity toward α-glucosidase than α-amylase. Compound 6d was identified as the most potent inhibitor of α-amylase (IC50 = 6.377 × 10−5 mol/L) with a 1.5-fold greater inhibitory activity than acarbose. Structural assessment of the molecules revealed that electron withdrawing (Cl) and electron donating (OCH3) groups at the ortho-position played a significant role in the inhibitory activity. Molecular docking studies of the molecular conjugates and simple rhodanine analogues in the active site of α-glucosidase were performed to describe and highlight the putative binding interactions attributing to the selective inhibition. The identification of these novel rhodanine–pyrazole molecular hybrids forms part of a potential treatment in the management of diabetes.

Synthesis, antimicrobial activity, and determination of the lipophilicity of ((cyclohex-3-enylmethylene)hydrazinyl)thiazole derivatives

Abstract: Synthesis and investigation of antimicrobial activity of fifteen novel thiazoles containing cyclohexene moiety are presented. Among the derivatives, compounds 3a–3d, 3f, 3n, and 3o showed very strong activity against the reference Candida spp. strains with MIC = 0.015–3.91 µg/ml. The activity of these compounds is similar and even higher than the activity of nystatin used as positive control. Compounds 3d, 3f, 3n, 3o showed the highest activity with very strong effect towards most of yeasts isolated from clinical materials with MIC = 0.015–7.81 µg/ml. The cytotoxicity studies for the most active compounds showed that Candida spp. growth was inhibited at noncytotoxic concentrations for the mammalian L929 fibroblast. In addition, a good correlation was obtained between lipophilicity of compounds determined using reversed phase thin-layer chromatography and their antifungal activity.

GC/MS analysis, and antioxidant and antimicrobial activities of alkaloids extracted by polar and apolar solvents from the stems of Anabasis articulata

Abstract: Anabasis articulata is a plant widely used in popular medicine to treat several pathologies in Algerian Sahara, such as diabetes. It is also associated with two other plants to cure certain types of cancer. Few research studies have been conducted on phytochemical analysis and in vivo biological activities of this species. However, no report is available on chemical elucidation of alkaloids and their antioxidant and antimicrobial properties. This study aims to characterise alkaloids in A. articulata stems and to evaluate their antioxidant and antimicrobial effects. Alkaloids extraction was carried out using polar (E1; E2.1; E2.2) and apolar solvents (E3), while chemical characterisation was performed by GC/MS. In vitro antioxidant activity was assessed by tree tests: total antioxidant capacity (TAC), DPPH scavenging assay and β-carotene–linoleate inhibition. For antimicrobial activity, eight different microorganisms were tested. The results suggest that E2.2 extract had the highest TAC value (14.742 ± 0.224 mg AAE/g DM), but E3 extract presented the highest DPPH scavenging activity (EC50 = 1.242 ± 0.168 mg/mL) and a strong β-carotene–linoleate inhibition (EC50 = 0.943 ± 0.027 mg/mL). In addition, E3 extract had the strongest inhibitory effects against all tested microorganisms and produced inhibition zones ranging between 9 and 20 mm, while the MICs of this extract ranged from 0.781 to >100 mg/mL and the MBCs ranged between 1.562 and >100 mg/mL. Forty-nine compounds belonging to 16 families, namely cyclopeptide alkaloids, steroid alkaloids, quinoline alkaloids, camptothecin alkaloids, quinazoline alkaloids, quinazoline alkaloids, isoquinoline alkaloids, isoquinolone alkaloids, indole alkaloids, terpene indole alkaloids, pyridine/pyrrolidine alkaloids, piperidine alkaloids, pyrrolizidine alkaloids, purine alkaloids, acridone alkaloids, benzazonine alkaloids and homolycorine-type Amaryllidaceae alkaloids were identified. Therefore, A. articulata can be considered as a source of antioxidant and antimicrobial agents.

Green synthesis, antileishmanial activity evaluation, and in silico studies of new amino acid-coupled 1,2,4-triazoles

Abstract: Candidates of triazole-containing amino acid derivatives 5a−k were prepared under green chemistry conditions via multicomponent reaction using lemon juice as an acidic catalyst. All compounds were characterized by different spectral and elemental analyses. They were evaluated for their in vitro antileishmanial activity against miltefosine and amphotericin B deoxycholate as reference drugs. Compounds 5c, 5d, 5e and 5f showed superior potencies to miltefosine by 200 folds. These compounds are well tolerated by experimental animals orally up to 250 mg/kg and parenterally up to 100 mg/kg. Reverse docking approach against validated leishmanial targets pinpointed mitogen-activated protein kinase (MAPK) as a possible putative antileishmanial target. In addition, in silico predictions revealed that these compounds exhibited promising drug-likeness and pharmacokinetics profile.

