WO2014138833A1 - Composés, utilisation, composition pharmaceutique inhibitrice de réductase dans des micro-organismes, ligand d'inha et procédé d'obtention de ligands d'inha - Google Patents

Composés, utilisation, composition pharmaceutique inhibitrice de réductase dans des micro-organismes, ligand d'inha et procédé d'obtention de ligands d'inha Download PDF

Info

Publication number
WO2014138833A1
WO2014138833A1 PCT/BR2014/000076 BR2014000076W WO2014138833A1 WO 2014138833 A1 WO2014138833 A1 WO 2014138833A1 BR 2014000076 W BR2014000076 W BR 2014000076W WO 2014138833 A1 WO2014138833 A1 WO 2014138833A1
Authority
WO
WIPO (PCT)
Prior art keywords
inha
formula
carbons
alkyl chain
chain containing
Prior art date
Application number
PCT/BR2014/000076
Other languages
English (en)
Portuguese (pt)
Inventor
Ivani PAULI
Osmar Norberto de SOUZA
Rafael Victório Carvalho GUIDO
Adriano Defini ANDRICOPULO
Original Assignee
União Brasileira De Educação E Assistência , Mantenedora Da Pucrs
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by União Brasileira De Educação E Assistência , Mantenedora Da Pucrs filed Critical União Brasileira De Educação E Assistência , Mantenedora Da Pucrs
Publication of WO2014138833A1 publication Critical patent/WO2014138833A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/10—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is in the field of biology, chemistry and pharmacy. More specifically, the present invention features novel enzyme inhibiting compounds in microorganisms. In one embodiment, the compounds of the present invention are useful for inhibiting the enzyme 2-transenoyl-ACP (CoA) reductase in microorganisms.
  • CoA 2-transenoyl-ACP
  • Tuberculosis is the fourth cause of death in the country from infectious diseases and the first cause of death in patients with AIDS (National Program for Tuberculosis Control, Secretary of Health Surveillance, Ministry of Health).
  • the present invention solves the problem of finding new drugs for the treatment of tuberculosis (TB) using the enzyme InhA, targeting the main drug employed in the treatment of this disease (isoniazid) (INH), as a therapeutic target.
  • InhA the enzyme employed in the treatment of this disease
  • IH isoniazid
  • the compounds of the present invention also have the potential to inhibit the InhA enzyme of these organisms.
  • Mycobacterium causes tuberculosis, leprosy, ulcers, and other infections
  • Plasmodium causes malaria, in particular cerebral malaria
  • Toxoplasma causes toxoplasmosis
  • Trypanosoma Causes Chagas disease
  • Klebsiella causes nosocomial infections, pneumonia
  • Chlamydia causes trachoma or chlamydia and chronic infections
  • Helycobacter. causes gastritis, ulcer and stomach cancer
  • Pseudomonas Causes Infections cholera and other
  • Yersinia Causes Black Death; Staphylococcus: causes nosocomial infection; Salmonella: Causes salmonellosis; Neisseria: causes venereal disease (gonorrhoeae) and meningitis (meningitidis).
  • US 2011/0092536 describes novel anti-infectious derivatives, method of production thereof, pharmaceutical compositions containing the compounds and their use in antimicrobial treatment
  • the derivatives comprise a general formula containing the combination of i) pyridine, pyridinium or dihydropyridine structures and structures related derivatives of isoniazid active metabolites; and ii) hydrophobic substituent targeting the active substrate site.
  • fatty acid inhibitors as potential antimicrobial agents in which an essential step of action of possible antimicrobial agents comprises being administered into a microbial cell to allow inhibition of an enzyme (synthase) related to the production of fatty acids.
  • the present invention provides novel microorganism reductase inhibiting compounds useful for inhibiting the enzyme InhA (2-fransenoyl-ACP (CoA) reductase) such as Mycobacterium tuberculosis InhA (EC: 1.3.1.9).
  • InhA 2-fransenoyl-ACP (CoA) reductase
  • Mycobacterium tuberculosis InhA EC: 1.3.1.9
  • any alkyl chain is a straight or branched chain, saturated or unsaturated, cyclic or not.
  • microorganism reductase inhibitor compound selected from the group comprising:
  • R1 and R4 being the same or distinct, comprise an alkyl chain containing from 1 to 10 carbons, a hydrogen atom, a halogen group atom, OH or O " ;
  • R2 comprises an alkyl chain containing from 1 to 10 carbons or an oxygen atom
  • R3 and R5 comprise an alkyl chain containing from 1 to 10 carbons or a hydrogen atom
  • R1-R2 being the same or distinct, comprising an alkyl chain containing from 1 to 10 carbons, a hydrogen atom, a halogen group atom, OH or O " ;
