Compound B2 Research Articles

Preparation and evaluation of polyphenol derivatives as potent antifouling agents: addition of a side chain affects the biological activity of polyphenols

In this study, eight polyphenol derivatives were prepared to serve as green antifoulants. Polyphenol derivatives, which can hinder the growth of bacteria and algae and decrease the adhesion of some marine organisms, showed good AF activity; in particular, the activities of these derivatives were much higher than those of the corresponding polyphenols. The antibacterial rates of the products (20 μg ml−1) exceeded 88%. Moreover, the anti-algal rates of compounds a3, b1, b2, b3 and b4 (15 μg ml−1) were over 57% at 240 h, but these compounds showed low toxicity, and the 120 h EC50 values were > 6.60 μg ml−1. In addition, there were fewer marine microorganisms on the test panel than on the control. The above results show that some polyphenol derivatives possess relatively high antibacterial, anti-algal, and AF activity; more notably, the addition of chlorine atoms and amide groups can further increase the activity of these derivatives.

ISOLATION AND CHARACTERIZATION OF A SECONDARY METABOLITE FROM THE AERIAL PARTS OF Launaea (Lactuca) taraxacifolia

Launaea (Lactuca) taraxacifolia also known as wild lettuce is a medicinally important plant of the Asteraceae family. The plant was selected for this study due to its widespread use in traditional medicine and on the basis that the plant is almost going into extinct in Nigeria. The extraction was carried out by subjecting the air dried pulverized plant materials into trichloromethane solvent for a period of some days, followed by filtration and concentration. Separation and purification of the various constituents of the crude were done using thin layer and column chromatography. The mobile phases and solvent blends employed were: normal hexane, trichloromethane, ethyl ethanoate and methanol. The extraction, purification, concentration and chromatographic separations of the extracts were carried out at Post-graduates, chemistry laboratory, Michael Okpara University of Agriculture, Umudike, Nigeria. The NMR spectra analysis was investigated at Monash University Malaysia while the FTIR and GC-MS were carried out at Nanotechnology and Research Institute Malaysia. The NMR analysis was done using a Bruker VSP 500MHZ model machine. The GC-MS was performed using an Agilent 7000 model while the FTIR analysis was carried out on an Agilent 4500 series FTIR system. The structural elucidation of the proposed compound was deduced using GC-MS, FTIR, NMR (13C and 1H) and 2D COSY NMR spectra. This chemical investigation resulted in the isolation of a novel compound SB3 (Octadecahydro-10-(1,2,3,4-tetrahydronaphtalen-3-yl)-4,4-dimethoxy-6b,12b,14b-trimethyl Picen-3-(4H,6bH,14bH)-one. Compound SB3 was isolated using 50% hexane and 50% trichloromethane at an Rf value of 0.692. The MS spectrum of compound SB3 gave a molecular ion peak at m/z 545.81, which corresponded to a molecular formula of C37H53O3.

Antioxidant Status of Broiler Chickens Fed Diets Supplemented with Vinification By-Products: A Valorization Approach.

Vinification by-products display great potential for utilization as feed additives rich in antioxidant compounds. Thus, the effect of dietary ground grape pomace (GGP), wine lees extract rich in yeast cell walls (WYC), and grape stem extracts (PE) on the relative expression of several genes involved in liver oxidative mechanisms and the oxidative status of the blood and breast muscle of broiler chickens was investigated. In total, 240 one-day-old as hatched chicks (Ross 308) were assigned to four treatments, with four replicate pens and 15 birds in each pen. Birds were fed either a basal diet (CON) or a basal diet supplemented with 25 g/kg GGP, or 2 g/kg WYC, or 1 g starch including 100 mg pure stem extract/kg (PE) for 42 days. The polyphenolic content of vinification by-products was determined using an LC-MS/MS library indicating as prevailing compounds procyanidin B1 and B2, gallic acid, caftaric acid, (+)-catechin, quercetin, and trans-resveratrol. Body weight and feed consumption were not significantly affected. The relative transcript level of GPX1 and SOD1 tended to increase in the liver of WYC-fed broilers, while NOX2 tended to decrease in the PE group. SOD activity in blood plasma was significantly increased in WYC and PE compared to the CON group. The total antioxidant capacity measured with FRAP assay showed significantly higher values in the breast muscle of PE-fed broilers, while the malondialdehyde concentration was significantly decreased in both WYC- and PE-fed broilers compared to the CON group. The exploitation of vinification by-products as feed additives appears to be a promising strategy to improve waste valorization and supply animals with bioactive molecules capable of improving animals’ oxidative status and products’ oxidative stability.