Synthesis and antimicrobial evaluation of novel N -substituted 4-ethylsulfanyl-2-pyridones and triazolopyridines

Abstract: The design and development of new methods for the synthesis of antimicrobial drugs is an important goal currently for medicinal chemistry. Sixteen novel N-substituted-amino-, N-arylsulfonylamino-, and N-aryl-4-ethylsulfanyl-2-pyridones were synthesized. Antimicrobial activities of the compounds were evaluated against four fungal and eight bacterial strains. Antimicrobial results showed that compound 14b had excellent activities as compared to all other newly synthesized compounds and a variety of standard ones against a variety of bacterial and fungal strains. Triazolo[1,5-a]pyridines 10c and 10e showed as well marked activities toward three of the tested Gram-negative bacteria.

Exploration of synthetic antioxidant flavonoid analogs as acetylcholinesterase inhibitors: an approach towards finding their quantitative structure–activity relationship

Abstract: The binding interactions between acetylcholinesterase (AChE) and a series of antioxidant flavonoid analogs were studied by fluorescence spectroscopic assay. The present study incorporated different classes of naturally occurring and synthetic flavonoid compounds like flavones, isoflavones, and chalcones as well as a few standard antioxidants. The AChE inhibitory (AChEI) activity of these compounds was further analyzed using in silico techniques, namely pharmacophore mapping, quantitative structure–activity relationship (QSAR) analysis, and molecular docking studies. We have also compared the AChE inhibitory and radical scavenging antioxidant activities of these compounds. Both the AChE inhibitory and antioxidant activities of these compounds were found to be highly dependent on their structural patterns. However, it was observed that, in general, flavones are comparatively better AChE inhibitors as well as antioxidants compared to chalcones.

New indole and indazole derivatives as potential antimycobacterial agents

Abstract: The study reports on the synthesis and in vitro assessment of the antimycobacterial activity of a series of new indole- and indazole-based aroylhydrazones evaluated against Mycobacterium tuberculosis H37Rv. Isoniazide and ethambutol were used as reference drugs. The most active compounds 3a (MIC 0.4412 μM) and 3e (MIC 0.3969 μM) demonstrated excellent antimycobacterial activity, a very low toxicity against the human embryonic kidney cell line HEK-293T and high selectivity index values (SI = 633.49 and SI > 1978.83, respectively). Importantly, the oral administration of compound 3e at the highest dose of 2000 mg/kg b.w. resulted in no mortalities or evidence of adverse effects, implying that compound 3e is nontoxic. The other derivatives with an indole and indazole scaffold also exhibited high antimycobacterial activity with exception of indole derivatives with Br substituents at the 5th position which exhibited activity weaker than that of ethambutol. The molecular docking investigations performed in an enoyl-ACP reductase (InhA) displayed good docking scores and promising insights on possible interactions with the InhA receptor.

Antimalarial, antiproliferative, and apoptotic activity of quinoline-chalcone and quinoline-pyrazoline hybrids. A dual action

Abstract: A series of quinoline-chalcone (E)-1-[3 or 4-(7-chloroquinolin-4-ylamino) phenyl]-3-(phenyl substituted) prop-2-ene-1-one (4, 5), and quinoline-pyrazoline hybrids 7-Chloro-N-[3 or 4-(4,5-dihydro-5-(phenyl-substituted)-1H-pyrazol-3-yl] phenyl) quinoline-4–amine (6, 7) were synthesized with the aim of achieving an antimalarial and anticancer dual action. Most of the compounds showed significant inhibition (%>80) of β-hematin formation. The existing structures were tested in vivo as potential antimalarials in mice infected with P. berghei ANKA, chloroquine susceptible strain. Some of the compounds exhibited antimalarial activity comparable to that of chloroquine. Moreover, the compounds induce cell death on two human cancer cell lines (Jurkat E6.1 and HL60) without affecting the primary culture of human lymphocytes. Flow cytometry analysis confirmed the increase in apoptotic cell death after 24 h. Based on the structural analysis, these quinoline hybrids represent new compounds potentially useful for malaria end leukemia treatments.

