Potent cholinesterase inhibitors for alzheimer’s disease: synthesis, biological evaluation and computational analysis of novel oxadiazole analogues

Background:Acquired immunodeficiency syndrome (AIDS) and cancer treatment have been a major task for research scientists and pharmaceutical industry for the last many years. Seeking to the development, many promising chemical entities especially five-membered heterocyclic rings like oxadiazole have revealed good anticancer and anti HIV activities. The current review enlists some recently developed anti-HIV and anti-cancer oxadiazole moieties.Methods:on the basis of structural modification for the syntheses of new oxadiazole analogs, the new anti-HIV and anti-cancer agents have been summarized, which can improve treatment of AIDs and cancer.Results:The oxadiazole ring is more potent in comparison to some other heterocyclic rings (five and six membered) towards anti-HIV and anti-cancer activities. The important mechanisms involved for anti HIV and anticancer activity are mainly inhibition of enzymes like protease, HIV-integrase, telomerase, histone deacetylase, methionine amino peptidase, thymidylate synthase and focal adhesion kinase and inhibition of some growth factors.Conclusion:By reviving the past literature about 50 most potent oxadiazole derivatives, depending upon activity and structural modifications, have been selected as potent anti-HIV, and anti-cancer agents. Thus, oxadiazole seems to be a ‘privileged structure’ for further screening and syntheses of the new drug analogs against life threatening HIV and cancer like diseases.

A new series of fourteen derivatives, N‐(substituted phenyl)‐2‐((5‐phenyl‐1,3,4‐oxadiazol‐2‐yl)thio)acetamides derivatives, were synthesized via nucleophilic substitution reaction by reacting 2‐chloro‐N‐(aryl)acetamides derivatives with 5‐phenyl‐1,3,4‐oxadiazole‐2‐thiol in N, N‐dimethylformamide. The parent compound, 5‐phenyl‐1,3,4‐oxadiazole‐2‐thiol, is well‐documented for its broad pharmacological activities, including antibacterial, antiviral, and antifungal properties. The structures of the synthesized compounds were confirmed through elemental analysis and spectral techniques (NMR, IR, and mass spectrometry). The biological activity of the derivatives was evaluated against bacterial strains (Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa), fungal strains (Candida albicans and Aspergillus niger), and Mycobacterium smegmatis. Among the tested derivatives, N‐(3‐nitrophenyl)‐2‐((5‐phenyl‐1,3,4‐oxadiazol‐2‐yl)thio)acetamide (3j) displayed exceptional antimicrobial properties, exhibiting the lowest minimum inhibitory concentration (MIC) values of 1.56 µg/mL against all bacterial strains, 3.25 µg/mL against fungal strains, and 3.96 µg/mL against Mycobacterium smegmatis. Furthermore, docking and simulation studies on the most active compound, 3j, revealed significant binding affinity within the active sites of glucosamine‐6‐phosphate synthase (PDB ID: 2VF5) and Mycobacterium tuberculosis enoyl‐ACP reductase (PDB ID: 2 × 22). The docking results provide insights into the compound's potential mechanisms of action and its promising therapeutic relevance. This study highlights the significant antimicrobial properties of N‐(substituted phenyl)‐2‐((5‐phenyl‐1,3,4‐oxadiazol‐2‐yl)thio)acetamides, supporting their advancement through detailed mechanistic investigations and in vivo efficacy assessments.

