DOCSLIB.ORG

Benzimidazole Derivatives Endowed with Potent Antileishmanial Activity

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Benzimidazole Derivatives Endowed with Potent Antileishmanial Activity Journal of Enzyme Inhibition and Medicinal Chemistry ISSN: 1475-6366 (Print) 1475-6374 (Online) Journal homepage: http://www.tandfonline.com/loi/ienz20 Benzimidazole derivatives endowed with potent antileishmanial activity Michele Tonelli, Elena Gabriele, Francesca Piazza, Nicoletta Basilico, Silvia Parapini, Bruno Tasso, Roberta Loddo, Fabio Sparatore & Anna Sparatore To cite this article: Michele Tonelli, Elena Gabriele, Francesca Piazza, Nicoletta Basilico, Silvia Parapini, Bruno Tasso, Roberta Loddo, Fabio Sparatore & Anna Sparatore (2018) Benzimidazole derivatives endowed with potent antileishmanial activity, Journal of Enzyme Inhibition and Medicinal Chemistry, 33:1, 210-226, DOI: 10.1080/14756366.2017.1410480 To link to this article: https://doi.org/10.1080/14756366.2017.1410480 © 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Published online: 13 Dec 2017. Submit your article to this journal Article views: 127 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ienz20 Download by: [Università degli Studi di Milano] Date: 08 January 2018, At: 06:19 JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2017 VOL. 33, NO. 1, 210–226 https://doi.org/10.1080/14756366.2017.1410480 RESEARCH PAPER Benzimidazole derivatives endowed with potent antileishmanial activity Michele Tonellia , Elena Gabrieleb , Francesca Piazzab, Nicoletta Basilicoc, Silvia Parapinid, Bruno Tassoa, Roberta Loddoe, Fabio Sparatorea and Anna Sparatoreb aDipartimento di Farmacia, Universita di Genova, Genova, Italy; bDipartimento di Scienze Farmaceutiche, Universita degli Studi di Milano, Milano, Italy; cDipartimento di Scienze Biomediche Chirurgiche e Odontoiatriche, Universita degli Studi di Milano, Milano, Italy; dDipartimento di Scienze Farmacologiche e Biomolecolari, Universita degli Studi di Milano, Milano, Italy; eDipartimento di Scienze e Tecnologie Biomediche, Universita di Cagliari, Cittadella Universitaria, Monserrato, Italy ABSTRACT ARTICLE HISTORY Two sets of benzimidazole derivatives were synthesised and tested in vitro for activity against promasti- Received 27 October 2017 gotes of Leishmania tropica and L. infantum. Most of the tested compounds resulted active against both Revised 22 November 2017 Accepted 22 November 2017 Leishmania species, with IC50 values in the low micromolar/sub-micromolar range. Among the set of 2-(long chain)alkyl benzimidazoles, whose heterocyclic head was quaternised, compound 8 resulted about KEYWORDS 100-/200-fold more potent than miltefosine, even if the selectivity index (SI) versus HMEC-1 cells was only Leishmania tropica and moderately improved. In the set of 2-benzyl and 2-phenyl benzimidazoles, bearing a basic side chain in infantum; promastigotes; position 1, compound 28 (2-(4-chlorobenzyl)-1-lupinyl-5-trifluoromethylbenzimidazole) was 12-/7-fold more anti-leishmania agents; alkyl potent than miltefosine, but exhibited a further improved SI. Therefore, compounds 8 and 28 represent benzimidazolium salts; interesting hit compounds, susceptible of structural modification to improve their safety profiles. 2-benzyl-1-lupinylbenzimi- dazole derivatives IC SI Compd. 