Green synthesis, molecular docking, anti-oxidant and anti-inflammatory activities of α-aminophosphonates

Abstract: The naturally viable α-amino acid surrogates have been synthesised via Kabachnik–Fields reaction by the condensation of 2-aminothiazole with various aldehydes and dialkyl phosphites in the presence of Caffeine hydrogen sulfate (CHS) as eco-friendly and reusable catalyst under microwave irradiation and solvent-free conditions. The title compounds were characterised by IR, 1H, 13C, 31P NMR and mass spectral data. All the synthesised (4a–j) compounds were screened for their insilico and in vitro studies. The results revealed that, out of all the titled compounds 4a, 4e, 4h and 4i have exhibited significant activity in terms of antioxidant and anti-inflammatory activity. In addition, molecular docking studies were also carried out against Cox-2 with celocoxib as the standard.

Synthesis and anticancer effects of conjugates of doxorubicin and unsaturated fatty acids (LNA and DHA)

Abstract: Doxorubicin (DOX) is a leading cytostatic drug with many adverse effects in use. We are still looking for methods that will allow us to preserve the therapeutic effect against the tumor cells and reduce the toxicity to the normal cells. In our work, we obtained amide derivatives of DOX by reaction of the amino group with α-linolenic (LNA) and docosahexaenoic (DHA) acids (2, 3), as well as double-substituted derivatives via amide and ester linkages (4, 5). The structures of the compounds were confirmed by Proton Nuclear Magnetic Resonance (1H NMR), Carbon-13 Nuclear Magnetic Resonance (13C NMR), and High Resolution Mass Spectrometry (HRMS) analyses. For all compounds 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine the cytotoxic effect on human cancer cell lines (SW480, SW620, and PC3) and Chinese hamster lung fibroblasts (V79) that were used as a control. The cytotoxic activity was established by calculation of the inhibitory concentration IC50. In addition, a cytotoxic capacity against tumor cells for tested compounds was expressed as a selectivity factor (selectivity index, SI). Lactate dehydrogenase (LDH) assay was performed for all compounds to assess the level of cell damage. To explain the basic mechanism of cell death induction the Annexin V-FITC/IP flow cytometry analysis was investigated. We found that all studied conjugates exhibit lower cytotoxicity but higher selectivity than DOX. Among the all derivatives, the conjugates formed by the amide and ester linkages (4, 5) were found to be more promising compared with conjugates (2, 3) formed only by the amide linkage. They show high cytotoxicity toward the tumor cell lines and moderate cytotoxicity towards the normal cell line.

An overview of tubulin modulators deposited in protein data bank

Abstract: Microtubules are cytoskeletal polymers of tubulin and composed of α- and β-tubulin heterodimers, which are regarded as one of the most important, promising and successful targets for chemotherapeutic agents to treat cancer. With more and more tubulin-modulator co-crystal complex structures being solved, the mechanism of action (MOA) of microtubule targeting agents (MTAs) are well understood, which in turn inspired the development of more efficient tubulin modulators. By analyzing the reported tubulin modulators (most of them are inhibitors) that have been co-crystalized with tubulin and deposited in protein data bank (PDB), two new discovered inhibitor binding sites (maytansine and pironetin binding sites) on tubulin are elucidated, while the typical modulator binding sites (colchicine, taxanes, vinca alkaloids, and laulimalid binding sites) are also characterized. Among all the reported tubulin modulators, several inhibitors that bind to taxanes or vinca alkaloids binding sites have been approved by FDA to treat cancer. Thus, tubulin inhibitors discovery and design is still a hotspot in anticancer drug development. In this review, all the reported tubulin modulators that have co-crystal structures with tubulin in PDB are sorted out and classified according to their binding sites in tubulin. Besides, the ease or complexity of developing tubulin inhibitor on different binding sites on tubulin is also discussed. This work could contribute to discovering and designing new potent and specific modulators of tubulin.

