New 1,2,4-oxadiazole derivatives as potential multifunctional agents for the treatment of Alzheimer's disease: design, synthesis, and biological evaluation.

A series of new 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their anti-AD potential. The results revealed that eleven compounds (1b, 2a-c, 3b, 4a-c, and 5a-c) exhibited excellent inhibitory potential against AChE, with IC50 values ranging from 0.00098 to 0.07920 µM. Their potency was 1.55 to 125.47 times higher than that of donepezil (IC50 = 0.12297 µM). In contrast, the newly synthesized oxadiazole derivatives with IC50 values in the range of 16.64-70.82 µM exhibited less selectivity towards BuChE when compared to rivastigmine (IC50 = 5.88 µM). Moreover, oxadiazole derivative 2c (IC50 = 463.85 µM) was more potent antioxidant than quercetin (IC50 = 491.23 µM). Compounds 3b (IC50 = 536.83 µM) and 3c (IC50 = 582.44 µM) exhibited comparable antioxidant activity to that of quercetin. Oxadiazole derivatives 3b (IC50 = 140.02 µM) and 4c (IC50 = 117.43 µM) showed prominent MAO-B inhibitory potential. They were more potent than biperiden (IC50 = 237.59 µM). Compounds 1a, 1b, 3a, 3c, and 4b exhibited remarkable MAO-A inhibitory potential, with IC50 values ranging from 47.25 to 129.7 µM. Their potency was 1.1 to 3.03 times higher than that of methylene blue (IC50 = 143.6 µM). Most of the synthesized oxadiazole derivatives provided significant protection against induced HRBCs lysis, revealing the nontoxic effect of the synthesized compounds, thus making them safe drug candidates. The results unveiled oxadiazole derivatives 2b, 2c, 3b, 4a, 4c, and 5a as multitarget anti-AD agents. The high AChE inhibitory potential can be computationally explained by the synthesized oxadiazole derivatives' significant interactions with the AChE active site. Compound 2b showed good physicochemical properties. All these data suggest that 2b could be considered as a promising candidate for future development.

Design, synthesis, and biological evaluation of 1,2,4-oxadiazole-based derivatives as multitarget anti-Alzheimer agents.

A series of novel 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their potential anti-Alzheimer disease activity. The results revealed that compounds 2b, 2c, 2d, 3a, 4a, 6, 9a, 9b, and 13b showed excellent inhibitory activity against acetylcholinesterase (AChE) with IC50 values in the range of 0.0158 to 0.121 µM. They were 1.01 to 7.78 times more potent than donepezil (IC50 = 0.123 µM). The newly synthesized compounds exhibited lower activity towards butyrylcholinesterase (BuChE) when compared to rivastigmine. Compounds 4b and 13b showed the most prominent inhibitory potential against BuChE with IC50 values of 11.50 and 15 µM, respectively. Moreover, 4b, and 9b were found to be more potent antioxidant agents (IC50 values of 59.25, and 56.69 µM, respectively) in comparison with ascorbic acid (IC50 = 74.55 µM). Compounds 2b and 2c exhibited monoamine oxidase-B (MAO-B) inhibitory activity with IC50 values of 74.68 and 225.48 µM, respectively. They were 3.55 and 1.17 times more potent than biperiden (IC50 = 265.85 µM). The prominent interactions of the compounds with the AChE active site can be used to computationally explain the high AChE inhibitory activity. The results unveiled 1,2,4-oxadiazole derivatives 2c and 3a as multitarget anti-AD agents. The predicted ADME properties for compounds 2b and 4a were satisfactory, and 4a had the highest likelihood of crossing the blood-brain barrier (BBB), making it the optimum compound for future optimization.

Novel sulfonamide derivatives as multitarget antidiabetic agents: design, synthesis, and biological evaluation.

