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Background: Many compounds containing a five-membered heterocyclic ring display exceptional chemical properties and versatile biological activities. Objective: The objective of the present study was to prepare the 5-substituted 2-amino-1,3,4- oxadiazole and 2-amino-1,3,4-thiadiazole derivatives and evaluate their potential anticancer, antibacterial and antifungal activities. Methods: Twenty-seven derivatives were synthesized by iodine-mediated cyclization of semicarbazones or thiosemicarbazones obtained from condensation of semicarbazide or thiosemicarbazide and aldehydes. The structures were confirmed by 1H-NMR, 13C-NMR and MS spectra. The antibacterial and antifungal activities were evaluated by diffusion method and the anticancer activities were evaluated by MTT assay. Results: Twenty-seven derivatives have been synthesized in moderate to good yields. A number of derivatives exhibited potential antibacterial, antifungal and anticancer activities. Conclusion: Compounds (1b, 1e and 1g) showed antibacterial activity against Streptococcus faecalis, MSSA and MRSA with MIC value ranging between 4 to 64 μg/mL. Compound (2g) showed antifungal activity against Candida albicans (8 μg/mL) and Aspergillus niger (64 μg/mL). Compound (1o) exhibited high cytotoxic activity against HepG2 cell line (IC50 value 8.6 μM) which is comparable to the activity of paclitaxel, and is non-toxic on LLC-PK1 normal cell line. The structure activity relationship and molecular docking study of the synthesized compounds have also been reported.

Background: Integrase enzyme is a validated drug target to discover novel structures as anti-HIV-1 agents. Objective: This study aimed at developing a novel series of thioimidazolyl diketoacid derivatives characterizing various substituents at N-1 and 2-thio positions of the central ring as HIV-1integrase inhibitors. Methods: In this study, eighteen novel thioimidazolyl DKA derivatives were synthesized in a fivestep parallel procedure and tested in vitro for the inhibition of both IN ST reaction and the singlecycle HIV-1 replication in HeLa cell culture. Results: The obtained molecules were evaluated using the enzyme assay, displaying promising integrase inhibitory activity with IC50 values ranging from 0.9 to 7.7 mM. The synthesized compounds were also tested for antiviral activity and cytotoxicity using HeLa cells infected by the single-cycle replicable HIV-1 NL4-3. Conclusion: The most potent compound was found to be 18i with EC50 = 19 μM, IC50 = 0.9 μM, and SI = 10.5. Docking studies indicated that the binding mode of the active molecule is well aligned with the known HIV-1integrase inhibitor.

Histone acetylation balance is one epigenetic mechanism controlling gene expression associated with disease progression. It has been observed that histone deacetylase 10 (HDAC-10) isozyme contributes to the chemotherapy resistance; in addition, the poor clinical outcome observed in patients with aggressive solid tumors, such as neuroblastoma, has been associated with its overexpression. Moreover, HDAC-10 selective inhibition suppresses the autophagic response, thus providing an improved risk-benefit profile compared to cytotoxic cancer chemotherapy drugs. On these bases, HDAC-10 is becoming an emerging target for drug design. Due to the rapid progress in the development of next-generation HDAC inhibitors, this review article aims to provide an overview on novel selective or dual HDAC-8/10 inhibitors, as new leads for cancer chemotherapy, able to avoid the severe side-effects of several actual approved “pan” HDAC inhibitors. A literature search was conducted in MedLine, PubMed, Caplus, SciFinder Scholar databases from 2015 to the present. Since the disclosure that the HDAC-6 inhibitor Tubastatin A was able to bind HDAC-10 efficiently, several related analogues were synthesized and tested. Both tricyclic (25-30) and bicyclic (31-42) derivatives were considered. The best pharmacological profile was shown by 36 (HDAC-10 pIC50 = 8.4 and pIC50 towards Class I HDACs from 5.2–6.4). In parallel, based on the evidence that high levels of HDAC-8 are a marker of poor prognosis in neuroblastoma treatment, dual HDAC-8/10 inhibitors were designed. The hydroxamic acid TH34 (HDAC-8 and 10 IC50 = 1.9 µM and 7.7 µM, respectively) and the hybrid derivatives 46d, 46e and 46g were the most promising both in terms of potency and selectivity. Literature surveys indicate several structural requirements for inhibitory potency and selectivity towards HDAC-10, e.g., electrostatic and/or hydrogen bond interactions with E274 and complementarity to the P(E,A) CE motif helix.

Background: Smokeless tobacco (SLT) is traditionally used in Middle East countries. The several toxic constituents with potential carcinogenicity make it a serious human health risk. Literature regarding their effects on cardiac and cancer disease is lacking in Saudi Arabia. Objective: This study was conducted to investigate the adverse effect of 11 different samples of widely used SLT varieties from the Tabuk region - Saudi Arabia, on Nitric Oxide (NO) level and their potential risk on cardiovascular health, etiology and/or progression of cancers. Methods: Samples were collected from Tabuk, KSA and analyzed by the GC-MS technique. Nitric oxide inhibition was performed using J774.2 macrophages by the Griess method. The retrieved crystallized structure of human inducible nitric oxide synthase (iNOS) from Brookhaven Protein Data Bank Repository PDB I.D: 3E7G with 2.20Å resolution was further prepared by structure using the MOE.2019 tool. The compounds abstracted from 11 different Shammah varieties were sketched by the MOE-Builder tool. Minimization for both receptor and compounds was performed via AMBER99 and MMFF99X force field implemented in MOE. Results: Nine samples (4 - 11) showed a potent suppressive effect on NO production with IC50 values ranging between (16.9-20.4 μg/mL), respectively. The samples (1 & 2) exhibited a moderate level of inhibition with IC50 ranging between 33.2 and 57.4 μg/mL, respectively. Interestingly, sample 4 consisting of compounds (13-15, 19-26, 28) that mostly belongs to the group fatty acid ester and phthalic acid ester showed the most potent suppressive effect. Molecular docking results revealed that the current local SLT constituents presented noticeable potency in different extract samples. Conclusion: Variable suppressive effects on NO were detected in the current SLT samples, where sample 4 was the most potent among all. The extract of the latter exhibited molecular interaction with the first shell amino acid residues of Inducible nitric oxide synthase (iNOS), which may anchor the plasticity and selectivity of the compounds present in it. The samples (4 -11) showed a potent inhibitory effect on the NO, where compound 26 (Phthalic acid ester) is common, and its adequate concentration may account for augmented biological activity. These results may effectively highlight their adverse effects on cardiovascular health and etiology and/or progression of cancer and may help in strengthening the social and governmental efforts in minimizing the use of these substances.