Synthesis and antimycobacterial activity of disubstituted benzyltriazoles

Abstract: The increasing prevalence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb), the pathogen of human tuberculosis (TB), serves as a strong incentive for the discovery and development of new agents for the treatment of this plight. In search for such drugs, we investigated a series of benzyltriazole derivatives. We herein report the design, synthesis and biological activity of disubstituted benzyltriazoles against the human virulent H37Rv strain of Mtb as well as the toxicity on human embryonic kidney (HEK-293) cells. The derivative 21 featuring trifluoromethyl substituent in para position on the phenyl ring and n-butyl chain in position 4 on the triazole ring was the most active with MIC90 and MIC99 values of 1.73 and 3.2 µM, respectively, in the albumin-free medium. It also displays high selectivity towards bacteria growth inhibition (SI > 58), thus stands as a better hit for further investigation, including lead optimization, DMPK parameters determination and assessment of its activity in animal models.

Design, synthesis and biological evaluation of some novel diastereoselective β-lactams bearing 2-mercaptobenzothiazole and benzoquinoline

Abstract: We report the synthesis of some novel β-lactam hybrids of 2-mercaptobenzothiazole and benzoquinoline. These compounds were synthesized by a [2 + 2]-cycloaddition reaction of imines 8a-d and ketenes derived from substituted acetic acids. The reaction was totally diastereoselective leading exclusively to the formation of cis-β-lactams 10a-m. All products were obtained in good to excellent yields and their structures were established based on IR, 1H NMR, 13C NMR spectral data and elemental analysis. Schiff bases 8a-d and β-lactam hybrids 10a-m were evaluated for antimicrobial activities against six bacterial species. The minimum inhibitory concentration (MIC) values indicate that two of the β-lactams, 10k and 10m, have good activities against the two Gram-negative bacteria, E. coli and P. aeruginosa, while three of the Schiff bases, 8a-c, are active against P. aeruginosa and the Gram-positive pathogen S. aureus. The molecular and cellular basis for these observed antibacterial properties are not determined. Moreover, the five most active compounds showed acceptably low cytotoxicity (less than 25% cell growth inhibition after 72 h of incubation) against the MCF-7 cell line, and below 10% in vitro hemolytic activity at 50 and 200 µM concentrations. These results suggest a need for further inquiry into the reason for why these compounds are bioactive, and as to what their full biological activities and antibiotic potential may be. The cis stereochemistry of β-lactam 10a was confirmed by X-ray crystallographic studies.

The modulatory effect of green tea catechin on drug resistance in human ovarian cancer cells

Abstract: Numerous in vitro and in vivo studies have demonstrated the antiproliferative effect of green tea. It has been speculated that one of its compounds — catechin, may affect multidrug resistance (MDR) phenomena. We examined the effect of catechin and cisplatin on human ovarian cancer cells’ SKOV-3 viability. It was also studied whether preincubation with catechin modulates drug resistance revealed by SKOV-3 cells. Catechin at concentrations up to 200 µM has been shown to be slightly toxic to the tested cells. Analysis of cells after preincubation with catechin revealed increased cytotoxicity of cisplatin compared to the cells treated only with cytostatic and changed expression of MDR-related proteins. Pre-treatment with catechin enhanced cisplatin cytotoxicity by promoting apoptosis and changing activity of membrane proteins involved in drug metabolism, uptake and efflux, especially P-glycoprotein, GST, LRP and BCRP. The obtained results and available reports prove that catechin and its derivatives can potentially be used in chemotherapy as a modulator of MDR phenomena.

Synthesis and cytotoxic effects on pancreatic cancer cells of resveratrol analogs

Abstract: In this study, a series of resveratrol analogs was synthesized and the effects on the viability of pancreatic cancer cell lines were evaluated. The new molecules were designed by removing the 3- and 5-OH groups of resveratrol, and by incorporating other substituents in 4-position, or by replacing the dihydroxybenzene with other aromatic systems. In all compounds the 4′-OH was kept unalterated. The effects of the compounds on cell viability were analyzed in three pancreatic cancer cell lines with distinct genetic profiles. Several compounds (e.g., 5, 9, and 12) exhibited improved cytotoxic activities as compared to the reference compounds, making them potential candidates for further evaluation as anticancer drugs.