A series of new sulfonamide derivatives connected through an imine linker to five or seven membered heterocycles were designed and synthesized. All synthesized derivatives were characterized using a variety of spectroscopic methods, including IR, 1HNMR, and 13CNMR. In vitro α-glucosidase and α-amylase inhibition activities, as well as glucose uptake were assessed for each of the synthesized compounds. Four sulfonamide derivatives namely 3a, 3b, 3h and 6 showed excellent inhibitory potential against α-glucosidase with IC50 values of 19.39, 25.12, 25.57 and 22.02 µM, respectively. They were 1.05- to 1.39-fold more potent than acarbose. Sulfonamide derivatives 3g, 3i and 7 (EC50 values of 1.29, 21.38 and 19.03 µM, respectively) exhibited significant glucose uptake activity that were 1.62- to 27-fold more potent than berberine. Both α-glucosidase protein (PDB: 2QMJ) and α-amylase (PDB: 1XCW) complexed with acarbose were adopted for docking investigations for the most active synthesized compounds. The docked compounds were able to inhabit the same space as the acarviosin ring of acarbose. The docking of the most active compounds showed an analogous binding with the active site of α-glucosidase as acarbose. The superior activity of the synthesized compounds against α-glucosidase enzyme than α-amylase enzyme can be rationalized by the weak interaction with the α-amylase. The physiochemical parameters of all synthesized compounds were aligned with Lipinski's rule of five.

Novel sofosbuvir derivatives against SARS-CoV-2 RNA-dependent RNA polymerase: an in silico perspective.

The human coronavirus, SARS-CoV-2, had a negative impact on both the economy and human health, and the emerging resistant variants are an ongoing threat. One essential protein to target to prevent virus replication is the viral RNA-dependent RNA polymerase (RdRp). Sofosbuvir, a uridine nucleotide analog that potently inhibits viral polymerase, has been found to help treat SARS-CoV-2 patients. This work combines molecular docking and dynamics simulation (MDS) to test 14 sofosbuvir-based modifications against SARS-CoV-2 RdRp. The results reveal comparable (slightly better) average binding affinity of five modifications (compounds 3, 4, 11, 12, and 14) to the parent molecule, sofosbuvir. Compounds 3 and 4 show the best average binding affinities against SARS-CoV-2 RdRp (- 16.28 ± 5.69 and - 16.25 ± 5.78 kcal/mol average binding energy compared to - 16.20 ± 6.35 kcal/mol for sofosbuvir) calculated by Molecular Mechanics Generalized Born Surface Area (MM-GBSA) after MDS. The present study proposes compounds 3 and 4 as potential SARS-CoV-2 RdRp blockers, although this has yet to be proven experimentally.

Design, synthesis, anticancer, and antibacterial evaluation of some quinazolinone-based derivatives as DHFR inhibitors.

Two series of quinazolinone derivatives were designed and synthesized as dihydrofolate reductase (DHFR) inhibitors. All compounds were evaluated for their antibacterial and antitumor activities. Antibacterial activity was evaluated against three strains of Gram-positive and Gram-negative bacteria. Compound 3d exhibited the highest inhibitory activity against Staphylococcus aureus DHFR (SaDHFR) with IC50 of 0.769 ± 0.04 µM compared to 0.255 ± 0.014 µM for trimethoprim. Compound 3e was also more potent than trimethoprim against Escherichia coli DHFR (EcDHFR) with IC50 of 0.158 ± 0.01 µM and 0.226 ± 0.014 µM, respectively. Compound 3e exhibited a promising antiproliferative effect against most of the tested cancer cells. It also showed potent activity against leukemia (CCRF-CEM, and RPMI-8226); lung NCI-H522, and CNS U251 with GI% of 65.2, 63.22, 73.28, and 97.22, respectively. The cytotoxic activity of compound 3e was almost half the activity of doxorubicin against CCRF-CEM cell line with IC50 of 1.569 ± 0.06 µM and 0.822 ± 0.03 µM, respectively. In addition, compound 3e inhibited human DHFR with IC50 value of 0.527 ± 0.028 µM in comparison to methotrexate (IC50 = 0.118 ± 0.006 µM). Compound 3e caused an arrest of the cell cycle mainly at the S phase and caused a rise in the overall apoptotic percentage from 2.03% to 48.51%. (23.89-fold). Treatment of CCRF-CEM cells with compound 3e produced a significant increase in the active caspase-3 level by 6.25-fold compared to untreated cells. Molecular modeling studies were performed to evaluate the binding pattern of the most active compounds in the bacterial and human DHFR.