Red blood cell (RBC) was an excellent choice for cell preparation research because of their biocompatibility, high drug loading, and long half-life. In this study, doxorubicin (DOX) was encapsulated with red blood cells as the carrier. The biotin-avidin system binding principle was used to modify biotinylated cyclic arginine-glycine-aspartic acid (cRGD) onto red blood cell surfaces for accurate targeting, high drug loading, and sustained drug release. The red blood cell drug delivery system (DDS) was characterized, and the concentration of surface sulfur in the energy spectrum was 6.330%. The physical and chemical properties of red blood cell DDS were as follows: drug content, 0.857 mg/mL; particle size, 3,339 nm; potential value, -12.5 mV; and cumulative release rate, 81.35%. There was no significant change in red blood cell morphology for up to seven days. The results of the targeting and cytotoxicity studies of red blood cell DDS showed that many red blood cells covered the surfaces of U251 cells, and the fluorescence intensity was higher than that of MCF-7 cells. The IC50 value of unmodified drug-loaded red blood cells was 2.5 times higher than that of targeted modified drug-loaded red blood cells, indicating that the targeting of cancer cells produced satisfactory inhibition. This study confirms that the red blood cell DDS has the characteristics of accurate targeting, high drug loading, and slow drug release, which increases its likelihood of becoming a clinical cancer treatment in the future.

Coronaviruses have caused worldwide outbreaks in different periods. SARS (severe acute respiratory syndrome) was the first emerged virus from this family, followed by MERS (Middle East respiratory syndrome) and SARS-CoV-2 (2019-nCoV or COVID 19), which is newly emerged. Many studies have been conducted on the application of chemical and natural drugs for treating these coronaviruses and they are mostly focused on inhibiting the proteases of viruses or blocking their protein receptors through binding to amino acid residues. Among many substances which are introduced to have an inhibitory effect against coronaviruses through the mentioned pathways, natural components are of specific interest. Secondary and primary metabolites from plants, are considered as potential drugs to have an inhibitory effect on coronaviruses. IC50 value (the concentration in which there is 50% loss in enzyme activity), molecular docking score and binding energy are parameters to understand the ability of metabolites to inhibit the specific virus. In this study we reviewed 154 papers on the effect of plant metabolites on different coronaviruses and data of their IC50 values, molecular docking scores and inhibition percentages are collected in tables. Secondary plant metabolites such as polyphenol, alkaloids, terpenoids, organosulfur compounds, saponins and saikosaponins, lectins, essential oil, and nicotianamine, and primary metabolites such as vitamins are included in this study.

Solanum nudum Dunal (Solanaceae) is most commonly known and used by the population of the colombian Pacific coast as an antimalarial treatment. This article study into optimization and quantitative analysis of compounds steroidal over time of development of this species when grown in vitro and wild. A new steroidal compound named SN6 was elucidated by NMR and a new method of quantification of seven steroidal compounds (Diosgenone DONA and six steroids SNs) using HPLC-DAD-MS in extracts of cultures in vitro and wild was investigated. Biology activity of extracts was found to a range of antiplasmodial activity in FCB2 and NF-54 with inhibitory concentration (IC50) between (17.04 -100 μg/mL) and cytotoxicity in U-937 of CC50 (7.18 -104.7 μg/mL). This method creates the basis for the detection of seven sterols antiplasmodial present in extracts from S. nudum plant as a quality parameter in the control and expression of phytochemicals.

Chemical investigation of the culture extract of an endophytic Penicillium citrinum from Dendrobium officinale, afforded nine citrinin derivatives ( 1 – 9 ) and a peptide-polyketide hybrid GKK1032B ( 10 ). The structures of these compounds were determined on the basis of spectroscopic methods. The absolute configurations of 1 and 2 were determined for the first time by calculations of electronic circular dichroism (ECD) data. Among them, GKK1032B ( 10 ) showed significant cytotoxicity against human osteosarcoma cell line MG63 with an IC50 value of 3.49 μmol·L–1, and a primary mechanistic study revealed that it induced the apoptosis of MG63 cells via caspase pathway.

Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) induced cytokine storm is the major cause of COVID-19 related deaths. Patients have been treated with drugs that work by inhibiting a specific protein partly responsible for the cytokines production. This approach provided very limited success, since there are multiple proteins involved in the complex cell signaling disease mechanisms. We targeted five proteins: Angiotensin II receptor type 1 (AT1R), A disintegrin and metalloprotease 17 (ADAM17), Nuclear Factor‑Kappa B (NF‑κB), Janus kinase 1 (JAK1) and Signal Transducer and Activator of Transcription 3 (STAT3), which are involved in the SARS‑CoV‑2 induced cytokine storm pathway. We developed machine-learning (ML) models for these five proteins, using known active inhibitors. After developing the model for each of these proteins, FDA-approved drugs were screened to find novel therapeutics for COVID‑19. We identified twenty drugs that are active for four proteins with predicted scores greater than 0.8 and eight drugs active for all five proteins with predicted scores over 0.85. Mitomycin C is the most active drug across all five proteins with an average prediction score of 0.886. For further validation of these results, we used the PyRx software to conduct protein-ligand docking experiments and calculated the binding affinity. The docking results support findings by the ML model. This research study predicted that several drugs can target multiple proteins simultaneously in cytokine storm-related pathway. These may be useful drugs to treat patients because these therapies can fight cytokine storm caused by the virus at multiple points of inhibition, leading to synergistically effective treatments.

Aim: : The aim of our research work is the synthesis of tetrahydroisoquinoline derivatives as anti-Angiogenesis and anti-cancer agents. Background: : Cancer is the second leading cause of deaths in United States. The current recovery rate from the advanced treatment for the cancer is unacceptably low. Therefore, identification of novel, potent and less toxic anticancer agents remains a top priority. Objective: To 1) evaluate anti-angiogenesis, anticancer activities of THIQs on different colorectal cancer cell lines (CRC) viz., Colo320, DLD-1, HCT116, SNU-C1, SW480 and GSK3b in pre-treated viability HCT116. 2) Undertake molecular docking studies of THIQs. Methods: Twenty synthesized THIQs were screened in the Eli Lilly’s Open Innovation Drug Discovery Program and selected twelve compounds for in vitro primary screening in the KRas (Kirsten rat sarcoma)-Wnt SL (Synthetic Lethal) in the basal viability of different colon cancer cell lines. Docking studies of the active THIQs were also performed in our laboratory, targeting the active sites of KRas and VEGF receptors. Results: Compound GM-3-18 was found to possess significant activities for KRas inhibition, with IC50 values in the range of 0.9 μM to 10.7 μM, for all colon cancer cell lines. Compound GM-3-121 showed potent anti-angiogenesis activity with IC50 = 1.72 μM. Molecular docking studies showed that the carbonyl oxygen atoms of GM-3-18 and GM-3-121 showed hydrogen bonding interactions with the hydrogen of - OH groups of THR 74 (A). Conclusion: The results indicated that all the compounds showed moderate to high activity for KRas inhibition. The THIQs bearing the chloro group at the 4-position of the phenyl ring (GM-3-18) exhibited significant KRas inhibition against all colon cancer cell lines.