50 (µM) HMEC Vero76 L. tropicaa 5.05 >27.1 - L. infantuma 10.09 >13.6 - L. tropicaa 0.19 4.10 30.5 L. infantuma 0.34 2.29 17.1 L. infantumb 0.31 - - L. tropicaa 3.70 4.58 >27 L. infantuma 4.76 3.61 >21 Downloaded by [Università degli Studi di Milano] at 06:19 08 January 2018 L. tropicaa 43.26 2.3 - Miltefosine L. infantuma 31.26 3.2 - L. infantumb 1.05 - - apromastigotes; bamastigotes CONTACT Michele Tonelli [email protected] Dipartimento di Farmacia, Universita degli Studi di Genova, 16132 Genova, Italy; Nicoletta Basilico nicoletta. [email protected] Dipartimento di Scienze Biomediche Chirurgiche e Odontoiatriche, Universita degli Studi di Milano, Via Pascal 36, Milano, 20133 Italy; Anna Sparatore [email protected] Dipartimento di Scienze e Tecnologie Biomediche, Universita degli Studi di Milano, Via L. Mangiagalli, 25, 20133 Milano, Italy ß 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distri- bution, and reproduction in any medium, provided the original work is properly cited. JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY 211 Introduction paromomycin and pentamidine are considered second-line drugs3a–c. Some other drugs as edelfosine, sitamaquine, fexinida- After malaria, leishmaniasis is the second most prevalent parasite zole, tamoxifene, imiquimod and pentoxyphylline are reported to infection worldwide for mortality in humans1. It is transmitted by give variable cure rates when used either alone or, better, in asso- the bite of a sand-fly infected by a flagellate protozoan of the ciation with antimonials to overcome resistance4 (Figure 1). genus Leishmania. Three different forms of the disease are All these drugs may cause several side effects and most of described: visceral, cutaneous and muco-cutaneous leishmaniasis. them are also expensive, and thus out of reach for the poor peo- The disease is endemic in many tropical and subtropical Countries, ple living in tropical and sub-tropical countries, where the disease leading annually to an estimated 700,000–1 million new cases and is endemic. The cited drugs exhibit very different chemical struc- 1 20,000–30,000 deaths , mostly due to the visceral form caused by tures and hit a variety of biological targets, but in several cases Leishmania donovani. The parasite exists in the ovoid non-flagel- the mechanism of action is still undefined or only partially known. late form (amastigote) and in the flagellate promastigote, found in To meet the need of novel more efficacious, safe and unexpen- the sand-fly. sive drugs to treat leishmaniasis, a number of studies are on- The therapy of leishmaniasis is still based on pentavalent anti- going, exploring a wide chemical space from several classes of monials (sodium stibogluconate and meglumine antimoniate) as natural products5 and or their semi-synthetic derivatives (sterols5, first choice drug2a,2b, whereas amphotericin B, miltefosine, mono-, sequi-, di- and tri-terpens6, alkaloids7, flavonoids8, etc.) to Downloaded by [Università degli Studi di Milano] at 06:19 08 January 2018 Figure 1. First and second line or synergistic agents to treat leishmaniasis: (a) meglumine antimoniate (predominant species in aqueous solution); (b) sodium stibogluc- onate (predominant species in aqueous solution); (c) amphotericin B; (d) miltefosine; (e) edelfosine; (f) paromomycin; (g) pentamidine; (h) sitamaquine; (i) imiquimod; (j) tamoxifene; (k) fexinidazole; (l) pentoxyphylline. 212 M. TONELLI ET AL. the most diversified synthetic compounds, from the simple chlor- Among the benzazolic derivatives, an important position is oacetoanilides9, to organometallics10a (as auranofin10b), aryldisele- held by the 2-trifluoromethyl-17 and 2-arylbenzimidazole18 deriva- nides11, adamantylidene alkyl phosphocoline12 and a variety of tives that, besides activity versus several other protozoa, display heterocycles13, particularly indole14, indazole15, benzotriazole16 antileishmanial action with potency in the low micromolar range. and benzimidazole17–20 derivatives. Examples of these compounds Interestingly, some bis-benzimidazoles19,20 exhibit sub-micromolar are depicted in Figures 2 and 3. IC50, resulting 7- to 26-fold more potent than pentamidine. Downloaded by [Università degli Studi di Milano] at 06:19 08 January 2018 Figure 2. Examples of investigational anti-leishmanial agents5–16. JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY 213 Figure 3. Benzimidazole derivatives previously tested as anti-leishmanial agents17–20. Since many years we are interested in the chemistry and bio- responsible for cutaneous leishmaniasis (CL), and 33 of them logical properties of benzimidazole derivatives, pursuing varied (depending on availability) were also tested against L. infantum, pharmacological aims, from analgesic-anti-inflammatory action21, the causative agent of visceral leishmaniasis (VL). The two best conditioned avoidance response (CAR) inhibition22, choleretic compounds were also assayed against L. infantum amastigotes. activity and gastric protection23, antiviral24 and antitumoral25 activ- Downloaded by [Università degli Studi di Milano] at 06:19 08 January 2018 ities. In order to further explore the biocidal potential of benzimi- dazole derivatives, we deemed interesting to evaluate the Materials and methods antileishmanial activity of a set of 2-alkyl/2-benzyl benzimidazoles General whose heterocyclic head was quaternised to mimic the ammo- nium head of miltefosine and edelfosine. Additionally, we selected, Chemicals, solvents and reagents used for the syntheses were pur- among our in house library of benzimidazoles, a second set of chased from Sigma-Aldrich, Fluka or Alfa Aesar, and were used 2-arylbenzimidazoles 1-substituted with basic side chains that without any further purification unless otherwise stated. CC ¼ flash might be loosely related to sitamaquine. As the anti-leishmanial column chromatography. Melting points (uncorrected) were deter- 1 13 activity of sitamaquine analogues is mainly related to the length mined with a Buchi€ apparatus. H NMR and C NMR spectra were
Load more

Recommended publications
  • Pharmacological Significance of Heterocyclic 1H-Benzimidazole
    Tahlan et al. BMC Chemistry (2019) 13:101 https://doi.org/10.1186/s13065-019-0625-4 BMC Chemistry REVIEW Open Access Pharmacological signifcance of heterocyclic 1H-benzimidazole scafolds: a review Sumit Tahlan, Sanjiv Kumar and Balasubramanian Narasimhan* Abstract Heterocyclic compounds are inevitable in a numerous part of life sciences. These molecules perform various note- worthy functions in nature, medication and innovation. Nitrogen-containing heterocycles exceptionally azoles family are the matter of interest in synthesis attributable to the way that they happen pervasively in pharmacologically dynamic natural products, multipurpose arranged useful materials also profoundly powerful pharmaceuticals and agrochemicals. Benzimidazole moiety is the key building block for several heterocyclic scafolds that play central role in the biologically functioning of essential molecules. They are considered as promising class of bioactive scafolds encompassing diverse varieties of activities like antiprotozoal, antihelminthic, antimalarial, antiviral, anti-infammatory, antimicrobial, anti-mycobacterial and antiparasitic. Therefore in the present review we tried to compile the various pharmacological activities of diferent derivatives of heterocyclic benzimidazole moiety. Keywords: Benzimidazole derivatives, Antiprotozoal activity, Anti-infammatory activity, Antimalarial activity, Antimycobacterial activity, Antiviral activity, Anticancer activity Introduction acetylcholinesterase [4], antiprotozoal [5], anti-infam- Among heterocyclic pharmacophores, the benzimida- matory [6], analgesic [7], antihistaminic [8], antimalarial zole ring system is quite common. Tese substructures [9], antitubercular [10], anti-HIV [11] and antiviral [12]. are often called ‘privileged’ due to their wide recurrence Some of the already synthesized compounds from the in bioactive compounds [1]. Benzimidazole moiety is above mentioned feld have found very strong application a fusion of benzene and imidazole ring system at the 4 in medicine praxis.