Οι σύγχρονες στρατηγικές στην ανακάλυψη νέων βιοδραστικών ενώσεων στοχεύουν, κατά κύριο λόγο, σε καλά χαρακτηρισμένους μοριακούς στόχους με σκοπό την επαγωγή ή την αναστολή συγκεκριμένων βιολογικών δράσεων και τον περιορισμό ανεπιθύμητων παρενεργειών. Έναν ανάλογο μοριακό στόχο αποτελεί η διαλυτή γουανυλική κυκλάση (sGC), η οποία βρίσκεται στο επίκεντρο του ερευνητικού ενδιαφέροντος την τελευταία δεκαετία. Παρόλο που ανακαλύφθηκε περίπου πριν από τέσσερις δεκαετίες ως μέλος της οικογένειας των κυκλασών, η έρευνα που ακολούθησε την ανακάλυψή της δεν χαρακτηρίστηκε από την ίδια πρόοδο που χαρακτήρισε έναν άλλο εκπρόσωπο της ίδιας οικογένειας, την αδενυλική κυκλάση. Μερικοί από τους λόγους της περιορισμένης μελέτης της sGC συνοψίζονται στην χαμηλή ενδοκυτταρική της συγκέντρωση, που συνεπάγεται δυσκολίες στην απομόνωση, στον καθαρισμό και το χειρισμό της, και στην έλλειψη ενός αποτελεσματικού συστήματος έκφρασής της. Επιπρόσθετα, μόνο μετά την ανακάλυψη του μονοξειδίου του αζώτου (ΝΟ), την αναγνώρισή του ως σηματοδοτικό μόριο καθώς και την ταυτοποίησή του ως τον EDRF στα τέλη της δεκαετίας του ’80, πραγματοποιήθηκε ουσιαστική πρόοδος στον τομέα των βιολογικών δράσεων της sGC. Ο καθαρισμός του ετεροδιμερούς ενζύμου και η ανακάλυψη ενός μορίου αίμης ανά διμερές έθεσε τη βάση για την αποσαφήνιση του μηχανισμού ενεργοποίησης της sGC από το ΝΟ και την ακόλουθη κατάλυση της μετατροπής του GTP σε κυκλικό GMP, αν και ο ακριβής μηχανισμός παραμένει μέχρι σήμερα άγνωστος. Η ταυτοποίηση, επομένως, του σηματοδοτικού μονοπατιού NO/sGC/cGMP αποτέλεσε τη βάση για την ανακάλυψη ότι φάρμακα όπως τα οργανικά νιτρώδη, που χρησιμοποιούνται στη θεραπεία της στηθάγχης για περισσότερο από έναν αιώνα, δρουν στην ουσία ως δότες μονοξειδίου του αζώτου μέσω βιομετατροπής τους και ασκούν τη δράση τους μέσω ενεργοποίησης της sGC και παραγωγής, ακολούθως, του δεύτερου αγγελιοφόρου cGMP. Tα παραπάνω δεδομένα οδήγησαν στον προσδιορισμό του ΝΟ ως σημαντικού σηματοδοτικού μορίου στη φυσιολογία καταρχήν του καρδιαγγειακού συστήματος. Η πρόοδος που ακολούθησε τη μελέτη του sGC-cGMP μονοπατιού αποκάλυψε την ευρεία παρουσία του ενζύμου - 243 - Κατερίνα Σπυριδωνίδου: Διδακτορική Διατριβή Περίληψη σχεδόν σε όλα τα κύτταρα των θηλαστικών και την εμπλοκή του σε ουσιαστικές φυσιολογικές λειτουργίες, όπως την καρδιακή ομοιόσταση, τη χάλαση αγγειακών και μη λείων μυικών ινών, την αναστολή της συσσώρευσης/συγκόλλησης αιμοπεταλίων, την περιφερειακή και κεντρική νευροδιαβίβαση, την ανοσολογική απόκριση, τη μεταγωγή του οπτικού ερεθίσματος, ενώ παρουσιάζει και ρυθμιστική δράση στο γαστρεντερικό και ουρογεννητικό σύστημα. Ταυτόχρονα, απορρύθμιση του σηματοδοτικού μονοπατιού έχει διαπιστωθεί να εμπλέκεται στην φυσιολογία και την εξέλιξη συγκεκριμένων παθολογικών καταστάσεων όπως αρτηριακή και πνευμονική υπέρταση, καρδιακή ανεπάρκεια, αρτηριοσκλήρυνση και θρόμβωση, διαβήτης, νεφρική ίνωση και ανεπάρκεια, φλεγμονώδεις και νευροεκφυλιστικές παθήσεις, γαστρεντερικές διαταραχές, σήψη και καρκίνος, όπου εντοπίζεται είτε να υπερλειτουργεί είτε να υπολειτουργεί. Εξαιτίας της σπουδαιότητας και της σοβαρότητας των καρδιαγγειακών παθήσεων, όπου το σηματοδοτικό μονοπάτι υπολειτουργεί, το μεγαλύτερο κομμάτι της έρευνας που ακολούθησε σχετικά με την ανακάλυψη νέων βιοδραστικών ενώσεων εστίασε κυρίως στην ανάπτυξη αγωνιστών της sGC, παρέχοντας όχι μόνο ΝΟ-δότες με βελτιωμένες ιδιότητες αλλά, επιπρόσθετα, δύο νέες κατηγορίες ΝΟ- ανεξάρτητων ενεργοποιητών που περιλαμβάνουν διακριτές δομικά ενώσεις. Η πρόοδος, ωστόσο, στην αναστολή του ενζύμου κρίνεται εμφανώς υποδεέστερη, παρόλη την προφανή σπουδαιότητα ανάλογων ενώσεων στη διερεύνηση των cGMP-εξαρτώμενων βιολογικών δράσεων.