New trends in synthetic drugs and natural products targeting 20S proteasomes in cancers.

Cancer is a global health challenge that remains to be a field of extensive research aiming to find new anticancer therapeutics. The 20S proteasome complex is one of the targets of anticancerdrugs, as it is correlated with several cancer types. Herein, we aim to discuss the 20S proteasome subunits and investigatethe currently studied proteasome inhibitors targeting the catalytically active proteasome subunits. In this review, we summarize the proteindegradation mechanism of the 20S proteasome complex and compareit with the 26S proteasome complex. Afterwards, the localization of the 20S proteasome is summarized as well as its use as a diagnosticandprognostic marker. The FDA-approved proteasome inhibitors (PIs) under clinical trials are summarized and their current limited use in solid tumors is also reviewed in addition to the expression of theß5 subunit in differentcell lines. The review discusses in-silico analysis of the active subunit of the 20S proteasome complex. For development of new proteasome inhibitor drugs, the natural products inhibiting the 20S proteasome are summarized, as well as novel methodologies and challenges for the natural product discovery and current information about the biosynthetic gene clusters encoding them. We herein briefly summarize some resistancemechanismsto the proteasomeinhibitors. Additionally, we focus on the three main classes of proteasome inhibitors: 1] boronic acid, 2] beta-lactone and 3] epoxide inhibitor classes, as well as other PI classes, and their IC50 values and their structure-activity relationship (SAR). Lastly,we summarize several future prospects of developing new proteasome inhibitors towards the treatment of tumors, especially solid tumors.

Design and synthesis of novel quinazolinone-based derivatives as EGFR inhibitors with antitumor activity.

Nineteen new quinazolin-4(3H)-one derivatives 3a-g and 6a-l were designed and synthesised to inhibit EGFR. The antiproliferative activity of the synthesised compounds was tested in vitro against 60 different human cell lines. The most potent compound 6d displayed superior sub-micromolar antiproliferative activity towards NSC lung cancer cell line NCI-H460 with GI50 = 0.789 µM. It also showed potent cytostatic activity against 40 different cancer cell lines (TGI range: 2.59-9.55 µM). Compound 6d potently inhibited EGFR with IC50 = 0.069 ± 0.004 µM in comparison to erlotinib with IC50 value of 0.045 ± 0.003 µM. Compound 6d showed 16.74-fold increase in total apoptosis and caused cell cycle arrest at G1/S phase in breast cancer HS 578T cell line. Moreover, the most potent derivatives were docked into the EGFR active site to determine their binding mode and confirm their ability to satisfy the pharmacophoric features required for EGFR inhibition.

Structure-Activity Relationships for 5'' Modifications of 4,5-Aminoglycoside Antibiotics.

Modification at the 5''-position of 4,5-disubstituted aminoglycoside antibiotics (AGAs) to circumvent inactivation by aminoglycoside modifying enzymes (AMEs) is well known. Such modifications, however, unpredictably impact activity and affect target selectivity thereby hindering drug development. A survey of 5''-modifications of the 4,5-AGAs and the related 5-O-furanosyl apramycin derivatives is presented. In the neomycin and the apralog series, all modifications were well-tolerated, but other 4,5-AGAs require a hydrogen bonding group at the 5''-position for maintenance of antibacterial activity. The 5''-amino modification resulted in parent-like activity, but reduced selectivity against the human cytosolic decoding A site rendering this modification unfavorable in paromomycin, propylamycin, and ribostamycin. Installation of a 5''-formamido group and, to a lesser degree, a 5''-ureido group resulted in parent-like activity without loss of selectivity. These lessons will aid the design of next-generation AGAs capable of circumventing AME action while maintaining high antibacterial activity and target selectivity.