    [Show full text]
  • Anthelmintic Activity of Yeast Particle-Encapsulated Terpenes
    molecules Article Anthelmintic Activity of Yeast Particle-Encapsulated Terpenes Zeynep Mirza 1, Ernesto R. Soto 1 , Yan Hu 1,2, Thanh-Thanh Nguyen 1, David Koch 1, Raffi V. Aroian 1 and Gary R. Ostroff 1,* 1 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; [email protected] (Z.M.); [email protected] (E.R.S.); [email protected] (Y.H.); [email protected] (T.-T.N.); [email protected] (D.K.); raffi[email protected] (R.V.A.) 2 Department of Biology, Worcester State University, Worcester, MA 01602, USA * Correspondence: gary.ostroff@umassmed.edu; Tel.: 508-856-1930 Academic Editor: Vaclav Vetvicka Received: 2 June 2020; Accepted: 24 June 2020; Published: 27 June 2020 Abstract: Soil-transmitted nematodes (STN) infect 1–2 billion of the poorest people worldwide. Only benzimidazoles are currently used in mass drug administration, with many instances of reduced activity. Terpenes are a class of compounds with anthelmintic activity. Thymol, a natural monoterpene phenol, was used to help eradicate hookworms in the U.S. South circa 1910. However, the use of terpenes as anthelmintics was discontinued because of adverse side effects associated with high doses and premature stomach absorption. Furthermore, the dose–response activity of specific terpenes against STNs has been understudied. Here we used hollow, porous yeast particles (YPs) to efficiently encapsulate (>95%) high levels of terpenes (52% w/w) and evaluated their anthelmintic activity on hookworms (Ancylostoma ceylanicum), a rodent parasite (Nippostrongylus brasiliensis), and whipworm (Trichuris muris). We identified YP–terpenes that were effective against all three parasites.
    [Show full text]
  • Albendazole: a Review of Anthelmintic Efficacy and Safety in Humans
    S113 Albendazole: a review of anthelmintic efficacy and safety in humans J.HORTON* Therapeutics (Tropical Medicine), SmithKline Beecham International, Brentford, Middlesex, United Kingdom TW8 9BD This comprehensive review briefly describes the history and pharmacology of albendazole as an anthelminthic drug and presents detailed summaries of the efficacy and safety of albendazole’s use as an anthelminthic in humans. Cure rates and % egg reduction rates are presented from studies published through March 1998 both for the recommended single dose of 400 mg for hookworm (separately for Necator americanus and Ancylostoma duodenale when possible), Ascaris lumbricoides, Trichuris trichiura, and Enterobius vermicularis and, in separate tables, for doses other than a single dose of 400 mg. Overall cure rates are also presented separately for studies involving only children 2–15 years. Similar tables are also provided for the recommended dose of 400 mg per day for 3 days in Strongyloides stercoralis, Taenia spp. and Hymenolepis nana infections and separately for other dose regimens. The remarkable safety record involving more than several hundred million patient exposures over a 20 year period is also documented, both with data on adverse experiences occurring in clinical trials and with those in the published literature and\or spontaneously reported to the company. The incidence of side effects reported in the published literature is very low, with only gastrointestinal side effects occurring with an overall frequency of just "1%. Albendazole’s unique broad-spectrum activity is exemplified in the overall cure rates calculated from studies employing the recommended doses for hookworm (78% in 68 studies: 92% for A. duodenale in 23 studies and 75% for N.
    [Show full text]
  • Structure–Activity Relationship Analysis of Benzimidazoles As Emerging Anti-Inflammatory Agents: an Overview
    pharmaceuticals Review Structure–Activity Relationship Analysis of Benzimidazoles as Emerging Anti-Inflammatory Agents: An Overview Ravichandran Veerasamy 1,2,*, Anitha Roy 3 , Rohini Karunakaran 4 and Harish Rajak 5 1 Pharmaceutical Chemistry Unit, Faculty of Pharmacy, AIMST University, Semeling 08100, Kedah, Malaysia 2 Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai 600077, Tamil Nadu, India 3 Department of Pharmacology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai 600077, Tamil Nadu, India; [email protected] 4 Faculty of Medicine, AIMST University, Semeling 08100, Kedah, Malaysia; [email protected] 5 SLT Institute of Pharmaceutical Sciences, Guru Ghasidas University, Bilaspur 495009, India; [email protected] * Correspondence: [email protected] Abstract: A significant number of the anti-inflammatory drugs currently in use are becoming obso- lete. These are exceptionally hazardous for long-term use because of their possible unfavourable impacts. Subsequently, in the ebb-and-flow decade, analysts and researchers are engaged in devel- oping new anti-inflammatory drugs, and many such agents are in the later phases of clinical trials. Molecules with heterocyclic nuclei are similar to various natural antecedents, thus acquiring immense consideration from scientific experts and researchers. The arguably most adaptable heterocyclic cores are benzimidazoles containing nitrogen in a bicyclic scaffold. Numerous benzimidazole drugs are broadly used in the treatment of numerous diseases, showing promising therapeutic poten- Citation: Veerasamy, R.; Roy, A.; tial. Benzimidazole derivatives exert anti-inflammatory effects mainly by interacting with transient Karunakaran, R.; Rajak, H. receptor potential vanilloid-1, cannabinoid receptors, bradykinin receptors, specific cytokines, 5- Structure–Activity Relationship lipoxygenase activating protein and cyclooxygenase.