Currently approved Alzheimer's disease medications mainly comprise acetylcholinesterase inhibitors. Many of these inhibitors are either natural compounds or synthetic molecules inspired in natural compounds. Hybrid molecules that can interact with different target sites of the enzyme could lead to the discovery of effective multitarget drugs. To design, synthesize, and evaluate a series of new aza-resveratrol analogs as in vitro acetyl- and butyrylcholinesterase inhibitors. The synthesis is achieved by a simple and efficient microwave-assisted method, from commercially available starting materials. Compounds are designed as hybrids of an aza-stilbene nucleus (Schiff base) connected to a tertiary amine by a hydrocarbon chain of variable length, designed to interact both with the peripheric anionic site and the catalytic site of the enzyme. All the derivatives inhibit both enzymes in a concentration-dependent manner, acting as moderate to potent cholinesterase inhibitors. The most potent inhibitors are compounds 12b (IC50 = 0.43 μM) and 12a (IC50 = 0.31 μM) for acetyl- and butyrylcholinesterase, respectively. Compounds 12a and 12b also exhibit significant acetylcholinesterase inhibition in SH-SY5Y human neuroblastoma cells without cytotoxic properties. Enzyme kinetic studies and molecular modeling reveal that inhibitor 12b targets both the catalytic active site and the peripheral anionic site of acetylcholinesterase what makes it able to modulate the self-induced β-amyloid aggregation. Furthermore, the molecular modeling analysis helps to assess the impact of the linker length in the inhibitory activity of this family of new cholinesterase inhibitors. These compounds have the potential to serve as a dual binding site inhibitor and might provide a useful template for the development of new anti-Alzheimer's disease agents.

Two novel series of oxadiazole and oxadiazoline analogs possessing an indole nucleus were synthesized for their potential anti-inflammatory activity. The structures of the compounds were elucidated by elemental and spectral (IR, 1H-NMR, 13C-NMR, and MS) analysis. Most of the test compounds demonstrated appreciable anti-inflammatory activities. The anti-inflammatory activity of oxadiazoles at doses of 100 mg/kg was shown by their ability to provide 27–66%, 14–32%, and 20-51%. protection against carrageenan-induced rat paw edema, moist cotton pellet-induced, and dry cotton pellet-induced granuloma, respectively. On the other hand, the anti-inflammatory properties of oxadiazolines at doses of 100 mg/kg were reflected by their ability to provide 20-56%, 11–26%, and 25–47% protection against carrageenan-induced rat paw edema, moist cotton pellet-induced, and dry cotton pellet-induced granuloma, respectively. The ulcerogenic potential of the compounds was determined. Structure–activity relationships among synthesized compounds were also established.

