Dual Inhibitory Activity Research Articles

Synthesis of novel 1,2-diarylpyrazolidin-3-one-based compounds and their evaluation as broad spectrum antibacterial agents.

There is a continuous need to develop new antibacterial agents with non-traditional mechanisms to combat the nonstop emerging resistance to most of the antibiotics used in clinical settings. We identified novel pyrazolidinone derivatives as antibacterial hits in an in-house library screening and synthesized several derivatives in order to improve the potency and increase the polarity of the discovered hit compounds. The oxime derivative 24 exhibited promising antibacterial activity against E. coli TolC, B. subtilis and S. aureus with MIC values of 4, 10 and 20µg/mL, respectively. The new lead compound 24 was found to exhibit a weak dual inhibitory activity against both the E. coli MurA and MurB enzymes with IC50 values of 88.1 and 79.5µM, respectively, which could partially explain its antibacterial effect. A comparison with the previously reported, structurally related pyrazolidinediones suggested that the oxime functionality at position 4 enhanced the activity against MurA and recovered the activity against the MurB enzyme. Compound 24 can serve as a lead for further development of novel and safe antibiotics with potential broad spectrum activity.

Two novel drugs as bio-functional inhibitors for copper performing excellent anticorrosion and antibacterial properties

Two drugs (cefpirome, cefixime) as dual-action inhibitors could self-organize on copper surface forming bio-functional protective film, which effectively prevents copper corrosion in the picking process with an excellent performance on the resistance of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Energy dispersive X-ray spectroscopy (EDS) and X-ray photoelectron spectroscopy (XPS) results showed that studied drugs can self-organize on copper surface successfully forming adsorption film to protect copper. The results also indicated that N/S atoms with the lone pair electrons in the drugs donated electrons to the vacant orbital of Cu occupying the active sites of copper surface. Electrochemistry and surface morphology study revealed that the corrosion inhibition efficiency of cefixime was better than cefpirome. Furthermore, adsorption isotherm study suggested that the adsorption was spontaneous chemical and physical adsorption, obeying Langmuir adsorption.

The Dual-Targeting Activity of the Metabolite Substrate of Para-amino Salicyclic Acid in the Mycobacterial Folate Pathway: Atomistic and Structural Perspectives

Therapeutic targeting of folate biosynthetic pathway has recently been explored as a viable strategy in the treatment of tuberculosis. The bioactive metabolite substrate of Para-amino salicyclic acid (PAS-M) reportedly dual-targets dihydrofolate reductase (DHFR) and flavin-dependent thymidylate synthase (FDTS), two essential enzymes in folate biosynthetic pathway. However, the molecular mechanisms and structural dynamics of this dual inhibitory activity of the PAS-M remain elusive. Molecular dynamics simulations revealed that binding of PAS-M towards DHFR is characterized by a recurrence of strong conventional hydrogen bond interactions between a peculiar DHFR binding site residue (Asp27) and the 2-amino-decahydropteridin-4-ol group of PAS-M. Similarly, the binding of PAS-M towards FDTS also involved consistent strong conventional hydrogen bond interactions between some specific residues (Tyr101, Arg172, Thr4, Gln103, Arg87 and Gln106) and, the 2-amino-decahydropteridin-4-ol group, thus establishing the cruciality of the group. Structural dynamics of the bound complexes of both enzymes revealed that, upon binding, PAS-M is anchored at the entrance of hydrophobic pockets by strong hydrogen bond interactions while the rest of the structure gains access to deeper hydrophobic residues to engage in favorable interactions. Further analysis of atomistic changes of both enzymes showed increased C-α atom deviations as well as an increase C-α atoms radius of gyration consistent with structural disorientations. These conformational changes possibly interfered with the biological functions of the enzymes and hence their inhibition as experimentally reported. Structural Insights provided could open up a novel paradigm of structure-based design of multi-targeting inhibitors of biological targets in the folate biosynthetic pathway toward tuberculosis therapy.