    [Show full text]
  • Estonian Statistics on Medicines 2016 1/41
    Estonian Statistics on Medicines 2016 ATC code ATC group / Active substance (rout of admin.) Quantity sold Unit DDD Unit DDD/1000/ day A ALIMENTARY TRACT AND METABOLISM 167,8985 A01 STOMATOLOGICAL PREPARATIONS 0,0738 A01A STOMATOLOGICAL PREPARATIONS 0,0738 A01AB Antiinfectives and antiseptics for local oral treatment 0,0738 A01AB09 Miconazole (O) 7088 g 0,2 g 0,0738 A01AB12 Hexetidine (O) 1951200 ml A01AB81 Neomycin+ Benzocaine (dental) 30200 pieces A01AB82 Demeclocycline+ Triamcinolone (dental) 680 g A01AC Corticosteroids for local oral treatment A01AC81 Dexamethasone+ Thymol (dental) 3094 ml A01AD Other agents for local oral treatment A01AD80 Lidocaine+ Cetylpyridinium chloride (gingival) 227150 g A01AD81 Lidocaine+ Cetrimide (O) 30900 g A01AD82 Choline salicylate (O) 864720 pieces A01AD83 Lidocaine+ Chamomille extract (O) 370080 g A01AD90 Lidocaine+ Paraformaldehyde (dental) 405 g A02 DRUGS FOR ACID RELATED DISORDERS 47,1312 A02A ANTACIDS 1,0133 Combinations and complexes of aluminium, calcium and A02AD 1,0133 magnesium compounds A02AD81 Aluminium hydroxide+ Magnesium hydroxide (O) 811120 pieces 10 pieces 0,1689 A02AD81 Aluminium hydroxide+ Magnesium hydroxide (O) 3101974 ml 50 ml 0,1292 A02AD83 Calcium carbonate+ Magnesium carbonate (O) 3434232 pieces 10 pieces 0,7152 DRUGS FOR PEPTIC ULCER AND GASTRO- A02B 46,1179 OESOPHAGEAL REFLUX DISEASE (GORD) A02BA H2-receptor antagonists 2,3855 A02BA02 Ranitidine (O) 340327,5 g 0,3 g 2,3624 A02BA02 Ranitidine (P) 3318,25 g 0,3 g 0,0230 A02BC Proton pump inhibitors 43,7324 A02BC01 Omeprazole
    [Show full text]
  • Pharmacokinetics and Metabolism Studies of Antifilarial Drugs Derivatives of Benzimidazole Carbamate
    v PHARMACOKINETICS AND METABOLISM STUDIES OF ANTIFILARIAL DRUGS DERIVATIVES OF BENZIMIDAZOLE CARBAMATE by SURASH RAMANATHAN Thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy • .. November 1996 TABLE OF CONTENTS Page Numbers Acknowledgement... .. ii Publications ................................................................................... XII List of Conferences .............................................................................. xiii List of Abbreviation ............................................................................. xiv Abstrak ............................................................................................. xv Abstract. ........................................................................................... xvii Chapter 1: INTRODUCTION .................................................................. 1 1.1 General Introduction ......................................................... ... 1 1.2 The Pathology and Clinical Manifestation of Lymphatic Filarasis ............................................................................3 1.2.1 The filarial life cycle .................................................... .3 1.2.2 Clinical manifestation of lymphatic filariasis infection ............. 7 1.3 Chemotherapy.. of Antifilarial Drugs ............................................ 8 1.3.1 Introduction ............................................................... 8 1.3.2 DEC and ivermectin ..................................................... 9 1.3.3
    [Show full text]
  • New Benzimidazole Derivatives As Inhibitors of Pteridine Reductase 1: Design, Molecular Docking Study and ADMET Prediction