Background: Cancer is one of the major health diseases worldwide with an approximately 14 million new cases of cancer and 8.2 million cancer related death tolls were reported in 2012. The major complications associated with chemotherapy are limited efficacy, selectivity, safety as well as higher cost, emergence of drug resistant cancer, and genotoxicity. Today we need more effective and safer cytotoxic agents to combat cancer. Method: Two new series of N-(2,6-dimethylphenyl)-5-aryl-1,3,4-oxadiazol-2-amine (4a–g) and N-{[5- aryl-1,3,4-oxadiazol-2-yl]methyl}-2,6-dimethylaniline (4h-n) were designed and synthesized based on the structure of IMC-038525 (tubulin polymerization inhibitor) and NSC 777948 as cytotoxic agents. The cytotoxicity of eight compounds was carried out as per National Cancer Institute (NCI US) protocol on nearly 60 cancer cell lines, while the cytotoxicity of five compounds was carried out as per Sulforhodamine B assay on two breast cancer cell lines. The molecular docking studies implying tubulin inhibition were also carried out to observe the binding mode of new oxadiazoles. Results: N-(2,6-Dimethylphenyl)-5-(4-chlorophenyl)-1,3,4-oxadiazol-2-amine (4b) showed significant cytotoxicity with comparatively higher sensitivity towards colon cancer (HT29), melanoma (LOX IMVI), leukemia (RPMI-8226), and melanoma (M14), with percent growth inhibitions (% GIs) of 80.99, 75.05, 63.25, and 62.19 respectively. Compound 4b showed better cytotoxicity than the standard drug imatinib. Further compound 4b showed maximum docking score and was found to have different binding mode than the rest of the compounds at the colchicine binding site of tubulin enzyme with a hydrogen bonding between NH with carbonyl oxygen of Thr353 (bond length = 3.05A). The hydrophilicity of compound 4b was another parameter that might play a major role and made it most effective when compared to the rest of the compounds. Conclusion: The oxadiazoles reported herein are cytotoxic agents. These findings may be helpful in future drug design of more potent cytotoxic agents. Keywords: Anticancer agent, cytotoxic agents, oxadiazoles, one dose assay, molecular docking, sulforhodamine B assay.

In continuance of our search for new anticancer agents, we report herein the design, synthesis, and anticancer evaluation of oxadiazole analogues. Two series (4a-h and 4i-q) of new oxadiazole analogues were designed based on heterocyclic (1,3,4-oxadiazole)-linked aryl core of IMC-038525 (tubulin polymerization inhibitor), NSC 776715, and NSC 776715 and synthesized. All the compounds were fully characterized by infrared, nuclear magnetic resonance spectroscopy, and mass spectral data and the purity of compounds was checked by elemental analysis (C, H, and N analysis). Further seven compounds were evaluated for anticancer activity on nine different panels of 60 cell lines (60 NCI cancer cell lines) according to the National Cancer Institute screening protocol and percent growth and percent growth inhibition was calculated at 10 µM drug concentration. Ten compounds were evaluated for anticancer activity on two cancer cell lines (HeLa and MDA-MB-435) as per the standard protocol reported at four different drug concentrations (10−7, 10−6, 10−5, and 10−4 µM) and GI50, LC50, and TGI dose-related parameters were calculated. The compound 4j showed maximum anticancer activity at 10 µM, and was found to have higher sensitivity against MOLT-4, IGROV1, HCT-116, and K-562 with percent growth inhibitions of 50.38, 48.45, 46.26, and 46.26 respectively. The compound 4j showed superior anticancer activity than imatinib on 41 human cancer cell lines. The compound 4p showed anticancer activity with GI50 of 36.7 and 46.5 µM against HeLa and MDA-MB-435 cell lines, respectively.

New LPA1 receptor modulators: Design, synthesis, in-silico, and anticancer studies of triazole and oxadiazole analogs

In continuance of our search for anticancer agents, we report herein the synthesis and anticancer activity of some novel oxadiazole analogues. The compounds were screened for anticancer activity as per National Cancer Institute (NCI US) protocol on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers cell lines. N-(2,4-Dimethylphenyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-amine (4s) showed maximum activity with mean growth percent (GP) of 62.61 and was found to be the most sensitive on MDA-MB-435 (melanoma), K-562 (leukemia), T-47D (breast cancer), and HCT-15 (colon cancer) cell lines with GP of 15.43, 18.22, 34.27, and 39.77, respectively. Maximum GP was observed on MDA-MB-435 (melanoma) cell line (GP = 6.82) by compound N-(2,4-dimethylphenyl)-5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-amine (4u).