Indoleamine 2,3-dioxygenase-1 (IDO1) plays an important role in tumor immune escape. However, unsatisfactory clinical efficacies of selective IDO1 inhibitors have impeded their further development, suggesting that they do not exert sufficient antitumor effects by selectively inhibiting IDO1. IDO2, an isoenzyme of IDO1, is overexpressed in some human tumors, and emerging evidence suggests that concomitant inhibition of IDO1/2 may have synergistic effects in cancer treatment, revealing a promising cancer immunotherapeutic strategy. Herein, we describe the discovery of compound 4t, the first inhibitor targeting both IDO1/2 that has excellent in vitro inhibitory activity (IDO1 IC50 = 28 nM and IDO2 IC50 = 144 nM). Notably, 4t (TGI = 69.7%) exhibited significantly stronger in vivo antitumor potency than epacadostat (TGI = 49.4%) in CT26 xenograft mouse models, highlighting the advantages of IDO1/2 dual inhibitors for tumor immunotherapy. Preliminary mechanistic studies in vivo further identified that 4t exerts its antitumor effect by inhibiting IDO1/2.

Evodiamine (Evo) is a quinazolinocarboline alkaloid found in Evodia rutaecarpa and exhibits moderate antiproliferative activity. Herein, we report using a scaffold-hopping approach to identify a series of novel polycyclic heterocyclic derivatives based on Evo as the topoisomerase I (Top1) inhibitor for the treatment of triple-negative breast cancer (TNBC), which is an aggressive subtype of breast cancer with limited treatment options. The most potent compound 7f inhibited cell growth in a human breast carcinoma cell line (MDA-MB-231) with an IC50 value of 0.36 μM. Further studies revealed that Top1 was the target of 7f, which directly induced irreversible Top1-DNA covalent complex formation or induced an oxidative DNA lesion through an indirect mechanism mediated by reactive oxygen species. More importantly, in vivo studies showed that 7f exhibited potent antitumor activity in a TNBC-patient-derived tumor xenograft model. These results suggest that compound 7f deserves further investigation as a promising candidate for the treatment of TNBC.

Naegleria fowleri is the protozoan pathogen that causes primary amoebic meningoencephalitis (PAM), with the death rate exceeding 97%. The amoeba makes sterols and can be targeted by sterol biosynthesis inhibitors. Here, we characterized N. fowleri sterol 14-demethylase, including catalytic properties and inhibition by clinical antifungal drugs and experimental substituted azoles with favorable pharmacokinetics and low toxicity. None of them inhibited the enzyme stoichiometrically. The highest potencies were displayed by posaconazole (IC50 = 0.69 μM) and two of our compounds (IC50 = 1.3 and 0.35 μM). Because both these compounds penetrate the brain with concentrations reaching minimal inhibitory concentration (MIC) values in an N. fowleri cellular assay, we report them as potential drug candidates for PAM. The 2.1 A crystal structure, in complex with the strongest inhibitor, provides an explanation connecting the enzyme weaker substrate specificity with lower sensitivity to inhibition. It also provides insight into the enzyme/ligand molecular recognition process and suggests directions for the design of more potent inhibitors.

Alterations of discoidin domain receptor1 (DDR1) may lead to increased production of inflammatory cytokines, making DDR1 an attractive target for inflammatory bowel disease (IBD) therapy. A scaffold-based molecular design workflow was established and performed by integrating a deep generative model, kinase selectivity screening and molecular docking, leading to a novel DDR1 inhibitor compound 2, which showed potent DDR1 inhibition profile (IC50 = 10.6 ± 1.9 nM) and excellent selectivity against a panel of 430 kinases (S (10) = 0.002 at 0.1 μM). Compound 2 potently inhibited the expression of pro-inflammatory cytokines and DDR1 autophosphorylation in cells, and it also demonstrated promising oral therapeutic effect in a dextran sulfate sodium (DSS)-induced mouse colitis model.

Androgen receptor (AR) has proved to be a vital drug target for treating prostate cancer. Here, we reported the discovery of a novel AR antagonist 92 targeting the AR ligand-binding pocket, but distinct from the marketed drug enzalutamide (Enz), 92 demonstrated inhibition on the AR ligand-binding domain (LBD) dimerization, which is a novel mechanism reported for the first time. First, a novel hit (26, IC50 = 5.57 μM) was identified through virtual screening based on a theoretical AR LBD dimer bound with the Enz model. Then, guided by molecular modeling, 92 was discovered with 32.7-fold improved AR antagonistic activity (IC50 = 0.17 μM). Besides showing high bioactivity and safety, 92 can inhibit AR nuclear translocation. Furthermore, 92 inhibited the formation of the AR LBD dimer, possibly through attenuating the hydrogen-bonding network between the two monomers. This interesting finding would pave the way for the discovery of a new class of AR antagonists.

Highly fluorinated candidates containing anticancer pharmacophores like thiosemicarbazone (5a-e) and its cyclic analogues hydrazineylidenethiazolidine (6a-e), 2-aminothiadiazole (7a-e), and 2-hydrazineylidenethiazolidin-4-one (8a-e) were synthesized, and their cytotoxic activity was assayed against 60 tumor cell lines. Compounds 6c, 7b, and 8b displayed the most potent activity with lower toxic effects on MCF-10a. In vitro phosphatidylinositol 3-kinase (PI3K) enzyme inhibition was performed. Compound 6c displayed half-maximal inhibitory concentration (IC50, μM) values of 5.8, 2.3, and 7.9; compound 7b displayed IC50 values of 19.4, 30.7, and 73.7; and compound 8b displayed IC50 values of 77.5, 53.5, and 121.3 for PI3Kα, β, and δ, respectively. Moreover, cell cycle progression caused cell cycle arrest at the S phase for compounds 6c and 8b and at G1/S for compound 7b, while apoptosis was induced. In silico studies; molecular docking; physicochemical parameters; and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis were performed. The results showed that compound 6c is the most potent one with a selectivity index (SI) of 39 and is considered as a latent lead for further optimization of anticancer agents.

Adenosine is an immunosuppressive factor in the tumor microenvironment mainly through activation of the A2A adenosine receptor (A2AR), which is a mechanism hijacked by tumors to escape immune surveillance. Small-molecule A2AR antagonists are being evaluated in clinical trials as immunotherapeutic agents, but their efficacy is limited as standalone therapies. To enhance the antitumor effects of A2AR antagonists, dual-acting compounds incorporating A2AR antagonism and histone deacetylase (HDAC) inhibitory actions were designed and synthesized, based on co-crystal structures of A2AR. Compound 24e (IHCH-3064) exhibited potent binding to A2AR (Ki = 2.2 nM) and selective inhibition of HDAC1 (IC50 = 80.2 nM), with good antiproliferative activity against tumor cell lines in vitro. Intraperitoneal administration of 24e (60 mg/kg, bid) inhibited mouse MC38 tumor growth with a tumor growth inhibition rate of 95.3%. These results showed that dual-acting compounds targeting A2AR and HDAC are potentially immunotherapeutic agents that are worth further exploring.