  • R3 comprising an alkyl chain containing from 1 to 10 carbons or an oxygen atom
  • R1 comprises an alkyl chain containing from 1 to 10 carbons, a hydrogen atom, a halogen group atom, OH or O " ; and R2 comprises an alkyl chain containing from 1 to 10 carbons or an oxygen atom;
  • R1 and R3 may, being the same or distinct, comprise an alkyl chain containing from 1 to 10 carbons, a hydrogen atom, a halogen group atom, OH or O " ;
  • R2 comprises an alkyl chain containing from 1 to 10 carbons or a hydrogen atom
  • a further object of the present invention is also a selected inhA binder a compound selected from the group comprising formula I, II, III and / or IV above, or combinations thereof.
  • a further object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • Figure 1 Analysis of intermolecular interactions between the InhA enzyme of Mycobacterium tuberculosis and N- (2-phenoxyphenyl) -2- [2- (2-pyridyl) thiazol-4-yl] acetamide.
  • Figure 3 Analysis of intermolecular interactions between Mycobacterium tuberculosis enzyme InhA and 4- (7-chloro-4-quinolyl) -2- (diethylaminomethyl) phenol.
  • the present invention has as a common inventive concept the process or method for obtaining inhA binders. From said common inventive concept, different molecular entities are obtained and solve the technical problem of providing new inhA ligands.
  • the process or method for obtaining inhA binders of the present invention comprises at least three steps:
  • the process or method for obtaining inhA binders of the present invention comprises:
  • an inhA binder is a compound selected from the above-selected group comprising formula I, II, III and / or IV, or combinations thereof, as well as their salts, solvates and / or hydrates.
  • Said binder is particularly useful for in vitro and / or in vivo detection of inhA, notably when said compounds are endowed with some radioactive marker and / or colorimetric reaction.
  • Those skilled in the art will readily be able to identify said markers together with the binders of the invention, thereby providing detection and / or quantification of inhA in biological samples.
  • pharmaceutically acceptable carrier any carrier that provides insertion into a formulation containing acceptable excipients and carriers known to those skilled in the art, as well as at doses and treatments suitable for use in particular compositions.
  • Said carrier may be described in a number of treatment regimens including oral, parenteral, intravenous, intranasal, intravitreal and intramuscular, intracerebral, intracerebroventricular and intraocular or other means of administration and / or formulation.
  • the present invention provides the use of a compound selected from the group comprising formula I, II, III and / or IV described above, or combinations thereof, for the manufacture of antimicrobially acting medicament.
  • R 1 and R 5 are hydrogen atoms
  • R 2 is CH 2; R3 are ethyl, R4 is a chlorine atom.
  • R 1 is a hydrogen atom; R 3 is -CH 2 and R 2 is a methyl in the ortho position.
  • R 1 is a hydrogen atom and R 2 is a -CH 2 .
  • R 1 is a hydrogen atom
  • R 2 is a propyl
  • R 3 is a methyl in the ortho position.
  • InhA or Mycobacterium tuberculosis 2-fransenoyl-ACP (CoA) reductase (EC: 1.3.1.9) is an attractive enzyme for drug discovery efforts due to its validation as an effective biological target for tuberculosis therapy.
  • two distinct in silico ligand screening approaches were used to identify novel InhA inhibitors from a selected ligand library from the ZINC database.
  • a pre-selection of compounds to be selected was performed using the Database - INGr Molecular Filters - 2D Identify molecules with favorable characteristics to interact with the InhA binding cavity: 4 ⁇ LogP ⁇ 7; rotary connections ⁇ 6; hydrogen bridge acceptors ⁇ 8; polar surface area ⁇ 40 ⁇ 2 ; and molecular weight between 250 Da and 400 Da.
  • the final set of compounds comprising the cited characteristics comprised 999,853 compounds and were used in both approaches described below.
  • Hydrogen bridges and hydrophobic contacts were also analyzed by LIGPLOT to obtain a more robust interaction pattern profile between MtlnhA and its crystallographic ligands.
  • Structural analysis of MtlnhA-complexed-ligands-bound to the substrate binding cavity indicates several key amino acid residues that may be involved in the molecular recognition process. Based on this, a four-point 3-D pharmacophoric model was developed.
  • the 3-D structure molecule library was transferred to a UNITY database in SYBYL 8.0.
  • the 3-D search with UNITY was based on the generated pharmacophoric model.
  • Donor and receptor atoms were defined by connecting the donor and receptor atoms of the ligand via partial correspondence.