Design, synthesis, and evaluation of N-phenyl-4-(2-phenylsulfonamido)-benzamides as microtubule-targeting agents in drug-resistant cancer cells, displaying HDAC inhibitory response

Microtubule-targeting agents (MTA) have enjoyed significant clinical success for decades. However, several mechanisms may cause inactivation of such drugs, leading to acquired resistance in patients treated with them. Therefore, drugs containing a stilbene-like skeleton and possessing dual inhibitory activity may provide a new and differentiated treatment for patients to overcome challenging acquired resistance. A new compound (16c) displays promising anticancer activity with GI50 of 22 ± 2 and 12 ± 0.1 nM in vincristine-resistant nasopharyngeal (KB-Vin) cancer cells and etoposide-resistant nasopharyngeal (KB-7D) cancer cells and is better than vincristine, etoposide, ABT-751, and MS-275. A mechanistic study revealed that 16c interferes with the cell cycle distribution and induces cell cycle arrest at the G2/M phase and severe mitotic spindle defects followed by apoptosis. In addition, it produces much more significant cytotoxicity than vincristine and etoposide in the corresponding resistant cells, indicating that it may be a promising candidate to overcome drug resistance in cancer cells. Compound 16c also displays inhibitory activity against HDAC 1 and HDAC 2 with IC50 values of 1.07 μM, and 1.47 μM, respectively. These findings may lead to a new type of structural motif for future development of drugs that could overcome acquired resistance to MTAs.

A novel derivative of valepotriate inhibits the PI3K/AKT pathway and causes Noxa-dependent apoptosis in human pancreatic cancer cells.

Natural compound valepotriate exhibits inhibitory activity against a number of cancers, but the effect of valepotriate against pancreatic cancer is unclear, and the structure–activity relationship of valepotriate has not been characterized. In this study, we performed a structure-based similarity search and found 16 hit compounds. Among the 16 hits, (1S,6S,7R)-6-(acetyloxy)-1-[(3-methylbutanoyl)oxy]-4a,5,6,7a-tetrahydro-1H-spiro[cyclopenta[c]pyran-7,2’-oxiran]-4-ylmethyl 3-methylbutanoate (denoted as Amcp) exhibited superior anticancer activity against human pancreatic cancer BxPC-3 and SW1990 cells. The anti-proliferation activity of Amcp was validated in human pancreatic cancer BxPC-3 and SW1990 cells in vitro. Amcp more effectively induced apoptosis in BxPC-3 and SW1990 cells than gemcitabine. At a concentration of 15 μM, Amcp significantly suppressed the PI3K/AKT pathway and disrupted the mitochondrial membrane equilibrium through modulation of Noxa and Mcl-1 balance in both cell lines. Meanwhile, knockdown of Noxa substantially attenuated Amcp-induced reduction of cell viability and anti-apoptotic protein Mcl-1 level in BxPC-3 cells. In addition, Amcp showed synergistic anticancer effects when combined with gemcitabine in BxPC-3 cells. To conclude, this work not only suggests that Amcp possesses a dual-inhibitory activity towards PI3K/AKT pathway and Mcl-1, but also enlightens further development of bioactive valepotriate derivatives.

Structure-Guided Improvement of a Dual HPIV3/RSV Fusion Inhibitor.

Human parainfluenza virus 3 (HPIV3) and respiratory syncytial virus (RSV) are leading causes of lower respiratory tract infections. There are currently no vaccines or antiviral therapeutics to treat HPIV3 or RSV infections. We recently reported a peptide (VIQKI), derived from the C-terminal heptad repeat (HRC) domain of the HPIV3 fusion (F) glycoprotein that inhibits infection by both HPIV3 and RSV. The dual inhibitory activity of VIQKI is due to its unique ability to bind to the N-terminal heptad repeat (HRN) domains of both HPIV3 and RSV F, thereby preventing the native HRN-HRC interactions required for viral entry. Here we describe the structure-guided design of dual inhibitors of HPIV3 and RSV fusion with improved efficacy. We show that VIQKI derivatives possessing one (I456F) or two (I454F/I456F) phenylalanine substitutions near the N-terminus exhibit more stable assemblies with the RSV-HRN domain and enhanced antiviral efficacy against both HPIV3 and RSV infection. Cocrystal structures of the new Phe-substituted inhibitors coassembled with HPIV3 or RSV-HRN domains reveal that the I456F substitution makes intimate hydrophobic contact with the core trimers of both HPIV3 and RSV F.

Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitor.

Phosphoinositide 3‐kinases, delta (PI3Kδ) and gamma (PI3Kγ) are enriched in immune cells and regulate the development and function of innate and adaptive immunity. Dual PI3Kδγ inhibitors are considered high value targets for their potential to treat a variety of immune‐mediated diseases, but their discovery has been challenging. Here we describe the preclinical pharmacology of HM5023507, an orally active dual inhibitor of δγ isoforms in immune signaling. HM5023507 inhibited PI3Kδ and PI3Kγ isoforms with greater than 100‐fold selectivity against PI3Kα and PI3Kβ in recombinant enzymatic assays and in primary human immune cells with an exquisite selectivity against other targets. HM5023507 attenuated the PI3Kδ/γ signaling in human basophils (IC50: 42/340 nmol/L; selectivity ratio ~1:8). HM5023507 attenuated the activation and function of human B and T cells, Th17 differentiation of CD4 T cells in the blood of healthy donors and rheumatoid arthritis patients, and cytokine and IgG production in human T and B cell cocultures, in vitro. Orally dosed HM5023507 attenuated PI3K δ/γ‐mediated immune signaling in the rat in a dose‐related manner. In addition, HM5023507 inhibited semiestablished collagen‐induced arthritic inflammation in the rats (ED50 of 0.25mg/kg, p.o. BID or 0.5 mg/kg, QD, AUC: 1422 ng/mL*h), improved histopathology‐ and micro‐computed tomography (µCT)‐based indices of joint damage, bone destruction, and attenuated the levels of anti‐collagen antibody, with an overall anti‐inflammatory profile matching that of a TNFα neutralizing antibody. The PI3K δγ inhibitory profile of HM5023507 and its selectivity make it a useful tool to further delineate immunobiology of dual PI3K δγ targeting.

Search for non-acidic ALR2 inhibitors: Evaluation of flavones as targeted agents for the management of diabetic complications.

Diabetic complications (DC) follow multiple pathophysiological pathways and one of the key pathways is the polyol pathway which involves the metabolism of glucose via aldose reductase (ALR2) and sorbitol dehydrogenase (SDH). ALR2 inhibitors such as epalrestat has already been established as promising candidates for the management of DC. On the basis of pathophysiological understanding of polyol pathway, simultaneous inhibition of ALR2 and SDH may be expected to provide synergistic outcomes in the treatment strategies for DC. Thus, in this study, dual inhibitors of ALR2 and SDH were identified using pharmacophore-based virtual screening. For this purpose, the pharmacophore model for SDH (model ID: AAADH.343) was generated and validated. For screening against ALR2, the pharmacophore model (model ID: AADRR.1109) which was previously reported by our group was applied. Initially, flavones reported by our research group were screened by those two pharmacophore models to obtain hits with an optimum affinity for the catalytic domain of both ALR2 and SDH. Inhibitory potential of identified hits for ALR2 and SDH were then experimentally determined using enzymatic assays reported in the literature. Additional focus was laid on the selectivity of the designed molecules towards ALR2 over ALR1, thus evaluation against ALR1 was also performed. Overall, four molecules FLV-2, FLV-11, FLV-12, and FLV-15 were found to possess significant dual inhibitory activity against ALR2 and SDH, with selectivity over ALR1. Among them, FLV-2 displayed significant dual inhibitory potential with an IC50 value of 0.689±0.018µM and 0.174±0.003µM against ALR2 and SDH respectively with a selectivity index of 52.902 to ALR2 over ALR1.

2-Thiopyrimidine/chalcone hybrids: design, synthesis, ADMET prediction, and anticancer evaluation as STAT3/STAT5a inhibitors

A novel 2-thiopyrimidine/chalcone hybrid was designed, synthesised, and evaluated for their cytotoxic activities against three different cell lines, K-562, MCF-7, and HT-29. The most active cytotoxic derivatives were 9d, 9f, 9n, and 9p (IC50=0.77–1.74 µM, against K-562 cell line), 9a and 9r (IC50=1.37–3.56 µM against MCF-7 cell line), and 9a, 9l, and 9n (IC50=2.10 and 2.37 µM against HT-29 cell line). Compounds 9a, 9d, 9f, 9n, and 9r were further evaluated for their cytotoxicity against normal fibroblast cell line WI38. Moreover, STAT3 and STAT5a inhibitory activities were determined for the most active derivatives 9a, 9d, 9f, 9n, and 9r. Dual inhibitory activity was observed in compound 9n (IC50=113.31 and 50.75 µM, against STAT3 and STAT5a, respectively). Prediction of physicochemical properties, drug likeness score, pharmacokinetic and toxic properties was detected.