Fabrication of Versatile Pyrazole Hydrazide Derivatives Bearing a 1,3,4-Oxadiazole Core as Multipurpose Agricultural Chemicals against Plant Fungal, Oomycete, and Bacterial Diseases.

Developing multipurpose agricultural chemicals is appealing in crop protection, thus eventually realizing the reduction and efficient usage of pesticides. Herein, an array of versatile pyrazole hydrazide derivatives bearing a 1,3,4-oxadiazole core were initially synthesized and biologically evaluated the antifungal, antioomycetes, and antibacterial activities. In addition, the pyrazole ring was replaced by the correlative pyrrole, thiazole, and indole scaffolds to extend the molecular diversity. The results showed that most of these hybrid compounds were empowered with multifunctional bioactivities, which are exemplified by compounds a1-a6, b1-b3, b7, b10, b13, and b18. For the antifungal activity, the minimal EC50 values could afford 0.47 (a2), 1.05 (a2), 0.65 (a1), and 1.32 μg/mL (b3) against the corresponding fungi Gibberella zeae (G. z.), Fusarium oxysporum, Botryosphaeria dothidea, and Rhizoctonia solani. In vivo pot experiments against corn scab (caused by G. z.) revealed that the compound a2 was effective with protective and curative activities of 90.2 and 86.3% at 200 μg/mL, which was comparable to those of fungicides boscalid and fluopyram. Further molecular docking study and enzymatic activity analysis (IC50 = 3.21 μM, a2) indicated that target compounds were promising succinate dehydrogenase inhibitors. Additionally, compounds b2 and a4 yielded superior anti-oomycete and antibacterial activities toward Phytophora infestins and Xanthomonas oryzae pv. oryzae with EC50 values of 2.92 and 8.43 μg/mL, respectively. In vivo trials against rice bacterial blight provided the control efficiency within 51.2-55.3% (a4) at 200 μg/mL, which were better than that of bismerthiazol. Given their multipurpose characteristics, these structures should be positively explored as agricultural chemicals.

Design, Synthesis, and Evaluation of o-(Biphenyl-3-ylmethoxy)nitrophenyl Derivatives as PD-1/PD-L1 Inhibitors with Potent Anticancer Efficacy In Vivo.

Two series of novel o-(biphenyl-3-ylmethoxy)nitrophenyl compounds (A1-31 and B1-17) were designed as programmed cell death protein 1 (PD-1)/PD-ligand 1 (PD-L1) inhibitors. All compounds showed significant inhibitory activity with IC50 values ranging from 2.7 to 87.4 nM except compound A17, and compound B2 displayed the best activity. Further experiments showed that B2 bound to the PD-L1 protein without obvious toxicity in Lewis lung carcinoma (LLC) cells. Furthermore, B2 significantly promoted interferon-gamma secretion in a dose-dependent manner in vitro and in vivo. Especially, B2 exhibited potent in vivo anticancer efficacy in an LLC-bearing allograft mouse model at a low dose of 5 mg/kg, which was more active than BMS-1018 (tumor growth inhibition rate: 48.5% vs 17.8%). A panel of immunohistochemistry and flow cytometry assays demonstrated that B2 effectively counteracted PD-1-induced immunosuppression in the tumor microenvironment, thereby triggering antitumor immunity. These results indicate that B2 is a promising PD-1/PD-L1 inhibitor worthy of further development.