Natural thiopeptides as a privileged scaffold for drug discovery and therapeutic development

Abstract: Since the start of the 21st century, antibiotic drug discovery and development from natural products has experienced a certain renaissance. Currently, basic scientific research in chemistry and biology of natural products has finally borne fruit for natural product-derived antibiotics drug discovery. A batch of new antibiotic scaffolds were approved for commercial use, including oxazolidinones (linezolid, 2000), lipopeptides (daptomycin, 2003), and mutilins (retapamulin, 2007). Here, we reviewed the thiazolyl peptides (thiopeptides), an ever-expanding family of antibiotics produced by Gram-positive bacteria that have attracted the interest of many research groups thanks to their novel chemical structures and outstanding biological profiles. All members of this family of natural products share their central azole substituted nitrogen-containing six-membered ring and are classified into different series. Most of the thiopeptides show nanomolar potencies for a variety of Gram-positive bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistant Streptococcus pneumonia (PRSP). They also show other interesting properties such as antiplasmodial and anticancer activities. The chemistry and biology of thiopeptides has gathered the attention of many research groups, who have carried out many efforts towards the study of their structure, biological function, and biosynthetic origin. Here we reviewed a total of 119 natural thiopeptides discovered during the last 50 years. Moreover, we summarized biological profiles, mechanisms of action, and biosynthesis of these thiopeptides.

Multifunctional indanone–chalcone hybrid compounds with anti-β-amyloid (Aβ) aggregation, monoamine oxidase B (MAO-B) inhibition and neuroprotective properties against Alzheimer’s disease

Abstract: To discover multifunctional agents for the treatment of Alzheimer’s disease (AD), a series of indanone–chalcone hybrid compounds were designed and synthesized based on the multitarget-directed ligand strategy. Their monoamino oxidases (MAO-A and MAO-B) and Aβ1–42 aggregation inhibitory activities were evaluated. The results were shown that all synthetic compounds exhibited mostly good multifunctional activities. Among all, compound TM-11 represented the best Aβ1–42 aggregation inhibitory potency (IC50 ~1.8 μM) and good disaggregation activity (IC50 ~7.9 μM). Both TEM images and docking studies provided good reasonable explanation to the hypothesis. Meanwhile, compound TM-11 was a selective MAO-B inhibitor, as well as a neuroprotective agent against Aβ1–42-induced toxicity. Based on the structural considerations, the lipophilicity of the compound TM-11 could render to pass through blood−brain barrier (BBB) in vitro in accordance with the Lipinski’s rule of five. In conclusion, these results were suggested that compound TM-11 might be a potential multifunctional agent for the treatment of AD.

Pyrazole–chalcone derivatives as selective COX-2 inhibitors: design, virtual screening, and in vitro analysis

Abstract: In the process of research and development of new drugs, in silico analyzes are widely used. They address the pharmacokinetics of the molecules in study and can predict the binding mode and affinity, using a docking software. This approach can optimize the development of new drugs, reducing costs, time, and resources. In this study, a library of 300 pyrazole–chalcone derivatives were designed, the in silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties were evaluated, and a structure-based virtual screening was performed using AutoDock Vina. The docking results exhibited that the derivatives binding mode at the COX-2 active site is similar to celecoxib, the reference drug, and presented similar binding energy. Six compounds were synthetized and tested for in vitro inhibition of the COX-1 and COX-2 isoenzymes and the selectivity index (SI) was calculated. The compound 2a11 showed the best activity for COX-2 (IC50COX-2 = 0.73 μM) whereas the control, celecoxib, resulted IC50COX-2 = 0.88 μM. All the other compounds synthetized presented better potency for COX-2 inhibition than the control. Compound 2a23 exhibited the higher SI, of 280.17 (IC50COX-1 = 210.13 μM/ IC50COX-2 = 0.75 μM), while celecoxib was 246.88 (IC50COX-1 = 217.26 μM/ IC50COX-2 = 0.88 μM). These results corroborate with a possible anti-inflammatory activity and COX-2 selectivity of the new compounds synthetized.

Different reactivity to glutathione but similar tumor cell toxicity of chalcones and their quinolinone analogues

Abstract: Non-enzyme catalyzed nucleophilic addition of reduced glutathione (GSH) onto two open-chain sulfonamide chalcones and two quinolinone-chalcone hybrids were studied to investigate the relationship between tumor cell cytotoxic activities and GSH-reactivities of the compounds. The consumption of the chalcones or the quinolinone-chalcone hybrids due to conjugation with GSH was evaluated by analytical high-performance liquid chromatography, and the formed diastereomeric adducts were identified by liquid chromatography–mass spectrometry. When the reaction was conducted with the open-chain chalcones, the equilibria were shifted towards formation of the respective GSH-conjugates. On the other hand, the cyclic chalcone derivatives with the quinolinone moiety were found to equilibrate to mixtures containing predominantly the reactants despite the strong electron withdrawing group present in the B-ring of the compounds. The observed opposite behavior can be rationalized by reduced thiol-reactivity of the quinolinone-chalcone hybrids and fast decomposition of their GSH-conjugates. A combined X-ray diffraction and theoretical approach were used to explain the observed difference in the reactivities towards GSH. However, structural differences did not influence tumor cell (SF-295, PC-3 and HCT-116) cytotoxicity of the evaluated compounds. Accordingly, the altered GSH-reactivity seems to be not a determining factor in the tested tumor cell cytotoxic activity of the investigated compounds.