Blockade of immune checkpoint PD-1/PD-L1 has been a promising anticancer strategy; however, clinically available PD-1/PD-L1 small-molecule inhibitors are lacking. In view of the high potency of compound 2 (BMS-1002), structural fine tuning of the methoxy linkage together with diverse modification in the solvent interaction region was conducted. A series of novel derivatives featuring a difluoromethyleneoxy linkage were designed. Compound 43 was identified as the most promising PD-1/PD-L1 inhibitor with an IC50 value of 10.2 nM in the HTRF assay. This compound is capable of promoting CD8+ T cell activation through inhibiting PD-1/PD-L1 cellular signaling. Moreover, in the Hepa1-6 syngeneic mouse model, administration of compound 43 at 1 mg/kg dosage promoted CD8+ T cell activation and delayed the tumor growth with good tolerance. Notably, the tumor in one mouse of the compound 43-treated group was completely regressed. These results indicate that compound 43 is a promising candidate worthy of further investigation.

One new citrinin monomer derivative (1), and two new natural products α-pyrone analogues (2a and 2b), were isolated from the sponge derived fungus Penicillium sp. SCSIO 41302. Their structures were determined by extensive spectroscopic analysis, chiral-phase HPLC analysis, modified Mosher's method, ECD calculations, and X-ray single-crystal diffraction. Bioactivity screening showed that compounds 2b and 8 exhibited obvious inhibitory activities against pancreatic lipase and acetyl cholinesterase with IC50 values of 48.5 and 4.8 μM, respectively, which indicated that different chiral center between enantiomers (2a and 2b) might result in different biological activities (IC50 value against PL for 2a >100 μg/ml).

Inhibiting PARP-1/2 offered an important arsenal for cancer treatments via interfering with DNA repair of cancer cells. Novel PARP-1/2 inhibitors were designed by capitalizing on methyl- or ethyl-substituted piperizine ring to capture the characteristics of adenine-ribose binding site (AD site), and their unique binding features were revealed by the cocrystal structures of compounds 4 and 6 in PARP-1. The investigation on structure-activity relationship resulted in compounds 24 and 32 with high enzymatic potency, binding selectivity, and significantly longer residence time for PARP-1 over PARP-2 (compound 24, PARP-1: IC50 = 0.51 nM, PARP-2: IC50 = 23.11 nM; compound 32, PARP-1: IC50 = 1.31 nM, PARP-2: IC50 = 15.63 nM). Furthermore, compound 24 was determined to be an attractive candidate molecule, which possessed an acceptable pharmacokinetic profile and produced remarkable antitumor activity in both breast cancer xenograft model and glioblastoma orthotopic model in mice, either alone or in combination treatment.

Inhibiting the polarization or survival of tumor-associated macrophages through blocking CSF-1/CSF-1R signal transduction has become a promising strategy for cancer immunotherapy. Herein, a series of (Z)-1-(3-((1H-pyrrol-2-yl)methylene)-2-oxoindolin-6-yl)-3-(isoxazol-3-yl)urea derivatives were designed, synthesized, and evaluated as novel and orally highly effective CSF-1R inhibitors for colorectal cancer immunotherapy. Among these derivatives, compound 21 was found to possess excellent CSF-1R inhibitory activity (IC50 = 2.1 nM) and potent antiproliferative activity against colorectal cancer cells. Compound 21 inhibited the progression of colorectal cancer by suppressing the migration of macrophages, reprograming M2-like macrophages to the M1 phenotype, and enhancing the antitumor immunity. More importantly, compound 21, as a single agent, showed significantly superior in vivo anticolorectal cancer efficacy over PLX3397, highlighting a promising candidate for the immunotherapy of colorectal cancer.

The important role of Red Blood Cells (RBCs) is to transport oxygen to the tissues from the lungs to provide oxygen to all cells. During circulation, RBCs are continuously exposed to both endogenous and exogenous sources of reactive oxygen species (ROS) that can injury the RBC and ruin its function. The imbalance between cellular production of reactive oxygen species and the counteracting antioxidant mechanism leads to Oxidative stress. Flavonoids are low molecular weight secondary polyphenolic metabolites present in plants characterized by their flavan nucleus. Rutin is a flavonol plentiful in a variety of commonly ingested foods. The term ‘Rutin’ came from a plant known as Ruta graveolens that also encompasses Rutin. Teas and fruits have high concentration of Rutin. Buckwheat seeds (Fagopyrum esculantum) are the richest source. Rutin protects the body from cellular damage caused by free radicals with its antioxidant properties. It helps to eliminate cholesterol from the body and increase elasticity of the arterial walls, which in turn promotes greater blood flow. The present investigation was aimed to assess the antihemolytic activity of the Rutin using phenyl hydrazine as hemolysin. This study uses RBC as model system to access the anti-hemolytic activity of Rutin using phenyl hydrazine as hemolysin. Phenyl hydrazine which was used previously in treating sickle cell anemia was used in this investigation as hemolysin. The result of the study shows that the addition of phenyl hydrazine [1-500 μg/ml] to the RBC suspension caused significant (P

Context The interaction between nobiletin and anemarsaponin BII could affect the pharmacological activity of these two drugs during their combination. Objective The co-administration of nobiletin and anemarsaponin BII was investigated to explore the interaction and the potential mechanism. Materials and methods Male Sprague-Dawley rats were only orally administrated with 50 mg/kg nobiletin as the control and another six rats were pre-treated with 100 mg/kg anemarsaponin BII for 7 d followed by the administration of nobiletin. The transport and metabolic stability of nobiletin were evaluated in vitro, and the effect of anemarsaponin BII on the activity of CYP3A4 was also assessed to explore the potential mechanism underlying the interaction. Results The increasing Cmax (2309.67 ± 68.06 μg/L vs. 1767.67 ± 68.86 μg/L), AUC (28.84 ± 1.34 mg/L × h vs. 19.57 ± 2.76 mg/L × h), prolonged t1/2 (9.80 ± 2.33 h vs. 6.24 ± 1.53 h), and decreased clearance rate (1.46 ± 0.26 vs. 2.42 ± 0.40) of nobilein was observed in rats. Anemarsaponin BII significantly enhanced the metabolic stability of nobiletin in rat liver microsomes (half-life increased from 31.56 min to 39.44 min) and suppressed the transport of nobiletin in Caco-2 cells (efflux rate decreased from 1.57 ± 0.04 to 1.30 ± 0.03). The inhibitory effect of anemarsaponin BII on CYP3A4 was also found with an IC50 value of 10.23 μM. Discussion and conclusions The interaction between anemarsaponin BII and nobiletin was induced by the inhibition of CYP3A4, which should draw special attention in their clinical co-administration.