Design, Synthesis, Activity Evaluation and Molecular Docking Study of Novel Janus kinase Inhibitors

AbstractJanus kinase (JAK) is a non receptor tyrosine protein kinase, which has attracted wide attention and JAK inhibitors are mainly used to screen therapeutic drugs for hematological diseases, tumors, rheumatoid arthritis (RA) and psoriasis. Filgotinib is an oral small molecule JAK inhibitor which is currently at the clinical stage to treat Crohn's disease (CD) and rheumatoid arthritis. In this study, we designed novel triazolopyridine derivatives A1–A4 using Filgotinib as the lead compound, then replaced cyclopropane with trifluoromethane and replaced triazolopyridine with imidazopyrazine to get B1–B4 by isosteric principle of bioelectronics. These compounds were prepared in this work, and the corresponding effects against JAK1, JAK2 and JAK3 were assessed. The results indicated that B2 had stronger inhibitory effect on JAK1 and JAK3. A1 and A2 showed a good inhibitory effect on JAK1. Molecular docking results showed that compounds A1, A2 and B2 bind well to protein binding sites. These compounds can supply leading compounds for developing rheumatoid arthritis and Crohn's drugs.

Synthesis and structural elucidation of a series of isoflavones-based on FPR antagonists

Synthesis and structural elucidation of a series of isoflavones-based on FPR antagonists

Synthesis, Molecular Docking, Molecular Dynamics, DFT and Antimicrobial Activity Studies of 5-substituted-2-(p-methylphenyl)benzoxazole Derivatives

In this study, new 2-(p-methylphenyl)-5-(2-substitutedacetamido)benzoxazole derivatives were synthesized, and antimicrobial activities on six bacteria and their twelve drug-resistant isolates and one fungus and its two drug-resistant isolates were investigated by microdilution method. B1 against Staphylococcus aureus isolate, and B1 and B2 against Escherichia coli isolate showed more potent antimicrobial activity with MIC value of 16 µg/mL than some of the reference drugs. The compounds' interactions on the DNA gyrase enzyme were evaluated by molecular docking and molecular dynamics simulations. Docked compounds have demonstrated superimposition in the DNA gyrase ATP binding site with similar protein-ligand interactions. With 50 ns duration molecular dynamics simulations, the average RMSD value of the DNA gyrase subunit B protein and B1, B2, B3, and B4 complexes were measured at about 0.15 nm. The ligands-bound DNA gyrase subunit B protein is a little less RMSF value and more stable than the apoprotein form between 45-49 residues in the active site amino acids region. Geometric optimization parameters, HOMO-LUMO orbital energies, and other electronic parameters derived from these energies, MEP, and NBO analysis were performed the DFT/B3LYP theory and 6-311G (d,p) basis set. The ΔE: LUMO-HOMO of the two most active compounds B1 and B2 are 4.2928 and 4.3219, respectively. The compounds' predicted ADME profiles were in line with Lipinski and other limiting rules.

Discovery of Piperidol Derivatives for Combinational Treatment of Azole-Resistant Candidiasis.

Effective strategies are needed to deal with invasive fungal infections caused by drug-resistant fungi. Previously, we designed a series of antifungal benzocyclane derivatives based on the drug repurposing of haloperidol. Herein, further structural optimization and antifungal mechanism studies were performed, leading to the discovery of new piperidol derivative B2 with improved synergistic antifungal potency, selectivity, and water solubility. In particular, the combination of compound B2 and fluconazole showed potent in vitro and in vivo antifungal activity against azole-resistant Candida albicans. Compound B2 inhibited important virulence factors by regulating virulence-associated genes and improved the efficacy of fluconazole by down-regulating the CYP51-coding gene and efflux pump gene. Taken together, the piperidol derivative B2 represents a promising lead compound for the combinational treatment of azole-resistant candidiasis.

Synthesis, Characterization and Antioxidant Activity of Some New Schiff base Derived from Cytosine

Cytosine is used to synthesize several derivatives of Schiff base when reacted with some aldehydes which are refluxed by using ethanol as a solvent and non solvent with adomestic microwave (Compounds A1 – A4). These products of the Schiff base are treated first with chloroacetyl chloride to synthesize four-membered heterocycles (Compounds B1 – B4). After that, they treated with hydroxyl acetic acid to synthesize five-membered heterocyclic (Compounds C1 – C4). In the third step, the products are used to react with amaleic acid anhydride to produce seven-membered heterocyclic (Compound D1 – D4). The antioxidant activity of the compounds (A1 – A4) and two of the compounds (B1, B3), (C1, C3) and (D1, D3) in different concentrations of (100, 200, 300, 400 and 500 mg/ml) are tested with 1,2 – Di Phenyl – 2 – Picryl Hydrazyl (DPPH) for scavenging a radical activity. Finally, these compounds are diagnosed by several technical devices such as IR, proton1HN.M. R and13C N.M.R. spectroscopy.