Small-Molecule Dual PLK1 and BRD4 Inhibitors are Active Against Preclinical Models of Pediatric Solid Tumors

Simultaneous inhibition of multiple molecular targets is an established strategy to improve the continuance of clinical response to therapy. Here, we screened 49 molecules with dual nanomolar inhibitory activity against BRD4 and PLK1, best classified as dual kinase-bromodomain inhibitors, in pediatric tumor cell lines for their antitumor activity. We identified two candidate dual kinase-bromodomain inhibitors with strong and tumor-specific activity against neuroblastoma, medulloblastoma, and rhabdomyosarcoma tumor cells. Dual PLK1 and BRD4 inhibitor treatment suppressed proliferation and induced apoptosis in pediatric tumor cell lines at low nanomolar concentrations. This was associated with reduced MYCN-driven gene expression as assessed by RNA sequencing. Treatment of patient-derived xenografts with dual inhibitor UMB103 led to significant tumor regression. We demonstrate that concurrent inhibition of two central regulators of MYC protein family of protooncogenes, BRD4, and PLK1, with single small molecules has strong and specific antitumor effects in preclinical pediatric cancer models.

In silico and in vitro studies of two non-imidazole multiple targeting agents at histamine H3 receptors and cholinesterase enzymes.

Recently, multi-target directed ligands have been of research interest for multifactorial disorders such as Alzheimer's disease (AD). Since H3 receptors (H3 Rs) and cholinesterases are involved in pathophysiology of AD, identification of dual-acting compounds capable of improving cholinergic neurotransmission is of importance in AD pharmacotherapy. In the present study, H3 R antagonistic activity combined with anticholinesterase properties of two previously computationally identified lead compounds, that is, compound 3 (6-chloro-N-methyl-N-[3-(4-methylpiperazin-1-yl)propyl]-1H-indole-2-carboxamide) and compound 4 (7-chloro-N-[(1-methylpiperidin-3-yl)methyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxamide), was tested. Moreover, molecular docking and binding free energy calculations were conducted for binding mode and affinity prediction of studied ligands toward cholinesterases. Biological evaluations revealed inhibitory activity of ligands in nanomolar (compound 3: H3 R EC50 =0.73nM; compound 4: H3 R EC50 =31nM) and micromolar values (compound 3: AChE IC50 =9.09µM, BuChE IC50 =21.10µM; compound 4: AChE IC50 =8.40µM, BuChE IC50 =4.93µM) for H3 R antagonism and cholinesterase inhibition, respectively. Binding free energies yielded good consistency with cholinesterase inhibitory profiles. The results of this study can be used for lead optimization where dual inhibitory activity on H3 R and cholinesterases is needed. Such ligands can exert their biological activity in a synergistic manner resulting in higher potency and efficacy.

Identification of antimalarial leads with dual falcipain-2 and falcipain-3 inhibitory activity

Falcipains (FPs), cysteine proteases in the malarial parasite, are emerging as the promising antimalarial drug targets. In order to identify novel FP inhibitors, we generated a pharmacophore derived from the reported co-crystal structures of inhibitors of Plasmodium falciparum Falcipain-3 to screen the ZINC library. Further, the filters were applied for dock score, drug-like characters, and clustering of similar structures. Sixteen molecules were purchased and subject to in vitro enzyme (FP-2 and FP-3) inhibition assays. Two compounds showed in vitro inhibition of FP-2 and FP-3 at low µM concentration. The selectivity of the inhibitors can be explained based on the predicted interactions of the molecule in the active site. Further, the inhibitors were evaluated in a functional assay and were found to induce morphological changes in line with their mode of action arresting Plasmodium development. Compound 15 was most potent inhibitor identified in this study.