Background: Santacruzamate A (SCA) is a natural product isolated from a marine cyanobacterium. Activity test results revealed that SCA is a highly potent HDAC2 inhibitor with an IC50 value of 0.112 nM. The IC50 of SCA in inhibiting cancer cell proliferation is 28.3 μM and 1.3μM on HCT116 and HuT-78 cells, respectively. Objective: To develop HDAC inhibitors with improved activity, SCA analogs were synthesized for the structure-activity relationship (SAR) studies. Method: Various substituted groups were introduced into the zinc binging group, linker, and cap regions of SCA by various chemical synthetic methods. Result: Compared with SCA, the derivatives of SCA did not exhibit improved HDAC2 inhibitory activity. Nevertheless, several molecules such as III-32, III-33, IV-4b, and IV-11 showed improved activity in inhibiting cell proliferation on HCT116 and HuT-78 cells. Conclusion: Collectively, a potent HDAC2 inhibitor SCA was discovered as a lead compound for further development of selective HDAC inhibitors.

Targeting P-glycoprotein (ABCB1 or P-gp) has been recognized as a promising strategy to overcome multidrug resistance. Here, we reported our medicinal chemistry efforts that led to the discovery of the triazolo[1,5-a]pyrimidine derivative WS-898 as a highly effective ABCB1 inhibitor capable of reversing paclitaxel (PTX) resistance in drug-resistant SW620/Ad300, KB-C2, and HEK293/ABCB1 cells (IC50 = 5.0, 3.67, and 3.68 nM, respectively), more potent than verapamil and zosuquidar. WS-898 inhibited the efflux function of ABCB1, thus leading to decreased efflux and increased intracellular PTX concentration in SW620/Ad300 cells. The cellular thermal shift assay indicated direct engagement of WS-898 to ABCB1. Furthermore, WS-898 stimulated the ATPase activity of ABCB1 but had minimal effects on cytochrome P450 3A4 (CYP3A4). Importantly, WS-898 increased PTX sensitization in vivo without obvious toxicity. The results suggest that WS-898 is a highly effective triazolo[1,5-a]pyrimidine-based ABCB1 inhibitor and shows promise in reversing ABCB1-mediated PTX resistance.

Background: 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. Objective: A series of N-monosubstituted aroylthioureas were designed and synthesized for evaluation as urease inhibitors. Methods: 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. Results: 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. Conclusion: 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.

Eight new substituted spiro-1,2,4,5-tetraoxane derivatives were synthesized and characterized by a number of analytical and spectroscopic techniques. The molecules were subsequently screened for in vitro antimalarial activity against chloroquine sensitive (3D7) and chloroquine resistant (RKL-9) strains of Plasmodium falciparum. These substituted spiro-1,2,4,5-tetraoxane derivatives were studied by molecular docking analysis in the active site of Falcipain-2 as a putative protein. Most of the synthesized compounds exhibited moderate to very good activity toward the parasite in comparison to the standard drug, chloroquine. Three compounds showed potent antimalarial activity against chloroquine sensitive strain of P. falciparum (3D7). One compound 5b (3-ethyl-3-methyl-1,2,4,5-tetraoxa-spiro[5.5]undecane) showed a very good activity against both chloroquine sensitive strain (3D7) with MIC = 1.95 ± 0.06 μg/mL and IC50 = 1.95 ± 0.06 μg/mL compared to chloroquine (MIC = 0.4 ± 0.10 μg/mL, IC50 = 0.04 ± 0.01 μg/mL) as well as chloroquine-resistant strain of P. falciparum (RKL-9) with MIC = 15.63 ± 0.70 μg/mL and IC50 = 3.90 ± 0.09 μg/mL compared to chloroquine (MIC = 25.00 ± 0.20 μg/mL, IC50 = 0.39 ± 0.02 μg/mL). The top scored compounds having low binding energy interact with the active site of Falcipain-2 in molecular docking studies.

The fruits of Eucalyptus globulus Labill. are known to have a plenty of medicinal properties, such as anti-tumor, anti-inflammatory, and immunosuppressive activity. Our previous study found that the phloroglucinol-sesquiterpene adducts in the fruits of E. globulus were immunosuppressive active constituents, especially Eucalyptin C (EuC). Phosphoinositide 3-kinases-γ (PI3Kγ) plays a pivotal role in T cell mediated excessive immune responses. In this study, EuC was first discovered to be a novel selective PI3Kγ inhibitor with an IC50 value of 0.9 μmol·L-1 and selectivity over 40-fold towards the other PI3K isoforms. Molecular docking, molecular dynamics simulation, and cellular thermal shift assay showed that EuC bound to PI3Kγ. Furthermore, EuC suppressed the downstream of PI3Kγ to induce the apoptosis and inhibit the activation of primary spleen cells derived from allergic contact dermatitis mice. This work highlights the role of the fruits of E. globulus as a source of bioactive plant with immunosuppressive activity.

Positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA) with gallium-68 (68Ga) and fluorine-18 (18F) radiotracers has aroused tremendous interest over the past few years. The use of organosilicon-[18F]fluoride acceptors (SiFA) conjugated to urea-based peptidomimetic PSMA inhibitors provides a "kit-like" multidose synthesis technology. Nine novel 18F-labeled SiFA-bearing PSMA inhibitors with different linker moieties were synthesized and analyzed for their in vitro binding against [125I]I-TAAG-PSMA in LNCaP cells. IC50 values ranged from 58-570 nM. Among all compounds, [18F]SiFA-Asp2-PEG3-PSMA (IC50 = 125 nM) showed the highest tumor uptake in LNCaP tumors (SUV60min 0.73). A substantial increase in molar activity (Am) (from 7.5 ± 0.5 to 86 ± 3 GBq/μmol) led to a significant increase in LNCaP tumor uptake (SUV60min 1.18; Δ 0.45 corresponding to +62%). In vivo blocking with DCFPyL resulted in -32% uptake after 60 min. The SiFA-isotopic exchange chemistry offers a method that is readily adaptable for a "kit-type" labeling procedure and clinical translation.

[Image: see text] A series of 1,3,4-oxadiazole tethered capsaicin derivatives was prepared by using one point modification at the vanillyl-hydroxyl group of capsaicin. All the prepared capsaicinoids were evaluated for their antiproliferative activity against NCI-60 human cancer cell lines at 10 μM. Among the compounds tested, compound 20a exhibited good cytotoxic activity against HCT-116, NCI-H460, and SKOV3 cell lines with IC(50) 8.55 μΜ, 5.41 μΜ, and 6.4 μΜ, respectively, compared to the parent natural product capsaicin. Further on, it significantly inhibited the colony formation in NCI-H460 in a dose dependent manner and enhanced the ROS effect. It also caused cell arrest at the S phase and induced apoptosis via suppressing the Pro parp marker. Compound 20a exhibited an antimigratory property and suppressed the expression of the VEGF marker in a dose dependent manner. Furthermore, compound 20a also suppressed the effects of the p-Erk, p-p38, and P-CNA makers. In silico studies supported the interaction of this class of compounds with the VEGFR2 protein.