    Journal of Applied Pharmaceutical Science Vol. 10(09), pp 030-039, September, 2020 Available online at http://www.japsonline.com DOI: 10.7324/JAPS.2020.10904 ISSN 2231-3354 New benzimidazole derivatives as inhibitors of Pteridine reductase 1: Design, molecular docking study and ADMET prediction Shraddha Phadke1*, Rakesh Somani2, Devender Pathak3 1Dr. L. H. Hiranandani College of Pharmacy, Thane, India. 2D. Y. Patil University School of Pharmacy, Navi Mumbai, India. 3Pharmacy College Saifai, Uttar Pradesh University of Medical Sciences, Etawah, India. ARTICLE INFO ABSTRACT Received on: 23/04/2020 Pteridine reductase 1 (PTR1) is a unique enzyme required for survival of Leishmania species, a causative organism for Accepted on: 14/06/2020 the disease leishmaniasis. We herein report the design, docking, and Absorption, Distribution, Metabolism, Excretion, Available online: 05/09/2020 Toxicity (ADMET) prediction studies of 2-substituted-5-[(6-substituted-1H-benzimidazol-2yl)methyl]azole derivatives (B1–B14) as PTR1 inhibitors. Molecular docking studies showed good binding interaction of the compounds with the active site of pteridine reductase from Leishmania Major, with compounds B5 and B12 showing docking scores Key words: of −61.5232 and −62.5897, respectively, which were comparable with the original ligand, dihydrobiopterin. Large Pteridine reductase 1, substituents on the azole ring, as well as substitutions on sixth position of the benzimidazole ring, were found to be leishmaniasis, benzimidazole favorable for interaction with PTR1 active site. Physicochemical properties, bioactivity prediction, and toxicity profiles derivatives, docking studies, of the compounds were studied using the Molinspiration and admetSAR web servers. All compounds followed Lipinski’s ADMET, druglikeness. rule of five and can be considered as good oral candidates.
    [Show full text]
  • The Benzimidazole-Based Anthelmintic Parbendazole: a Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer
    cancers Article The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer Rosalba Florio 1, Serena Veschi 1, Viviana di Giacomo 1, Sara Pagotto 2,3, Simone Carradori 1,* , Fabio Verginelli 1,3 , Roberto Cirilli 4, Adriano Casulli 5,6, Antonino Grassadonia 2,3, Nicola Tinari 2,3, Amelia Cataldi 1, Rosa Amoroso 1 , Alessandro Cama 1,3,* and Laura De Lellis 1 1 Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; rosalba.fl[email protected] (R.F.); [email protected] (S.V.); [email protected] (V.d.G.); [email protected] (F.V.); [email protected] (A.C.); [email protected] (R.A.); [email protected] (L.D.L.) 2 Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; [email protected] (S.P.); [email protected] (A.G.); [email protected] (N.T.) 3 Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy 4 Centro nazionale per il controllo e la valutazione dei farmaci, Istituto Superiore di Sanità, 00161 Rome, Italy; [email protected] 5 WHO Collaborating Centre for the Epidemiology, Detection and Control of Cystic and Alveolar Echinococcosis (in Animals and Humans), Istituto Superiore di Sanità (ISS), 00161 Rome, Italy; [email protected] 6 European Union Reference Laboratory for Parasites, Istituto Superiore di Sanità (ISS), 00161 Rome, Italy * Correspondence: [email protected] (S.C.); [email protected] (A.C.); Tel.: +39-0871-3554583 (S.C.); +39-0871-3554559 (A.C.) Received: 26 November 2019; Accepted: 14 December 2019; Published: 17 December 2019 Abstract: Pancreatic cancer (PC) is one of the most lethal, chemoresistant malignancies and it is of paramount importance to find more effective therapeutic agents.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 6,693,125 B2 Borisy Et Al