Dual PDK1/Aurora Kinase A Inhibitors Reduce Pancreatic Cancer Cell Proliferation and Colony Formation.

Deregulation of different intracellular signaling pathways is a common feature in cancer. Numerous studies indicate that persistent activation of the phosphoinositide 3-kinase (PI3K) pathway is often observed in cancer cells. 3-phosphoinositide dependent protein kinase-1 (PDK1), a transducer protein that functions downstream of PI3K, is responsible for the regulation of cell proliferation and migration and it also has been found to play a key role in different cancers, pancreatic and breast cancer amongst others. As PI3K is being described to be aberrantly expressed in several cancer types, designing inhibitors targeting various downstream molecules of PI3K has been the focus of anticancer agent development for a long time. In particular, dual inhibitory drugs targeting key signaling molecules in the PI3K pathway have attracted the attention of scientists. Several drugs have progressed to clinical trials, with limited success due to toxicity and bioavailability concerns. Very few anticancer drugs targeting the PI3K pathway have been approved for clinical use and their efficacy is particularly limited towards certain tumors such as pancreatic cancer. Here, we tested two drugs displaying dual inhibitory activity towards PDK1 and Aurora kinase A in a panel of pancreatic cancer cell lines and in two in vivo models of pancreatic cancer. Our data show that both inhibitors are able to impair cell proliferation and clonogenic potential in pancreatic cancer cells. However, the limited activity of both compounds in vivo indicates that further optimization of the pharmacokinetics properties is required.

Synthesis and biological evaluation of tetrazole derivatives as TNF-α, IL-6 and COX-2 inhibitors with antimicrobial activity: Computational analysis, molecular modeling study and region-specific cyclization using 2D NMR tools

A group of tetrazole bearing compounds were synthesized and evaluated for their in vitro cyclooxygenase (COX) isozymes (COX-1/COX-2) inhibitory activity, in vitro anti-inflammatory activity through measuring levels of expression of IL-6 and TNF-α and antimicrobial activity. Cyclization of pyridine derivative 5b was confirmed using 2D NMR such as NOESY and HMBC experiments. Within the synthesized compounds, compound 7c was identified as effective and selective COX-2 inhibitors (COX-2 IC50 = 0.23 uM; COX-2 selectivity index = 16.91). Moreover 7c was the most effective derivative on TNF-α (37.6 pg/ml). While, the most active compound on IL-6 was isoxazole derivative 6 (42.8 pg/ml). Dual inhibitory activity on both IL-6 and TNF-α was exhibited by compounds 2 and 3 (IL-6 = 47.5 and 82.7 pg/ml, respectively) and (TNF-α = 31.7 and 33.8 pg/ml, sequentially).Additionally, compound 7a, showed broad spectrum antimicrobial activity against Gram positive cocci, Gram positive rods and yeast fungus (inhibition zone = 20 and 19 mm). None of the test compounds exhibited activity against Gram negative rods. Compounds 3 and 7c exhibited good antifungal activity at MIC equal to 64.5 µg/ml. While compound 6 showed antibacterial activities against Micrococcus lysodicticus and Bacillus subtilis at MIC = 32.25 and 64.5 µg/ml, respectively.Computational analysis was used to predict molecular properties and bioactivity of the target compounds. To confirm the mode of action of the synthesized compounds as anti-inflammatory agents, molecular docking was done. Appreciable binding interactions were observed for compound 7c containing COX-2 pharmacophore (SO2NH2), with binding energy −10.6652 Kcal/mol, forming two hydrogen bonding interactions with His90 and Tyr355 amino acids. It was fully fitted within COX-2 active site having the highest COX-2 selectivity index between all the test compounds (S.I. = 16.91).