MGAT2 inhibition is a potential therapeutic approach for the treatment of metabolic disorders. High-throughput screening of the BMS internal compound collection identified the aryl dihydropyridinone compound 1 (hMGAT2 IC50 = 175 nM) as a hit. Compound 1 had moderate potency against human MGAT2, was inactive vs mouse MGAT2 and had poor microsomal metabolic stability. A novel chemistry route was developed to synthesize aryl dihydropyridinone analogs to explore structure-activity relationship around this hit, leading to the discovery of potent and selective MGAT2 inhibitors 21f, 21s, and 28e that are stable to liver microsomal metabolism. After triaging out 21f due to its inferior in vivo potency, pharmacokinetics, and structure-based liabilities and tetrazole 28e due to its inferior channel liability profile, 21s (BMS-963272) was selected as the clinical candidate following demonstration of on-target weight loss efficacy in the diet-induced obese mouse model and an acceptable safety and tolerability profile in multiple preclinical species.

A simple methylenedioxy dibromoindole alkaloid, amakusamine (1), was isolated from a marine sponge of the genus Psammocinia, and its structure was determined from spectroscopic data, time-dependent density-functional theory calculations, and synthesis. Compound 1 inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced formation of multinuclear osteoclasts with an IC50 value of 10.5 μM in RAW264 cells. The structure-activity relationship of 1 was also investigated with synthetic derivatives.

Embryonic ectoderm development (EED) is a promising therapeutic target for human cancers and other diseases. We report herein the discovery of exceptionally potent and efficacious EED inhibitors. By conformational restriction of a previously reported EED inhibitor, we obtained a potent lead compound. Further optimization of the lead yielded exceptionally potent EED inhibitors. The best compound EEDi-5273 binds to EED with an IC(50) value of 0.2 nM and inhibits the KARPAS422 cell growth with an IC(50) value of 1.2 nM. It demonstrates an excellent PK and ADME profile, and its oral administration leads to complete and persistent tumor regression in the KARPAS422 xenograft model with no signs of toxicity. Co-crystal structures of two potent EED inhibitors with EED provide a solid structural basis for their high-affinity binding. EEDi-5273 is a promising EED inhibitor for further advanced preclinical development for the treatment of human cancer and other human diseases.

We synthesize various substituted triazole-containing flavonoids and identify potent, nontoxic, and highly selective BCRP inhibitors. Ac18Az8, Ac32Az19, and Ac36Az9 possess m-methoxycarbonylbenzyloxy substitution at C-3 of the flavone moiety and substituted triazole at C-4' of the B-ring. They show low toxicity (IC50 toward L929 > 100 μM), potent BCRP-inhibitory activity (EC50 = 1-15 nM), and high BCRP selectivity (BCRP selectivity over MRP1 and P-gp > 67-714). They inhibit the efflux activity of BCRP, elevate the intracellular drug accumulation, and restore the drug sensitivity of BCRP-overexpressing cells. Like Ko143, Ac32Az19 remarkably exhibits a 100% 5D3 shift, indicating that it can bind and cause a conformational change of BCRP. Moreover, it significantly reduces the abundance of functional BCRP dimers/oligomers by half to retain more mitoxantrone in the BCRP-overexpressing cell line and that may account for its inhibitory activity. They are promising candidates to be developed into combination therapy to overcome MDR cancers with BCRP overexpression.

Colony-stimulating factor-1 receptor (CSF1R) is implicated in tumor-associated macrophage (TAM) repolarization and has emerged as a promising target for cancer immunotherapy. Herein, we describe the discovery of orally active and selective CSF1R inhibitors by property-driven optimization of BPR1K871 (9), our clinical multitargeting kinase inhibitor. Molecular docking revealed an additional nonclassical hydrogen-bonding (NCHB) interaction between the unique 7-aminoquinazoline scaffold and the CSF1R hinge region, contributing to CSF1R potency enhancement. Structural studies of CSF1R and Aurora kinase B (AURB) demonstrated the differences in their back pockets, which inspired the use of a chain extension strategy to diminish the AURA/B activities. A lead compound BPR1R024 (12) exhibited potent CSF1R activity (IC50 = 0.53 nM) and specifically inhibited protumor M2-like macrophage survival with a minimal effect on antitumor M1-like macrophage growth. In vivo, oral administration of 12 mesylate delayed the MC38 murine colon tumor growth and reversed the immunosuppressive tumor microenvironment with the increased M1/M2 ratio.

Muzamil Yaqub Want,1,2 Priya Yadav,1,3 Rakin Khan,1 Garima Chouhan,1,4 Mohammad Islamuddin,1,5 Sheka Yagub Aloyouni,6 Asoke P Chattopadhyay,7 Suliman Yousef AlOmar,8 Farhat Afrin1,9 1Parasite Immunology Laboratory, Department of Biotechnology, Jamia Hamdard (Hamdard University), New Delhi, 110062, India; 2Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA; 3Department of Microbiology, University of Kalyani, Kalyani, West Bengal, 741235, India; 4Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, 201306, India; 5Molecular Virology and Vaccinology Laboratory, Department of Biotechnology, Jamia Millia Islamia, New Delhi, 110025, India; 6Health Sciences Research Center, Princess Nourah Bint Abdulrahman University, Riyadh, 11671, Saudi Arabia; 7Department of Chemistry, University of Kalyani, Kalyani, West Bengal, 741235, India; 8Doping Research Chair, Department of Zoology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia; 9Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Taibah University, Madina, 41477, Saudi ArabiaCorrespondence: Farhat Afrin; Suliman Yousef AlOmar Tel +91-7596846639; +966-500767717Email farhatafrin@gmail.com; syalomar@ksu.edu.saIntroduction: The current therapeutic armory for visceral leishmaniasis (VL) caused by Leishmania donovani complex is inadequate, coupled with serious limitations. Combination therapy has proved ineffective due to mounting resistance; however, the search for safe and effective drugs is desirable, in the absence of any vaccine. There is a growing interest in the application of nanoparticles for the therapeutic effectiveness of leishmaniasis. Aimed in this direction, we assessed the antileishmanial effect of gold nanoparticles (GNP) against L. donovani in vitro.Methods: GNP were synthesized and characterized for particle size by dynamic light scattering (DLS) and atomic force microscopy (AFM) and for optical properties by UV-visible spectroscopy. Cytotoxicity of GNP was measured by the MTT proliferation assay. The antileishmanial activity of the nanoparticles was evaluated against L. donovani promastigotes and macrophage-infected amastigotes in vitro.Results: GNP showed a strong SPR peak at 520 nm and mean particle size, polydispersity index (PDI), and zeta potential of 56.0 ± 10 nm, 0.3 ± 0.1 and − 27.0 ± 3 mV, respectively. The GNPs were smooth and spherical with a mean particle diameter of 20 ± 5 nm. Nanoparticles [1.2– 100 μM] did not reveal any cytotoxicity on RAW 264.7 murine macrophage cell line, but exerted significant activity against both promastigotes and amastigote stages of L. donovani with 50% inhibitory concentrations (IC50) of 18.4 ± 0.4 μM and 5.0 ± 0.3 μM, respectively. GNP showed significant antileishmanial activity with deformed morphology of parasites and the least number of surviving promastigotes after growth reversibility analysis.Conclusion: GNP may provide a platform to conjugate antileishmanial drugs onto the surface of nanoparticles to enhance their therapeutic effectiveness against VL. Further work is warranted, involving more in-depth mechanistic studies and in vivo investigations.Keywords: gold nanoparticles, surface plasmon resonance, visceral leishmaniasis L. donovani, promastigotes, amastigotes