Design, synthesis and evaluation of anticancer activity of new pyrazoline derivatives by down-regulation of VEGF: Molecular docking and apoptosis inducing activity.

Two series of pyrazoline compounds were designed and synthesized as antiproliferative agents by VEGFR pathway inhibition. All synthesized compounds were screened by the National Cancer Institute (NCI), Bethesda, USA for anticancer activity against 60 human cancer cell lines. Compound 3f exhibited the highest anticancer activity on the ovarian cell line (OVCAR-4) with IC50 = 0.29 µM and on the breast cell line (MDA-MB-468) with IC50 = 0.35 µM. It also exhibited the highest selectivity index (SI = 74). Compound 3f caused cell cycle arrest in OVCAR-4 cell line at the S phase which consequently inhibited cell proliferation and induced apoptosis. Moreover, 3f showed potent down-regulation of VEGF and p-VEGFR-2. Docking studies showed that compound 3f interacts in a similar pattern to axitinib on the VEGFR-2 receptor. The same compound was also able to fit into the gorge of STAT3 binding site, the transcription factor for VEGF, which explains the VEGF down-regulation.

Novel adenosine derivatives against SARS-CoV-2 RNA-dependent RNA polymerase: an in silico perspective.

BACKGROUND: SARS-CoV-2 is a newly emerged human coronavirus that severely affected human health and the economy. The viral RNA-dependent RNA polymerase (RdRp) is a crucial protein target to stop virus replication. The adenosine derivative, remdesivir, was authorized for emergency use 10 months ago by the United States FDA against COVID-19 despite its doubtful efficacy against SARS-CoV-2. METHODS: A dozen modifications based on remdesivir are tested against SARS-CoV-2 RdRp using combined molecular docking and dynamics simulation in this work. RESULTS: The results reveal a better binding affinity of 11 modifications compared to remdesivir. Compounds 8, 9, 10, and 11 show the best binding affinities against SARS-CoV-2 RdRp conformations gathered during 100 ns of the Molecular Dynamics Simulation (MDS) run (- 8.13 ± 0.45 kcal/mol, - 8.09 ± 0.67 kcal/mol, - 8.09 ± 0.64 kcal/mol, and - 8.07 ± 0.73 kcal/mol, respectively). CONCLUSIONS: The present study suggests these four compounds as potential SARS-CoV-2 RdRp inhibitors, which need to be validated experimentally.

Design and synthesis of methoxyphenyl- and coumarin-based chalcone derivatives as anti-inflammatory agents by inhibition of NO production and down-regulation of NF-κB in LPS-induced RAW264.7 macrophage cells.

Exaggerated inflammatory responses may cause serious and debilitating diseases such as acute lung injury and rheumatoid arthritis. Two series of chalcone derivatives were prepared as anti-inflammatory agents. Methoxylated phenyl-based chalcones 2a-l and coumarin-based chalcones 3a-f were synthesized and compared for their inhibition of COX-2 enzyme and nitric oxide production suppression. Methoxylated phenyl-based chalcones showed better inhibition to COX-2 enzyme and nitric oxide suppression than the coumarin-based chalcones. Among the 18 synthesized chalcone derivatives, compound 2f exhibited the highest anti-inflammatory activity by inhibition of nitric oxide concentration in LPS-induced RAW264.7 macrophages (IC50 = 11.2 µM). The tested compound 2f showed suppression of iNOS and COX-2 enzymes. Moreover, compound 2f decreases in the expression of NF-κB and phosphorylated IκB in LPS-stimulated macrophages. Finally, docking studies suggested the inhibition of IKKß as a mechanism of action and highlighted the importance of 2f hydrophobic interactions.

An Advanced Apralog with Increased in†vitro and in†vivo Activity toward Gram-negative Pathogens and Reduced ex vivo Cochleotoxicity.