1,3,4-Thiadiazolo (3,2-Α) Pyrimidine-6-Carbonitrile Scaffold as PARP1 Inhibitors.

1,3,4-thiadiazolo pyrimidine is a lead molecule that is versatile for a wide variety of biological activities and in continuation of our interest in establishing some novel heterocyclic compounds for antitumor activity. The objective of the study was to synthesize a series of 5-amino-7-(substituted aldehyde)-2[(naphthalene- 2-yloxy)methyl] -[1,3,4]thiadiazolo-[3,2-α]-pyrimidine-6- carbonitrile derivatives and evaluate their possible in vitro and in vivo anticancer activity. Herein, we report the synthetic scheme, which was followed for the preparation of a series of title compounds B1- B9 outlined in scheme 1. The intermediate 5-[(naphthalen-2- yloxy)methyl]-1,3,4-thiadiazolo- 2-amine was prepared by heating 2-naphthoxyacetic acid and thiosemicarbazide in the presence of phosphoryl chloride at a temperature of 65-75°C. The obtained compound reacted with malononitrile and an appropriate amount of aromatic and heteroaromatic aldehydes in refluxing ethanol yielded 5-amino-7-(substituted aldehyde)-2[(naphthalene-2-yloxy)methyl] -[1,3,4]thiadiazolo-[3,2-α]-pyrimidine-6- carbonitrile derivatives (B1 - B9). The purity of the synthesized compounds was ensured by various spectral analyses. In in silico molecular docking studies, compounds B3 and B9 show binding affinity like known PARP1 inhibitor olaparib. The cellular evaluation indicates that the anticancer profile of compounds B1, B3, and B9 is significant when compared to the standard drug (olaparib) against MDA-MB-232 cell line and compounds B3, B6, and B7 are the most active against MCF-7 cell lines. The most active compound B3 was subjected to acute oral toxicity studies by OECD 423 guidelines and in vivo anti-cancer studies were carried out using DMBA induced model. The in silico docking study of the newly synthesized compounds was performed; the results showed good binding mode in the active site of PARP1 enzyme. In silico ADME properties of synthesized compounds were also studied and showed good drug-like properties.

Design, Synthesis and Biological Evaluation of Dimethyl Cardamonin (DMC) Derivatives as P-glycoprotein-mediated Multidrug Resistance Reversal Agents

Background: P-glycoprotein (P-gp) has been regarded as an important factor in the multidrug resistance (MDR) of tumor cells within the last decade, which can be solved by inhibiting Pgp to reverse MDR. Thus, it is an effective strategy to develop inhibitor of P-gp. Objective: In this study, the synthesis of a series of derivatives had been carried out by bioisosterism design on the basis of Dimethyl Cardamonin (DMC). Subsequently, we evaluated their reversal activities as potential P-glycoprotein (P-gp)-mediated Multidrug Resistance (MDR) agents. Methods: Dimethyl cardamonin derivatives were synthesized from acetophenones and the corresponding benzaldehydes in the presence of 40% KOH by Claisen-Schmidt reaction. Their cytotoxicity and reversal activities in vitro were assessed with MTT. Moreover, the compound B4 was evaluated by Doxorubicin (DOX) accumulation, Western blot and wound-healing assays deeply. Results and Conclusion: The results showed that compounds B2, B4 and B6 had the potency of MDR reversers with little intrinsic cytotoxicity. Meanwhile, these compounds also demonstrated the capability to inhibit MCF-7 and MCF-7/DOX cells migration. Besides, the most compound B4 was selected for further study, which promoted the accumulation of DOX in MCF-7/DOX cells and inhibited the expressionof P-gp at protein levels. Conclusion: The above findings may provide new insights for the research and development of Pgp- mediated MDR reversal agents.