Nine new highly oxygenated 3,5-dimethylorsellinic acid-derived meroterpenoids, talaromynoids A-I (1-9), were isolated from the marine-derived fungus Talaromyces purpureogenus SCSIO 41517. Their structures including absolute configurations were elucidated by HRMS, NMR, single-crystal X-ray diffraction analysis, and electronic circular dichroism calculations. Compounds 1 and 7-9 possessed unprecedented 5/7/6/5/6/6, 6/7/6/6/6/5, 6/7/6/5/6/5/4, and 7/6/5/6/5/4 polycyclic systems, respectively. Biologically, compound 5 showed selective inhibitory activity against phosphatase CDC25B with an IC50 value of 13 μM. Moreover, 7-9 and 12 exhibited the activity of reducing triglyceride in 3T3-L1 adipocytes in a dosage-dependent manner.

Three new polyketide derivatives, 2-ethoxycarbonyl-endocrocin (1), 6-methoxy-2-ethoxycarbonyl-endocrocin (2) and pannorin C (3), along with sixteen known compounds (4-19) were isolated from a plant endophytic fungus Aspergillus cristatus 2H1. Their structures were elucidated by 1D/2D NMR and HR-ESI-MS data analysis. Compound 3 showed weak antibacterial activity against Staphylococcus aureus (MIC 20 μg/ml). Compounds 14 and 15 showed effective cytotoxicity on human melanoma A375 cells (IC50 4.13 μM for 14, 3.39 μM for 15).

The ethyl acetate and dichloromethane-soluble fractions, from a soft coral Sarcophyton trocheliophorum total methanolic extract, exhibited significant anti-leishmanial and cytotoxic activities. These active fractions yielded a new cembranoid diterpene (1), two known analogues [sarcotrocheliol (2) and sarcophine (3)], and two sterols [(24S)-24-methylcholesterol (4) and gorgosterol (5)]. The structure of the new diterpene (1) was determined via a detailed analysis of its spectroscopic data. Compounds 3 and 5 demonstrated noticeable cytotoxicity on A549 (IC50 17.4 ± 1.9 µg/ml) and HepG2 (IC50 17.7 ± 1.5 µg/ml) cell lines, respectively. None of the isolates 1‒5 showed detectable anti-leishmanial activity (IC50 >100 µg/ml).

This study describes a novel series of UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The original hit was a selective inhibitor of Pseudomonas aeruginosa LpxA with no activity against Escherichia coli LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against P. aeruginosa LpxA (best half-maximal inhibitory concentration (IC50) 20 μM and MIC > 128 μg/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa.

[Image: see text] An indazole/aza-indazole scaffold was developed as a novel chemotype for JNK3 inhibition. Extensive structure activity relationship (SAR) studies utilizing various in vitro and in vivo assays led to potent and highly selective JNK3 inhibitors with good oral bioavailability and high brain penetration. One lead compound, 29, was a potent and selective JNK3 inhibitor (IC(50) = 0.005 μM) that had significant inhibition (>80% at 1 μM) to only JNK3 and JNK2 in a panel profiling of 374 wild-type kinases, had high potency in functional cell-based assays, had high stability in the human liver microsome (t(1/2) = 92 min), and was orally bioavailable and brain penetrant (brain/plasma ratio: 56%). The cocrystal structure of 29 in human JNK3 at a 2.1 Å resolution showed that indazole or aza-indazole-based JNK3 inhibitors demonstrated a type I kinase inhibition/binding.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease, and its incidence rate is rapidly rising. However, effective therapies for the treatment of IPF are still lacking. Phosphodiesterase 4 (PDE4) inhibitors were reported to be potential anti-fibrotic agents, but their clinical use was hampered by side effects like emesis and nausea. Herein, structure-based hit-to-lead optimizations of natural mangostanin resulted in the novel and orally active PDE4 inhibitor 18a with potent inhibitory affinity (IC50 = 4.2 nM), favorable physico-chemical properties, and a different binding pattern from roflumilast. Emetic activity tests on dogs demonstrated that 18a cannot cause emesis even at an oral dose of 10 mg/kg, whereas rolipram had severe emetic effects at an oral dose of 1 mg/kg. Finally, the oral administration of 18a (10 mg/kg) exhibited comparable anti-pulmonary fibrosis effects with pirfenidone (150 mg/kg) in a bleomycin-induced IPF rat model, indicating its potential as a novel anti-IPF agent with improved safety.

To develop novel norepinephrine transporter (NET)-targeting positron emission tomography (PET) probes with optimal pharmacokinetic properties, a series of meta-bromobenzylguanidine derivatives was synthesized. 4-Fluorodiethoxyethane-3-bromobenzylguanidine (compound 12) showed relatively good affinity for the NET (IC50 = 1.00 ± 0.04 μM). The corresponding radiotracer 18F-12 was prepared in high radiochemical purity (>98%) via a three-step method. The in vitro cellular uptake results demonstrated that 18F-12 was specifically taken up by NET-expressing SK-N-SH cells by the uptake-1 mechanism. Biodistribution studies in mice showed that 18F-12 exhibited high cardiac uptake (10.45 ± 0.66 %ID/g at 5 min p.i. and 6.44 ± 0.40 %ID/g at 120 min p.i.), faster liver clearance, and a lower dose of absorbed radiation than [123I]-labeled meta-iodobenzylguanidine ([123I]MIBG). Small animal PET imaging confirmed the high heart-to-background ratio of 18F-12 and the uptake-1 mechanism specific for the NET in rats, indicating its potential as a promising PET radiotracer for cardiac sympathetic nerve imaging.