Synthesis, characterization, and in vitro anticancer evaluation of 2-substituted 5-arylsulfonyl-1,3-oxazole-4-carbonitriles

Abstract: In this series, six new 2-substituted 5-arylsulfonyl-1,3-oxazole-4-carbonitriles were synthesized and characterized by IR, 1H NMR, 13C NMR spectroscopy, elemental analysis and chromato-mass-spectrometry. The anticancer activities of the compounds were evaluated via single high dose (10−5M) against 60 cancer cell lines by the National Cancer Institute according to its own screening protocol. In the next phase, the compounds have been selected for five-dose assay. All synthesized compounds displayed growth inhibitory (GI50) and cytostatic activities (TGI) against the most sensitive cell lines at submicromolar (0.2–0.6 μM) and micromolar concentrations (1–3 μM), respectively. Cytotoxic activity (LC50) of these compounds, with the exception of 4d, against the most sensitive cell lines was also high (5–6 μM). All compounds exhibit high selectivity towards leukemia cell lines, and among them, 4e and 4f showed the best antiproliferative and cytostatic selectivity. Compounds 4c and 4f displayed considerable cytotoxic selectivity towards the renal and breast cancer subpanels. Our results provided evidence for anticancer activities of novel 2-substituted 5-arylsulfonyl-1,3-oxazole-4-carbonitriles which could be useful for developing new anticancer drugs. These substances could also be used as an excellent framework in anticancer research that may lead to discovery of potent antitumor agents.

Synthesis and in vitro biological evaluation of 1,3-bis-(1,2,3-triazol-1-yl)-propan-2-ol derivatives as antifungal compounds fluconazole analogues

Abstract: A novel series of 1,3-bis-(1,2,3-triazol-1-yl)-propan-2-ol derivatives was synthesized from 1-aryl-1,3-diazidopropan-2-ol derivatives and diverse alkynes using copper catalyzed azide-alkyne cycloaddition in the key step. Most of synthesized compounds showed high activity against Candida spp. strains at a 0.04–0.5 μg/mL concentration range compared to Itraconazole and Fluconazole (MIC 2.56 and 1.28 μg/mL, respectively), which were used as reference compounds. A 1,3-bis-(1,2,3-triazol-1-yl)-propan-2-ol derivative (R1 = F and R2 = cyclopropyl) displayed an outstanding selectivity against Candida albicans and Candida krusei (MIC = 0.0075 µg/mL). Moreover, Artemia salina bioassay on 1,3-bis-(1,2,3-triazol-1-yl)-propan-2-ol derivatives revealed low toxicity in this kind of compounds. In addition, molecular docking studies suggest good binding affinity of halogen atoms in some 1-aryl-1,3-diazidopropan-2-ol derivatives to HEME group present in 14-alpha demethylase (CYP51), which might explain the high antifungal activity found in these compounds.

Chemical constituents of the Vietnamese plants Dalbergia tonkinensis Prain and Cratoxylum formosum (Jack) Dyer in Hook and their DPPH radical scavenging activities

Abstract: Phytochemical investigations of the leaves and roots of Dalbergia tonkinensis led to the isolation of a new isoflavone glycoside derivative, isocaviunin 7-O-β-D-apiofuranosyl-(1 → 6)-β-D-glucopyranoside (1), and a new scalemic sesquiterpene lactone, 3,7-dimethyl-3-vinylhexahydro-6,7-bifuran-3(2H)-one (2), along with the previously known compounds 3-16, and nine other known compounds 17-25 were isolated from the leaves of Cratoxylum formosum. The chemical structures of the isolated compounds were elucidated by 1D- and 2D-NMR analyses as well as MS spectroscopic data. The results suggest that flavonoids are characteristic of both plants. In the DPPH radical scavenging assay, (3 R)-vestitol (5) and isoquercetin (24) possessed the strongest antioxidative IC50 values of 42.20 µg/mL and 45.63 µg/mL, respectively, and their values were comparable to that of the positive control catechin (IC50 42.98 µg/mL).