Molecular modeling of three-dimensional structure of hTRPV4 protein and experimental verification of its antagonist binding sites

The transient receptor potential vanilloid type 4 (TRPV4) is a polymodal receptor. Antagonists of human TRPV4 (hTRPV4) represent a novel therapeutic approach for acute lung injury (ALI). However, the discovery of various hTRPV4 antagonists has been difficult due to the unavailability of 3D-structure of hTRPV4 protein. We constructed the 3D-structure of hTRPV4 protein by homology modelling, and the binding pocket of antagonist with hTRPV4 was predicted for the first time. The pocket was consistent with the same subfamily rabbit TRPV5. The detailed interactions of different protein-ligand complexes were calculated by molecular docking and molecular dynamics (MD) simulation, and the outcome revealed the rationality of the binding pocket. Based on the docking and MD results of this model and the structure of compound A2, a TRPV4 antagonist reported in literature, two small molecular compounds, B1 and B2, were designed and synthesized as hTRPV4 antagonists. The results of biological evaluation in vitro showed that these compounds have good inhibitory activity on hTRPV4. Moreover, the results were in good agreement with those predicted by molecular simulation, which in turn suggested that the modeling 3D structure and the predicted active sites of hTRPV4 are reasonable and reliable. The compound B2, with novel structure and potent inhibitory activity against hTRPV4, can be a promising lead compound for discovering new hTRPV4 antagonists in the future.

Structural optimization of pyrazolo[1,5-a]pyrimidine derivatives as potent and highly selective DPP-4 inhibitors.

Our previous discovery of pyrazolo [1,5-a]pyrimidin-7(4H)-one scaffold-based DPP-4 inhibitors yielded two potent compounds b2 (IC50=79nM) and d1 (IC50=49nM) but characterized by cytotoxicity. Herein, with scaffold hopping and fragment-based drug design strategies, highly potent and selective pyrazolo [1,5-a]pyrimidine DPP-4 inhibitors were found featured by reduced or diminished cytotoxicity. Specifically, c24 (IC50=2nM) exhibits a 25 to 40-fold increase of inhibitory activity respect to those of b2 and d1, respectively, 2-fold from Alogliptin (IC50=4nM), and remarkable selectivity over DPP-8 and DPP-9 (>2000 fold). Further docking studies confirmed that the pyrazolo [1,5-a]pyrimidine core interacts with the S1 pocket whereas its substituted aromatic ring interacts with the sub-S1 pocket. The interactive mode in this case resembles that of Alogliptin and Trelagliptin. Further invivo IPGTT assays in diabetic mice demonstrated that c24 effectively reduces glucose excursion by 48% at the dose of 10mg/kg, suggesting that c24 is worthy of further development as a potent anti-diabetes agent.

Synthesis and Structure-Activity Relationship Studies of N-monosubstituted Aroylthioureas as Urease Inhibitors.

Thiourea is a classical urease inhibitor which is usually used as a positive control, and many N,N'-disubstituted thioureas have been determined as urease inhibitors. However, due to steric hindrance, N,N'-disubstituted thiourea motif could not bind urease as thiourea. On the contrary, N-monosubstituted thiourea with a tiny thiourea motif could theoretically bind into the active pocket as thiourea. A series of N-monosubstituted aroylthioureas were designed and synthesized for evaluation as urease inhibitors. Urease inhibition was determined by the indophenol method and IC50 values were calculated using computerized linear regression analysis of quantal log dose-probit functions. The kinetic parameters were estimated via surface plasmon resonance (SPR) and by nonlinear regression analysis based on the mixed type inhibition model derived from Michaelis-Menten kinetics. Compounds b2, b11, and b19 reversibly inhibited urease with a mixed mechanism, and showed excellent potency against both cell-free urease and urease in the intact cell, with IC50 values being 90- to 450-fold and 5- to 50-fold lower than the positive control acetohydroxamic acid, respectively. The most potent compound b11 showed an IC50 value of 0.060 ± 0.004μM against cell-free urease, which bound to urea binding site with a very low KD value (0.420±0.003nM) and a very long residence time (6.7 min). Compound b11 was also demonstrated to have very low cytotoxicity to mammalian cells. The results revealed that N-monosubstituted aroylthioureas bound to the active site of urease as expected, and represent a new class of urease inhibitors for the development of potential therapeutics against infections caused by urease-containing pathogens.