We describe the convergent synthesis of a 5-O-ß-D-ribofuranosyl-based apramycin derivative (apralog) that displays significantly improved antibacterial activity over the parent apramycin against wild-type ESKAPE pathogens. In addition, the new apralog retains excellent antibacterial activity in the presence of the only aminoglycoside modifying enzyme (AAC(3)-IV) acting on the parent, without incurring susceptibility to the APH(3') mechanism that disables other 5-O-ß-D-ribofuranosyl 2-deoxystreptamine type aminoglycosides by phosphorylation at the ribose 5-position. Consistent with this antibacterial activity, the new apralog has excellent 30 nM activity (IC50 ) for the inhibition of protein synthesis by the bacterial ribosome in a cell-free translation assay, while retaining the excellent across-the-board selectivity of the parent for inhibition of bacterial over eukaryotic ribosomes. Overall, these characteristics translate into excellent in vivo efficacy against E. coli in a mouse thigh infection model and reduced ototoxicity vis à vis the parent in mouse cochlear explants.

Design, synthesis and antiproliferative evaluation of new tricyclic fused thiazolopyrimidines targeting topoisomerase II: Molecular docking and apoptosis inducing activity.

A novel series of thiazolopyrimidines and fused thiazolopyrimidines was designed and synthesized as topoisomerase II alpha inhibitors. All synthesized compounds were screened by the National Cancer Institute (NCI), Bethesda, USA for anticancer activity against 60 human cancer cell lines representing the following cancer types: leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancers. Compound 3a was found to be the most potent inhibitor on renal cell line (A-498) causing 83.03% inhibition (IC50 = 1.89 µM). DNA-flow cytometric analysis showed that compound 3a induce cell cycle arrest at G2/M phase leading to cell proliferation inhibition and apoptosis. Moreover, fused thiazolopyrimidines 3a showed potent topoisomerase II inhibitory activity (IC50 = 3.19 µM) when compared with reference compound doxorubicin (IC50 = 2.67 µM). Docking study of all the synthesized compounds showed that compound 3a interacts in a similar pattern to etoposide and stabilizing the topoisomerase cleavage complex (Top2-cc) that accounts for its high potency.

Synthesis of a Pseudodisaccharide Suitable for Synthesis of Ring I Modified 4,5-2-Deoxystreptamine Type Aminoglycoside Antibiotics.

To facilitate the synthesis of paromomycin and/or neomycin analogues, we describe a cleavage of ring I from paromomycin that proceeds in the presence of azides and affords a glycosyl acceptor for the installation of a modified ring I. A paromomycin 4',6'-diol is oxidized by the Dess-Martin periodinane followed by m-chloroperoxybenzoic acid. Base treatment then affords a protected pseudodisaccharide, which functions as a glycosyl acceptor. The method should also apply to the cleavage of pyranosyl 4,6-diols from oligosaccharides and glycoconjugates.

Apralogs: Apramycin 5-O-Glycosides and Ethers with Improved Antibacterial Activity and Ribosomal Selectivity and Reduced Susceptibility to the Aminoacyltranserferase (3)-IV Resistance Determinant.

Apramycin is a structurally unique member of the 2-deoxystreptamine class of aminoglycoside antibiotics characterized by a monosubstituted 2-deoxystreptamine ring that carries an unusual bicyclic eight-carbon dialdose moiety. Because of its unusual structure, apramycin is not susceptible to the most prevalent mechanisms of aminoglycoside resistance including the aminoglycoside-modifying enzymes and the ribosomal methyltransferases whose widespread presence severely compromises all aminoglycosides in current clinical practice. These attributes coupled with minimal ototoxocity in animal models combine to make apramycin an excellent starting point for the development of next-generation aminoglycoside antibiotics for the treatment of multidrug-resistant bacterial infections, particularly the ESKAPE pathogens. With this in mind, we describe the design, synthesis, and evaluation of three series of apramycin derivatives, all functionalized at the 5-position, with the goals of increasing the antibacterial potency without sacrificing selectivity between bacterial and eukaryotic ribosomes and of overcoming the rare aminoglycoside acetyltransferase (3)-IV class of aminoglycoside-modifying enzymes that constitutes the only documented mechanism of antimicrobial resistance to apramycin. We show that several apramycin-5-O-ß-d-ribofuranosides, 5-O-ß-d-eryrthofuranosides, and even simple 5-O-aminoalkyl ethers are effective in this respect through the use of cell-free translation assays with wild-type bacterial and humanized bacterial ribosomes and of extensive antibacterial assays with wild-type and resistant Gram negative bacteria carrying either single or multiple resistance determinants. Ex vivo studies with mouse cochlear explants confirm the low levels of ototoxicity predicted on the basis of selectivity at the target level, while the mouse thigh infection model was used to demonstrate the superiority of an apramycin-5-O-glycoside in reducing the bacterial burden in vivo.