  • the hydrophobic characteristic was partially characterized based on the two rings present in the ligand structure. The bead diameters were adjusted so that a test sample could be obtained, composed of MtlnhA crystallographic ligands.
  • a flexible UNITY 3-D search was performed.
  • the UNITY algorithm scores high for molecules that match the pharmacophoric points in their flexible searches, and because of this, the optimized geometry of the compounds under analysis may be affected. Thus, the molecular structures of the selected set of compounds were minimized to avoid false positive results. THE Energy minimization of the molecules was performed using the same protocol described in the Computational Approach section.
  • the GOLD software suite was used to perform molecular docking simulations.
  • the MtInhA crystal structure used as a receptor (PDB ID, 1 P44) was chosen from among the 36 available structures because of its better relationship between the binding cavity volume (3.007.8 A 3 ) and protein resolution (2.7 ⁇ ).
  • hydrogen atoms were added to the protein with standard geometry using the Biopolymer module implemented in SYBYL 8.0.
  • the active site was defined as incorporating all amino acid residues with a 8.0 A sphere radius centered on the bound crystallographic ligand (Genz-10850).
  • Coenzyme NADH was treated as part of the protein in all docking simulations.
  • GOLD Genetic Optimization for Ligand Docking
  • the program gives some options related to the scoring function and among them we have chosen GoldScore to be used in our simulations.
  • FlexX was implemented as Incremental Construction Algorithm, where the base fragment (the center of the binder) is automatically selected and placed within the active site using an algorithmic approach based on a pattern recognition technique called pose clustering. After a good set of locations has been obtained as a base, the remaining portions of the binder are divided into small fragments and incrementally "grow" within alternative bases.
  • the Surflex-Dock algorithm applies the Hammerhead empirical scoring function and uses an idealized active site ligand, or "protomol", to generate ligands by incremental construction, and also uses an information crossing procedure that combines pieces with distinct configurations. Protomols were computed using the cognate ligand position to define the binding site.
  • the protein receptor chosen from the MtlnhA simulations was that with the PDB code 1 P44 and coenzyme NADH was treated as part of the receptor. In all docking simulations the receiver structure was kept rigid while the ligands were treated with complete flexibility.
  • the set of molecules was the same as that used for the pharmacophore-based approach.
  • OSIRIS drug discovery computer system
  • OS ⁇ RIS Property Explorer available at http://www.organic-chemistry.org/prog/peo/
  • OS ⁇ RIS Property Explorer is an integral part of Actelion's internal substance registration system. It calculates drug-relevant properties simultaneously while the user draws the molecule.
  • the molecules selected by both The approaches used in the present invention were subjected to OSIRIS and all those with unfavorable characteristics were removed from the final set of molecules for in vitro testing.
  • Equation 1 is adequate for the behavior of non-competitive inhibitors, with K values of 24 (+ 3) ⁇ and 20 ( ⁇ 2) ⁇ for NADH and 2-fraA7S-dodecenoil-CoA, respectively.
  • This inhibition profile indicates that the inhibitor binds exclusively to the enzyme-substrate (ES) complex, leading to inactivation of the enzyme-substrate-inhibitor (ESI) complex, and the affinity of the inhibitor is maximum at substrate saturating concentrations.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés agissant comme ligands et/ou inhibiteurs enzymatiques dans des micro-organismes. Dans un mode de réalisation préféré, les composés de la présente invention sont utilisés pour inhiber l'enzyme 2-trans-énoyl-ACP (Coa) réductase dans des micro-organismes, et sont donc utiles comme antimicrobiens.
PCT/BR2014/000076 2013-03-13 2014-03-13 Composés, utilisation, composition pharmaceutique inhibitrice de réductase dans des micro-organismes, ligand d'inha et procédé d'obtention de ligands d'inha WO2014138833A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BRBR102013006007-0 2013-03-13
BR102013006007-0A BR102013006007A2 (pt) 2013-03-13 2013-03-13 Compostos, uso, composição farmacêutica inibidora de redutase em microorganismos, ligante de inha, e, método para obtenção de ligantes de inha a partir de derivados de acetamida, ureia, fenol e carboxamida