New oxadiazoles with selective-COX-2 and EGFR dual inhibitory activity: Design, synthesis, cytotoxicity evaluation and in silico studies

Novel heterocyclic oxadiazoles viz. 2-subsituted-5-(4-pyridyl)-1,3,4-oxadiazoles, 2-subsituted-5-(3-pyridyl)-1,3,4-oxadiazoles and 2-subsituted-5-(phenyl or 4-chlorophenyl-1,3,4-oxadiazoles) were designed and synthesized as potential anticancer agents. In this investigation, all compounds were evaluated for their COX-1 and COX-2 inhibitory activity in vitro as new therapeutic approaches assumed cytotoxic effect associated with selective COX-2 inhibition. Results showed that most of the derivatives demonstrated inhibition towards both isoforms of COX comparable to the standard reference drugs indomethacin, diclofenac sodium and celecoxib. Then, nine selected compounds (IIId, VIb, VIIc, IX, XI, XIIa, XIVa, XVIb and XVIIIb) were subjected to cytotoxic screening against UO-31 renal cancer cell line using MTT assay. Compounds IIId, IX and XIIa displayed promising behavior by showing good anticancer activity. Moreover, kinase inhibitory assay against the tyrosine kinase EGFR was performed for the three compounds showing the highest cytotoxic activity. The tested compounds were potent against EGFR with the highest activity being observed for compound IX showing nearly double the potency of the reference drug Erlotinib. Moreover, molecular docking and molecular dynamics were performed for IIId, IX and XIIa against EGFR, in an attempt to elucidate a model for their binding at the molecular level, simulate and understand the possible binding interactions underlying the association between these small molecules and the kinase enzyme ATP binding pocket essential amino acids. Finally, in silico pharmacokinetic profile predication was investigated for IIId, IX and XIIIa using SWISS/ADME to identify the most promising small-molecule cytotoxic agent on the basis of displaying the best drug-like properties. Results indicated that compound IX has a potential to serve as a lead compound for developing novel anticancer therapeutic agents.

Synthesis, biological evaluation, and molecular modeling of nitrile-containing compounds: Exploring multiple activities as anti-Alzheimer agents.

Based on the monoamine oxidase (MAO) inhibition properties of aminoheterocycles with a carbonitrile group we have carried out a systematic exploration to discover new classes of carbonitriles endowed with dual MAO and AChE inhibitory activities, and Aβ anti-aggregating properties. Eighty-three nitrile-containing compounds, 13 of which are new, were synthesized and evaluated. in vitro screening revealed that 31, a new compound, presented the best lead for trifunctional inhibition against MAO A (0.34 μM), MAO B (0.26 μM), and AChE (52 μM), while 32 exhibited a lead for selective MAO A (0.12 μM) inhibition coupled to AChE (48 μM) inhibition. Computational analysis revealed that the malononitrile group can find an advantageous position with the aromatic cleft and FAD of MAO A or MAO B. However, the total binding energy can be handicapped by an internal penalty caused by twisting of the ligand molecule and subsequent disruption of the conjugation (32 in MAO B compared to the conjugated 31). Conjugation is also important for AChE as well as the hydrophilic character of malononitrile that allows this group to be in close contact with the aqueous environment as seen for 83. Although the effect of 31 and 32 against Aβ1-42 , was very weak, the effect of 63 and 65, and of the new compound 75, indicated that these compounds were able to disaggregate Aβ1-42 fibrils. The most effective was 63, a (phenylhydrazinylidene)propanedinitrile derivative that also inhibited MAO A (1.65 μM), making it a potential lead for Alzheimer's disease application.

Fatty acid composition, TLC screening, ATR-FTIR analysis, anti-cholinesterase activity, and in vitro cytotoxicity to A549 tumor cell line of extracts of 3 macroalgae collected in Madeira