Synthesis, ribosomal selectivity, and antibacterial activity of netilmicin 4'-derivatives.

Halogenation of a suitably protected netilmicin derivative enables preparation of 4'-chloro-, bromo-, and iodo derivatives of netilmicin after deprotection. Suzuki coupling of a protected 4'-bromo derivative with phenylboronic acid or butyltrifluoroborate affords the corresponding 4'-phenyl and 4'-butyl derivatives of netilmicin. Sulfenylation of suitably protected netilmicin derivative with ethanesulfenyl chloride followed by deprotection affords 4'-ethylsulfanylnetilmicin. All netilmicin 4'-derivatives displayed reduced levels of inhibition for prokaryotic ribosomes and reduced antibacterial activity against typical Gram-positive and Gram-negative strains. None of the derivatives displayed enhanced target selectivity.

Effects of the 1- N-(4-Amino-2 S-hydroxybutyryl) and 6'- N-(2-Hydroxyethyl) Substituents on Ribosomal Selectivity, Cochleotoxicity, and Antibacterial Activity in the Sisomicin Class of Aminoglycoside Antibiotics.

Syntheses of the 6'- N-(2-hydroxyethyl) and 1- N-(4-amino-2 S-hydroxybutyryl) derivatives of the 4,6-aminoglycoside sisomicin and that of the doubly modified 1- N-(4-amino-2 S-hydroxybutyryl)-6'- N-(2-hydroxyethyl) derivative known as plazomicin are reported together with their antibacterial and antiribosomal activities and selectivities. The 6'- N-(2-hydroxyethyl) modification results in a moderate increase in prokaryotic/eukaryotic ribosomal selectivity, whereas the 1- N-(4-amino-2 S-hydroxybutyryl) modification has the opposite effect. When combined in plazomicin, the effects of the two groups on ribosomal selectivity cancel each other out, leading to the prediction that plazomicin will exhibit ototoxicity comparable to those of the parent and the current clinical aminoglycoside antibiotics gentamicin and tobramycin, as borne out by ex vivo studies with mouse cochlear explants. The 6'- N-(2-hydroxyethyl) modification restores antibacterial activity in the presence of the AAC(6') aminoglycoside-modifying enzymes, while the 1- N-(4-amino-2 S-hydroxybutyryl) modification overcomes resistance to the AAC(2') class but is still affected to some extent by the AAC(3) class. Neither modification is able to circumvent the ArmA ribosomal methyltransferase-induced aminoglycoside resistance. The use of phenyltriazenyl protection for the secondary amino group of sisomicin facilitates the synthesis of each derivative and their characterization through the provision of sharp NMR spectra for all intermediates.

Selective Protection of Secondary Amines as the N-Phenyltriazenes. Application to Aminoglycoside Antibiotics.

Selective protection of secondary amines as triazenes in the presence of multiple primary amines is demonstrated, with subsequent protection of the primary amines as either azides or carbamates in the same pot. Aminoglycoside antibiotic examples reveal broad functional group compatibility. The triazene group is removed with trifluoroacetic acid and, because of the low barrier to rotation, affords sharp (1)H NMR spectra at room temperature.