    USOO6693125B2 (12) United States Patent (10) Patent No.: US 6,693,125 B2 Borisy et al. (45) Date of Patent: Feb. 17, 2004 (54) COMBINATIONS OF DRUGS (E.G., A Fraser et al., “Endo-Exonuclease of Human Leukaemic BENZIMIDAZOLE AND PENTAMIDINE) Cells: Evidence for a Role in Apoptosis,” J. Cell Sci., FOR THE TREATMENT OF NEOPLASTIC 109:2343-2360, 1996. DSORDERS Gambari et al., “ DNA-Binding Activity and Biological effects of Aromatic Polyamidines,” Biochem Pharmacol, (75) Inventors: Alexis Borisy, Boston, MA (US); 47:599–610, 1994. Curtis Keith, Boston, MA (US); Klemes et al., “Inhibition of Phorbol-Ester-Induced Adhe Michael A. Foley, Chestnut Hill, MA sion of Differentiating Human Myeloid Leukemic Cells by (US); Brent R. Stockwell, Boston, MA Pentamidine-Isethionate,” Differentiation, 27:141-145, (US) 1984. Kopac, M.J., “Section of Biology,” The New York Academy (73) Assignee: CombinatoRx Incorporated, Boston, of Sciences, 5-10, 1945. MA (US) Kopac, M.J., “Some Cellular and Surface Chemical Aspects of Tumor Chemotherapy,” Approaches to Tumor Chemo (*) Notice: Subject to any disclaimer, the term of this therapy ed. F.R. Moulton, AAAS, Washington, D.C. 1947. patent is extended or adjusted under 35 Libby et al., “Inhibition of Enzymes of Polyamine Back U.S.C. 154(b) by 0 days. Conversion by Pentamidine and Berenil,” Biochemical Pharmacology, 44:830–832, 1992. (21) Appl. No.: 09/768,870 Luck et al., “Interaction of Nonintercalative Antitumour Drugs SN-6999 and SN-18071 with DNA: Influence of (22) Filed: Jan. 24, 2001 Ligand Structure on the Binding Specificity,” Journal of (65) Prior Publication Data Biomolecular Structure & Dynamics 4:1079–1094, 1987.
    [Show full text]
  • Screening of Benzimidazole-Based Anthelmintics and Their Enantiomers As Repurposed Drug Candidates in Cancer Therapy
    pharmaceuticals Article Screening of Benzimidazole-Based Anthelmintics and Their Enantiomers as Repurposed Drug Candidates in Cancer Therapy Rosalba Florio 1, Simone Carradori 1,* , Serena Veschi 1 , Davide Brocco 1, Teresa Di Genni 1, Roberto Cirilli 2 , Adriano Casulli 3,4 , Alessandro Cama 1,5,* and Laura De Lellis 1 1 Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; rosalba.fl[email protected] (R.F.); [email protected] (S.V.); [email protected] (D.B.); [email protected] (T.D.G.); [email protected] (L.D.L.) 2 Centro Nazionale per il Controllo e la Valutazione dei Farmaci, Istituto Superiore di Sanità, 00161 Rome, Italy; [email protected] 3 WHO Collaborating Centre for the Epidemiology, Detection and Control of Cystic and Alveolar Echinococcosis (in Animals and Humans), Department of Infectious Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy; [email protected] 4 European Union Reference Laboratory for Parasites, Department of Infectious Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy 5 Center for Advanced Studies and Technology, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy * Correspondence: [email protected] (S.C.); [email protected] (A.C.) Citation: Florio, R.; Carradori, S.; Abstract: Repurposing of approved non-antitumor drugs represents a promising and affordable Veschi, S.; Brocco, D.; Di Genni, T.; strategy that may help to increase the repertoire of effective anticancer drugs. Benzimidazole-based Cirilli, R.; Casulli, A.; Cama, A.; De anthelmintics are antiparasitic drugs commonly employed both in human and veterinary medicine. Lellis, L. Screening of Benzimidazole- Benzimidazole compounds are being considered for drug repurposing due to antitumor activities Based Anthelmintics and Their displayed by some members of the family.