Solution-phase microwave assisted parallel synthesis, biological evaluation and in silico docking studies of N,N′-disubstituted thioureas derived from 3-chlorobenzoic acid

Solution-phase microwave assisted parallel synthesis, biological evaluation and in silico docking studies of 2-chlorobenzoyl thioureas derivatives

Event Abstract Back to Event Synthesis, characterization and pharmacological evaluation of pyrimidine analogues for the management of Alzheimer’s disease Rakesh Yadav1*, Monika Maan1 and Divya Yadav1 1 Banasthali University, Pharmaceutical Chemistry, India Alzheimer’s disease (AD) is a highly complex neurodegenerative disorder, which is characterized by the loss of memory and manifests in the cholinergic branch of central nervous system. Cholinesterase inhibitors have been found to be efficacious in reducing the symptoms of early medium stage of AD. There are number of drugs, which have been reported such as donepezil, galantamine, tacrine for the treatment of Alzheimer's. The pyrimidine scaffold is an important pharmacological structural component in well-known anti-AD drugs. In the present study, we have designed, synthesized and evaluated a series of 2, 4-disubstituted pyrimidine derivatives (RY-114 to RY-123) for the treatment of neurodegenerative diseases. The synthesis of a key intermediate i.e. 4-(substituted aniline)-2-chloropyrimidine was performed using 2, 4-dichloropyrimidine (1) as a starting material. The condensation of 1 with various substituted aniline in the presence of DIPEA and ethanol gave the desired key intermediate. The titled compounds were synthesized by condensation of the key intermediate with various primary or secondary substituted amines using direct fusion method in microwave or reflux in the presence of DIPEA and n-butanol. The structures of newly synthesized compounds were characterized using various spectral techniques viz. FT-IR, NMR, elemental analysis etc. The biological evaluation (in vivo or in vitro) of the synthesized derivatives RY-114 to RY-123 showed gradient effect with respect to the standard drug (Donezepil). The outcome of the work may lead to be selective and medicinally active chemical entities for the management of Alzheimer’s disease. Keywords: Galantamine, Tacrine, Alzheimer’s disease, donepezil, Neurodegenerative disorders Conference: 14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016. Presentation Type: YIC04: Young Investigator Colloquium 4 Topic: 14th Meeting of the Asian-Pacific Society for Neurochemistry Citation: Yadav R, Maan M and Yadav D (2016). Synthesis, characterization and pharmacological evaluation of pyrimidine analogues for the management of Alzheimer’s disease. Conference Abstract: 14th Meeting of the Asian-Pacific Society for Neurochemistry. doi: 10.3389/conf.fncel.2016.36.00065 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Aug 2016; Published Online: 11 Aug 2016. * Correspondence: Dr. Rakesh Yadav, Banasthali University, Pharmaceutical Chemistry, Banasthali, Rajasthan, India, rakesh_pu@yahoo.co.in Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Rakesh Yadav Monika Maan Divya Yadav Google Rakesh Yadav Monika Maan Divya Yadav Google Scholar Rakesh Yadav Monika Maan Divya Yadav PubMed Rakesh Yadav Monika Maan Divya Yadav Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

A structural series of 7-MEOTA-adamantylamine thioureas was designed, synthesized and evaluated as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). The compounds were prepared based on the multi-target-directed ligand strategy with different linker lengths (n = 2–8) joining the well-known NMDA antagonist adamantine and the hAChE inhibitor 7-methoxytacrine (7-MEOTA). Based on in silico studies, these inhibitors proved dual binding site character capable of simultaneous interaction with the peripheral anionic site (PAS) of hAChE and the catalytic active site (CAS). Clearly, these structural derivatives exhibited very good inhibitory activity towards hBChE resulting in more selective inhibitors of this enzyme. The most potent cholinesterase inhibitor was found to be thiourea analogue 14 (with an IC50 value of 0.47 µM for hAChE and an IC50 value of 0.11 µM for hBChE, respectively). Molecule 14 is a suitable novel lead compound for further evaluation proving that the strategy of dual binding site inhibitors might be a promising direction for development of novel AD drugs.

Discovery of 7H-pyrrolo[2,3-d]pyridine derivatives as potent FAK inhibitors: Design, synthesis, biological evaluation and molecular docking study

Highly efficient synthesis of medium-sized lactams via intramolecular Staudinger–aza-Wittig reaction of ω-azido pentafluorophenyl ester: synthesis and biological evaluation of LY411575 analogues