Background: The role of zinc in diabetes has been a subject of considerable interest due to the insulin-mimetic properties associated with this mineral. On the other hand, phenolic acids are known as plant-derived polyphenols with antioxidative and antidiabetic pharmacological credence. Objective: This study was conducted in order to develop a novel therapeutic nutraceutical with an improved and multi-mode antidiabetic and antioxidative pharmacological property using cinnamic acid and Zn(II) mineral framework. Methods: A Zn(II) acetate complex of cinnamic acid was synthesized and characterized using FT-IR and 1HNMR spectroscopy. Cytotoxicity evaluation was done using Chang liver cells and differentiated L6 myotubes. DPPH and ABTS scavenging, as well as Fe3+ reducing effects, were used to evaluate the antioxidant capacity. The antiglycation, as well as α-glucosidase and α-amylase inhibitory properties, were evaluated. Insulin mimetic property was evaluated as glucose uptake in L6 myotubes, while the complex was docked against GLUT-4 and PKB. Results: FTIR and 1HMR suggested that Zn(II) complexed with cinnamic acid through a Zn(O4) coordination mode, thus affording the resulting complex 2 cinnamic acid molecules. Hence, complexation increased (p ˂ 0.05) the antiglycation effect of cinnamic acid (IC50 = 29.3 μM) by 2 folds (IC50 = 13.9 μM). Also, Zn(II) conferred a potent glucose uptake (EC50 = 31 μM) and α-glucosidase inhibitory (IC50 = 59.4 μM) property on cinnamic acid; hence the activity of the complex was 162 and 2.1 folds higher than (p ˂ 0.05) its precursor, respectively. Further molecular docking studies showed that the complex had a stronger interaction with insulin signaling proteins (GLUT-4 and PKB) than its precursor. Interestingly, the complex showed no severe cytotoxicity. Conclusion: Data suggested a structure-activity relationship. Complexation of Zn(II) to cinnamic acid resulted in a complex with improved and multi-facet pharmacological effects, which may be further studied as a safe glycemic control nutraceutical for T2D and glycation-induced complications.

Background: The inhibition of α-amylase enzyme is one of the best therapeutic approach for the management of type II diabetes mellitus. Chalcone possesses a wide range of biological activities. Objective: In the current study chalcone derivatives (1-16) were synthesized and evaluated their inhibitory potential against α-amylase enzyme. Methods: For that purpose, a library of substituted (E)-1-(naphthalene-2-yl)-3-phenylprop-2-en-1-ones was synthesized by Claisen-Schmidt condensation reaction of 2-acetonaphthanone and substituted aryl benzaldehyde in the presence of base and characterized via different spectroscopic techniques such as EI-MS, HRESI-MS, 1H-, and 13C-NMR. Results: Sixteen synthetic chalcones were evaluated for in vitro porcine pancreatic α-amylase inhibition. All the chalcones demonstrated good inhibitory activities in the range of IC50 = 1.25 ± 1.05 to 2.40 ± 0.09 μM as compared to the standard commercial drug acarbose (IC50 = 1.34 ± 0.3 μM). Conclusion: Chalcone derivatives (1-16) were synthesized, characterized, and evaluated for their α- amylase inhibition. SAR revealed that electron donating groups in the phenyl ring have more influence on enzyme inhibition. However, to insight the participation of different substituents in the chalcones on the binding interactions with the α-amylase enzyme, in silico (computer simulation) molecular modeling analyses were carried out.

A new series of quinolotacrine hybrids including cyclopenta- and cyclohexa-quinolotacrine derivatives were designed, synthesized, and assessed as anti-cholinesterase (ChE) agents. The designed derivatives indicated higher inhibitory effect on the acetylcholinesterase (AChE) with IC50 values of 0.285–100 µM compared to butyrylcholinesterase (BChE) with IC50 values of > 100 µM. Of these compounds, cyclohexa-quinolotacrine hybrids displayed a little better anti-AChE activity than cyclopenta-quinolotacrine hybrids. Compound 8-amino-7-(3-hydroxyphenyl)-5,7,9,10,11,12-hexahydro-6H-pyrano[2,3-b:5,6-c'] diquinolin-6-one (6m) including 3-hydroxyphenyl and cyclohexane ring moieties exhibited the best AChE inhibitory activity with IC50 value of 0.285 µM. The kinetic and molecular docking studies indicated that compound 6m occupied both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE as a mixed inhibitor. Using neuroprotective assay against H2O2-induced cell death in PC12 cells, the compound 6h illustrated significant protection among the assessed compounds. In silico ADME studies estimated good drug-likeness for the designed compounds. As a result, these quinolotacrine hybrids can be very encouraging AChE inhibitors to treat Alzheimer’s disease. A novel series of quinolotacrine hybrids were designed, synthesized, and evaluated against AChE and BChE enzymes as potential agents for the treatment of AD. The hybrids showed good to significant inhibitory activity against AChE (0.285–100 μM) compared to butyrylcholinesterase (BChE) with IC50 values of > 100 μM. Among them, compound 8-amino-7-(3-hydroxyphenyl)-5,7,9,10,11,12-hexahydro-6H-pyrano[2,3-b:5,6-c′] diquinolin-6-one (6 m) bearing 3-hydroxyphenyl moiety and cyclohexane ring exhibited the highest anti-AChE activity with IC50 value of 0.285 μM. The kinetic and molecular docking studies illustrated that compound 6 m is a mixed inhibitor and binds to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE.

This study aims to investigate the antibacterial and anti-biofilm activities of YycG inhibitors H2-60 and H2-81 against Streptococcus agalactiae. A total of 118 nonduplicate S. agalactiae clinical isolates were collected, and the minimal inhibitory concentrations (MICs) of H2-60 and H2-81 were determined. H2-60 and H2-81 inhibit biofilm formation of S. agalactiae were detected by crystal violet staining, and against established biofilms of S. agalactiae were observed by confocal laser scanning microscope. Inhibitory effect of H2-60 and H2-81 on the phosphorylation activity of the HisKA domain of YycG' protein was measured. The MIC50/MIC90 was 3.13/6.25 μM for H2-60 and 6.25/12.5 μM for H2-81 against S. agalactiae, respectively. S. agalactiae planktonic cells can be decreased by H2-60 or H2-81 for more than 3 × log10 CFU ml-1 after 24 h treatment. Biofilm formation of 8 S. agalactiae strains (strong biofilm producers) was significantly reduced after treated with 1/4 × MIC of H2-60 or H2-81 for 24 h. H2-60 and H2-81 could reduce 45.79% and 29.56% of the adherent cells in the established biofilm of S. agalactiae after 72 h treatment, respectively. H2-60 combined with daptomycin reduced 83.63% of the adherent cells in the established biofilm of S. agalactiae, which was significantly better than that of H2-60 (45.79%) or daptomycin (55.07%) alone. The half maximal inhibitory concentrations (IC50) were 35.6 μM for H2-60 and 46.3 μM for H2-81 against the HisKA domain of YycG' protein. In conclusion, YycG inhibitors H2-60 and H2-81 exhibit excellent antibacterial and anti-biofilm activities against S. agalactiae.