Synthesis of novel 18β‐glycyrrhetinic piperazine amides displaying significant in vitro and in vivo antibacterial activities against intractable plant bacterial diseases

The limited amount of agrochemicals targeting plant bacterial diseases has motivated us to study innovative antibacterial surrogates with fresh modes of action. Notably, fabrication of violent apoptosis inducers to control the reproduction of pathogenic bacteria should be a feasible way to control plant bacterial diseases. To achieve this aim, we constructed a series of novel 18β-glycyrrhetinic piperazine amides based on the natural bioactive ingredient 18β-glycyrrhetinic acid to evaluate the in vitro and in vivo antibacterial activity and induced apoptosis behaviors on tested pathogens. Screening results suggested that these designed compounds were extremely bioactive against two notorious pathogens, Xanthomonas oryzae pv. oryzae and X. axonopodis pv. citri. This conclusion was highlighted by the biological effects of compounds A3 and B1 , affording the related EC50 values of 2.28 and 0.93 μg mL-1 . In vivo trials confirmed the prospective application for managing rice bacterial blight disease with control efficiency within 50.57-53.70% at 200 μg mL-1 . In particular, target compounds could induce the generation of excessive reactive oxygen species (ROS) in tested pathogens, subsequently leading to a strong apoptotic effect at a very low drug concentration (≤ 10 μg mL-1 ). This finding was consistent with the observed ROS-enhanced fluorescent images and morphological changes of pathogens from scanning electron microscopy patterns. Given these features, we anticipate that these novel piperazine-tailored 18β-glycyrrhetinic hybrids can provide an perceptible insight for fighting bacterial infections by activation of the apoptosis mechanism. Novel 18β-glycyrrhetinic piperazine amides were reported to have excellent antibacterial efficacy toward phytopathogens Xanthomonas oryzae pv. oryzae and X. axonopodis pv. citri. A possible apoptosis mechanism was proposed from the remarkable apoptotic behaviors triggered by target compounds. © 2020 Society of Chemical Industry.

Synthesis <i>N</i>-Phenyl Pyrazoline from Dibenzalacetone and Heme Polymeration Inhibitory Activity (HPIA) Assay

The synthesis of 1,5-diphenyl-3-styryl-4,5-dihydro-1H-pyrazole (B1) and 5-(3,4-dimethoxyphenyl)-3-(3,4-dimethoxystyryl)-1-phenyl-4,5-dihydro-1H-pyrazole (B2) have been conducted from 1,5-diphenylpenta-1,4-dien-3-on (A1) and 1,5-bis(3,4-dimethoxyphenyl)penta-1,4-dien-3-one (A2). Heme polymerization inhibitory activity (HPIA) assay of the synthesized compounds has also been carried out. The first step of reaction was Claisen-Schmidt condensation of benzaldehyde derivatives and acetone using NaOH 20% and ethanol as solvent. Dibenzalacetone derivatives were reacted with phenylhydrazine using acetic acid to form N-phenylpyrazoline. The structure of products was characterized by FT-IR, GC-MS, DI-MS, 1H- and 13C-NMR The result of heme polymerization inhibitory activity assay showed that IC50 of B1 and B2 1.26 and 0.79 mM while quinine 1.26 mM. The result indicated that compound B2 was more potent as antimalarial than quinine.

Theoretical study on structural, mechanical and electronic properties of ternary mononitride Ti0.5W0.5N from first-principles calculations