Three macroalgae collected at Madeira Island were included in this study to determine their potential for drug, nutraceutical, food, or supplement application. Fatty acid content was higher in Zonaria tournefortii (12.32 mg g−1 dw) with 16.58% of PUFAs, eicosapentaenoic acid (C20:5ω3), and arachidonic acid (20:4ω6) having concentrations of 2.59 and 1.17%, respectively. The anti-thrombogenic and anti-atherogenicity potential was higher for Z. tournefortii due to relevant fatty acids in the biochemical composition this macroalgae. Lipid classes were assessed in the lipid extract and neutral lipids (NL) were in higher yield in Asparagopsis taxiformis (51.16%) and lower in Z. tournefortii (26.96%). The glycolipids (GL) were between 36.03 and 16.11% in Z. tournefortii and Ulva lactuca. Phospholipids (PL) fraction varied from 35.91 and 31.60% in A. taxiformis and Z. tournefortii. TLC screening identified that U. lactuca contains phytol and cholesterol in its NL, digalactosyldiacylglycerol in its GL, and cardiolipin and L-α-phosphatidylcholine in its PL. Zonaria tournefortii contains phytol and cholesterol in its NL classes, and the PL classes contain L-α-phosphatidylethanolamine and 1-(3-sn-phosphatidyl)-rac-glycerol. The macroalgae A. taxiformis revealed cholesterol in its NL fraction and the same phospholipids as Z. tournefortii in its PL fraction. ATR-FTIR analysis enabled a “fingerprint” spectra and important sulfation absorption bands were identified, revealing the functional polysaccharides within these macroalgae. Anti-cholinesterasic activity was assessed in A. taxiformis, with a low IC50 for AChE (8.92 ± 0.43 μg mL−1) and BuChE (13.96 ± 0.32 μg mL−1), demonstrating dual inhibitory activity, justifying the interest to identify the active principle which may be the scaffold of a novel drug.

Pharmacological Characterization of RS-1259, an Orally Active Dual Inhibitor of Acetylcholinesterase and Serotonin Transporter, in Rodents: Possible Treatment of Alzheimer’s Disease

Pharmacological Characterization of RS-1259, an Orally Active Dual Inhibitor of Acetylcholinesterase and Serotonin Transporter, in Rodents: Possible Treatment of Alzheimer’s Disease

Development of Dual Chitinase Inhibitors as Potential New Treatment for Respiratory System Diseases

Acidic mammalian chitinase (AMCase) and chitotriosidase-1 (CHIT1) are two enzymatically active proteins produced by mammals capable of cleaving the glycosidic bond in chitin. Based on the clinical findings and animal model studies, involvement of chitinases has been suggested in several respiratory system diseases including asthma, COPD, and idiopathic pulmonary fibrosis. Exploration of structure-activity relationships within the series of 1-(3-amino-1H-1,2,4-triazol-5-yl)-piperidin-4-amines, which was earlier identified as a scaffold of potent AMCase inhibitors, led us to discover highly active dual (i.e., AMCase and CHIT1) inhibitors with very good pharmacokinetic properties. Among them, compound 30 was shown to reduce the total number of cells in bronchoalveolar lavage fluid of mice challenged with house dust mite extract after oral administration (50 mg/kg, qd). In addition, affinity toward the hERG potassium channel of compound 30 was significantly reduced when compared to the earlier reported chitinase inhibitors.

Multifunctional Urea Cocrystal with Combined Ureolysis and Nitrification Inhibiting Capabilities for Enhanced Nitrogen Management

The novel ternary Zn(II)-thiourea–urea ionic cocrystal [Zn(thiourea)(urea)Cl₂], (ZnTU) has been prepared by both solution and mechanochemical processes and structurally characterized by solid-state methods. ZnTU exhibited improved response properties to water as relative humidity as inherited from thiourea. The results of enzymatic activity measurements provide evidence that ZnTU is effective in modulating urea hydrolysis both in vitro (negatively impacting on the activity of isolated urease) and in vivo (decreasing the ureolytic activity of Sporosarcina pasteurii, a widespread soil bacterium), and that Zn(II) is the component of the cocrystal acting as the actual urease inhibitor. Concomitantly, the analysis of the ammonia monooxygenase (AMO) enzymatic activity in Nitrosomonas europaea, taken as a representative of soil ammonia-oxidizing bacteria, in the presence of ZnTU reveals that thiourea is the only component of ZnTU able to inhibit ammonia conversion to nitrite. It has also been shown that ZnTU maintains these capabilities when applied to bacterial cultures containing both S. pasteurii and N. europaea working in tandem. The compound can thus act both as a fertilizer via urea and via the Zn(II) and thiourea components, as a dual action inhibitor of the activities of the enzymes urease and AMO, which are responsible for the negative environmental and economic impact of the agricultural use of urea as soil fertilizer. These results indicate that ZnTU should be considered a novel material to improve N fertilization efficiency, toward a more environment-friendly agricultural practice.