    [Show full text]
  • Synthesis, Reactions, Structure-Activity Relationship of 2-Benzimidazole Analogs As Anticancer Agents and Study Their Molecular Docking
    Available online a t www.derpharmachemica.com Scholars Research Library Der Pharma Chemica, 2013, 5(5):243-257 (http://derpharmachemica.com/archive.html) ISSN 0975-413X CODEN (USA): PCHHAX Synthesis, reactions, structure-activity relationship of 2-benzimidazole analogs as anticancer agents and study their molecular docking Nahed F. Abdel-Ghaffar Department of Chemistry , Faculty of Science(Girls), Al-Azhar University, Nasr City, Cairo, Egypt _____________________________________________________________________________________________ ABSTRACT A new series of benzimidazolederivatives , 1,2,3 are reported herein. Their reactions with some nucleophiles gave 4 and 6. The reaction of 3 with sodium azide gave 5and with primary amines gave 7a-c. Treatment of 7c with acrylonitrile, cinnamaldehyde, phenylisothiocyanate, gave 8,9 and 10. Treatment of 10 with chloroacetic acid and/or malonic acid gave 11 and 12 . The benzimidazol-2-thione derivative 2 reacted with acetylacetone to give the dicarbonyl derivative 13 which on hydrazinolysis gave the pyrazole derivative 14. Reaction of 2 with benzalacetophenone derivative, anthranilic acid, sodium nitrite and/or thiourea gave 15,16,17 and 18 respectively. The formation of the 2-benzimidazolyl pyrimidine thione derivative 19 was also investigated. Some of the new synthesized derivatives were screened for their antitumor activities and theirmolecular docking and the results were encouraging. Keywords: Benzimidazolederivatives , Biological activity , Synthesis, Antitumor activity _____________________________________________________________________________________________ INTRODUCTION Benzimidazole derivatives represent one of the most biologically active classof compounds, possessing a wide spectrum of activities and these are well-documented in literature asthey show selective neuropeptides YY, receptor antagonists [1], potent inhibitors of TiE-2 and VEGFER_2 tyrosine kinase receptor [2], gamma-amino butyric acid (GABA) agonists and 5-HT3 antagonists [3].
    [Show full text]
  • Estonian Statistics on Medicines 2013 1/44
    Estonian Statistics on Medicines 2013 DDD/1000/ ATC code ATC group / INN (rout of admin.) Quantity sold Unit DDD Unit day A ALIMENTARY TRACT AND METABOLISM 146,8152 A01 STOMATOLOGICAL PREPARATIONS 0,0760 A01A STOMATOLOGICAL PREPARATIONS 0,0760 A01AB Antiinfectives and antiseptics for local oral treatment 0,0760 A01AB09 Miconazole(O) 7139,2 g 0,2 g 0,0760 A01AB12 Hexetidine(O) 1541120 ml A01AB81 Neomycin+Benzocaine(C) 23900 pieces A01AC Corticosteroids for local oral treatment A01AC81 Dexamethasone+Thymol(dental) 2639 ml A01AD Other agents for local oral treatment A01AD80 Lidocaine+Cetylpyridinium chloride(gingival) 179340 g A01AD81 Lidocaine+Cetrimide(O) 23565 g A01AD82 Choline salicylate(O) 824240 pieces A01AD83 Lidocaine+Chamomille extract(O) 317140 g A01AD86 Lidocaine+Eugenol(gingival) 1128 g A02 DRUGS FOR ACID RELATED DISORDERS 35,6598 A02A ANTACIDS 0,9596 Combinations and complexes of aluminium, calcium and A02AD 0,9596 magnesium compounds A02AD81 Aluminium hydroxide+Magnesium hydroxide(O) 591680 pieces 10 pieces 0,1261 A02AD81 Aluminium hydroxide+Magnesium hydroxide(O) 1998558 ml 50 ml 0,0852 A02AD82 Aluminium aminoacetate+Magnesium oxide(O) 463540 pieces 10 pieces 0,0988 A02AD83 Calcium carbonate+Magnesium carbonate(O) 3049560 pieces 10 pieces 0,6497 A02AF Antacids with antiflatulents Aluminium hydroxide+Magnesium A02AF80 1000790 ml hydroxide+Simeticone(O) DRUGS FOR PEPTIC ULCER AND GASTRO- A02B 34,7001 OESOPHAGEAL REFLUX DISEASE (GORD) A02BA H2-receptor antagonists 3,5364 A02BA02 Ranitidine(O) 494352,3 g 0,3 g 3,5106 A02BA02 Ranitidine(P)
    [Show full text]