In the present work, systematic structure searching is carried out using CALYPSO (Crystal structure AnaLYsis by Particle Swarm Optimization) method combined with first-principles calculations, in the pressure range of 0–300 GPa for ternary mononitride Ti0.5W0.5N. A new possible structure with Cmc21 space group has been uncovered to be the ground-state phase which is much more energetically favorable than the well known B1 structure at 0 GPa and 0 K conditions. There is an excellent enhancement of mechanical properties for the Cmc21-Ti0.5W0.5N relative to B1–Ti0.5W0.5N and its parent compounds B1–TiN and NbO-type WN. The dynamical, mechanical and thermodynamic stabilities are verified through calculating the phonon spectra, elastic constants and formation enthalpy. The elastic properties are fully investigated and the results show that its Vickers hardness value is up to 34 GPa evaluated from bulk modulus (335 GPa) and shear modulus (255 GPa), wihch is much more than that of B1–TiN and NbO-type WN. Meanwhile, the elastic anisotropy is also studied through the dependence of Young's, linear bulk and shear moduli along the crystal orientations. According with the elastic properties, the calculated ideal strengths also confirm that there is a great improvement for the Cmc21-Ti0.5W0.5N relative to that of the above binary mononitrides. Further analysis of the electronic density of states and the chemical bonding nature reveals that the component of Ti plays an important role through tuning the valence-electron concentration (VEC) to enhance the stability and the mechanical properties.

Ex vivo efficacy of selective chalcone derivatives on reference strains and field isolates of Plasmodium falciparum

ABSTRACTThe extension of Plasmodium falciparum resistance to existing antimalarial drugs is worrying. Faced with this problem, the search for new and effective molecules is necessary. In this context, six chalcone derivatives (B1, B11, B14, B17, SCA02 and SCA03) were tested on field isolates and then reference strains to evaluate their antiplasmodial activity by using the Rieckmann semi-microtest, recommended by WHO, for in vitro and ex vivo activity tests. Compounds B14 and B17 exhibited promising antiplasmodial activities (IC50s: 14.41–16.40 μM) regardless of the type of isolate. Compounds B1, B11, SCA02 and SCA03 showed a moderate inhibition of field isolates (IC50S: 25.63–48.29 μM) and very good activity against reference strains (IC50s: 3.82–10.03 μM). Therefore, more structural modulations should improve their efficiency and make these molecules very good candidates for future effective antimalarial drugs.

Synthesis, Antimicrobial Evaluation and Molecular Docking of Some Potential 2,6-disubstituted 1H-Benzimidazoles; Non-Classical Antifolates.

Dihydrofolate reductase is one of the important enzymes for thymidylate and purine synthesis in micro-organisms. A large number of drugs have been designed to inhibit microbial DHFR but over the period of time, some drugs have developed resistance and cross reactivity towards the enzyme. Over the past few decades, benzimidazoles, triazoles and their derivatives have been grabbing the attention of the synthetic chemists for their wide gamut of antibacterial and antifungal activities targeting microbial protein DHFR. Our goal behind present investigation is to explore benzimidazoles class of drugs as microbial DHFR inhibitors by studying ligand-receptor binding interactions, in vitro enzyme inhibition assay and confirmation of anti-microbial activity against selected pathogenic microorganisms. A library containing thirty novel 2,6-disubstituted 1H-benzimidazoles was synthesized by one pot condensation of o-nitro aniline or 2,4-dinitro aniline with series of aldehydes or acetophenones using Na2S2O4 or SnCl2 respectively and reflux for 5-6hr. Structures of compounds have been confirmed by spectroscopic methods as 1H and 13C NMR, FT-IR and MS. In vitro DHFR inhibition study was performed by using Epoch microplate reader and IC50 of the test compounds was compared with Trimethoprim. In vitro antimicrobial activity was performed against selected clinical pathogens by agar disk diffusion method and MIC (µg/mL) was reported. Moderate to good level of DHFR inhibition was observed with IC50 values in the range of 7-23 µM. Compounds B1, B19, B22, B24 and B30 expressed 1.1 to 1.4 folds more prominent DHFR inhibitory activity as compared to standard Trimethoprim. Remarkable antimicrobial activity was exhibited by B1, B19, B22, B24 and B30. Molecular docking study revealed perfect binding of test ligands with key amino acids of DHFR as Phe31, Ile94, Ile5, Asp27, Gln32 and Phe36. Nature of 1H-benzimidazole substituents at position 2 and 6 had influence over magnitude and type of molecular binding and variation in the biological activity. The present series of 1H-benzimidazoles could be considered promising broad-spectrum antimicrobial candidates that deserve in future for preclinical antimicrobial evaluation and development of newer antimicrobial agents targeting microbial DHFR.