Novel chromenes and benzochromenes bearing arylazo moiety: molecular docking, in-silico admet, in-vitro antimicrobial and anticancer screening

Abstract: Novel derivatives of benzochromene 9a–e and chromene 10a–e were synthesized via multi components reaction that utilizes azo dyes, malononitrile, and arylaldehydes as starting materials. The structures of the newly synthesized compounds were elucidated by the IR, 1H-NMR, 13C-NMR and mass spectral data. The new synthesized compounds were explored for their in-silico ADMET properties. The docking investigations verified good docking outcomes in terms of score and binding affinities of the examined compounds on the desired proteins, namely the GlcN-6-P synthase and PI3Ks. The in-vitro studies, which encompassed the antibacterial activity against two types of Gm +ve and two of Gm –ve, and the antifungal activity against four fungi micro-organisms were evaluated by the well diffusion method for the synthesized compounds. Moreover, the anticancer activity was tested against three human carcinoma cell lines [human colon carcinoma (HCT-116), human breast adenocarcinoma (MCF-7), and liver carcinoma (HEPG-2)], exhibiting promising anticancer activity in comparison to Vinblastine, Colchicine and Doxorubicin as standard drugs. The data suggests that some of the new derivatives of chromene scaffold which emerged promising in the in-silico molecular docking studies displayed good in-vitro antimicrobial and anticancer activities and could be exploited as leads for further optimization.

Synthesis, cytotoxicity against cancer and normal cell lines of novel hydrazide–hydrazone derivatives bearing 5H-chromen-5-one

Abstract: The reaction of cyclohexan-1,3-dione with either of malononitrile or ethyl cyanoacetate gave the 4-amino-6,7-dihydro-5H-chromen-5-one derivatives 3a and 3b, respectively. The reaction of the latter compounds with cyanoacetylhydrazine gave the hydrazide–hydrazone derivatives 5a and 5b, respectively. Compounds 5a,b were used as the key starting materials for the synthesis of thiophen, coumarin, and pyridine derivatives. The newly synthesized compounds were evaluated against three human cancer cell lines, including HCT116 (colon carcinoma cell), MGC803 (gastric carcinoma cell), and Huh7 (hepatoma carcinoma cell). The results showed that 3b, 5b, 6b, 6d, 8b, 8c, 8d, 8f, 10b. 12a–h, 14a–d, 15a–h, and 16b–h displayed higher cytotoxic activity than 5-FU against HCT116 and MGC803 cell lines. Compounds 14d and 16f were the most promising compounds with IC50’s 0.25 and 0.09 μM against HCT116 cell line. The most potent compounds were selected for the in vitro against peripheral blood lymphocytes (PBL) from healthy donors. All compounds were practically devoid of significant cytotoxic activity in quiescent lymphocytes, with GI50’s of 42–68 μM, while with the mitogenic stimulus phytohaemagglutinin (PHA), the GI50’s were reduced to about 20–32 μM.

Synthesis and biological evaluation of ursolic acid derivatives containing an aminoguanidine moiety

Abstract: Three series of ursolic acid derivatives containing an aminoguanidine moiety were designed, synthesized, and evaluated for anti-bacterial and anti-inflammatory activity. Some compounds displayed potent anti-bacterial activity against Gram-positive bacterial strains (including multidrug-resistant clinical isolates) and Gram-negative bacterial strains, with minimum inhibitory concentration (MIC) values in the range of 2–64 µg/mL. Compounds 3a, 5a, and 7l showed significant inhibitory activity against the Gram-positive bacterial strain Staphylococcus aureus RN 4220, the Gram-negative bacterial strain Escherichia coli 1924, and four multidrug-resistant Gram-positive bacterial strains, with MIC values of 2 and 4 µg/mL. In anti-inflammatory tests, most of the compounds exhibited potent activity, in particular compound 3a displayed the most potent activity with 81.61% inhibition after intraperitoneal administration, which was more potent than ursolic acid and the reference drugs (ibuprofen and indomethacin). The cytotoxic activity of compound 3a was assessed in HeLa, Hep3B, and A549 cells.