Publications (1)

Publication Number Publication Date
WO2014138833A1 true WO2014138833A1 (fr) 2014-09-18

Family

ID=51535638

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/BR2014/000076 WO2014138833A1 (fr) 2013-03-13 2014-03-13 Composés, utilisation, composition pharmaceutique inhibitrice de réductase dans des micro-organismes, ligand d'inha et procédé d'obtention de ligands d'inha

Country Status (2)

Country Link
BR (1) BR102013006007A2 (fr)
WO (1) WO2014138833A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108707114A (zh) * 2018-05-03 2018-10-26 上海泰禾国际贸易有限公司 一种乙酰胺类化合物及其制备方法和应用
JPWO2020149295A1 (fr) * 2019-01-18 2020-07-23

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5614551A (en) * 1994-01-24 1997-03-25 The Johns Hopkins University Inhibitors of fatty acid synthesis as antimicrobial agents
US20110092536A1 (en) * 2008-02-07 2011-04-21 Centre National De La Recherche Scientifoque (C.N. Novel anti-infectious derivatives, method for the production thereof, pharmaceutical compositions containing same and uses of said derivatives in treatment

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5614551A (en) * 1994-01-24 1997-03-25 The Johns Hopkins University Inhibitors of fatty acid synthesis as antimicrobial agents
US20110092536A1 (en) * 2008-02-07 2011-04-21 Centre National De La Recherche Scientifoque (C.N. Novel anti-infectious derivatives, method for the production thereof, pharmaceutical compositions containing same and uses of said derivatives in treatment

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ANIL KOUL ET AL., NATURE, vol. 469, 2011, pages 483 - 490 *
ANNAÏK QUÉMARD ET AL.: "Enzymatic Characterization of the Target for Isoniazid in Mycobacterium tuberculosis", BIOCHEMISTRY, vol. 34, 1995, pages 8235 - 8241, XP002039610, DOI: doi:10.1021/bi00026a004 *
IVANI PAULI ET AL.: "Geração de um Farmacóforo 3D Baseado na Estrutura da InhA de Mycobacterium tuberculosis para a Triagem em Larga Escala de Novos Inibidores", 34A REUNIÃO ANUAL DA SOCIEDADE BRASILEIRA DE QUIMICA, MED001, May 2011 (2011-05-01) *
SYLVIA R. LUCKNER ET AL.: "Tight Binding Inhibitor of InhA, the Enoyl-Acyl Carrier Protein Reductase from Mycobacterium tuberculosis", J. BIOL CHEM., vol. 285, 2010, pages 14330 - 14337 *
TODD J. SULLIVAN ET AL.: "High Affinity InhA Inhibitors with Activity against Drug-Resistant Strains of Mycobacterium tuberculosis", ACS CHEMICAL BIOLOGY, vol. 1, no. 1, 2006, pages 43 - 53 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108707114A (zh) * 2018-05-03 2018-10-26 上海泰禾国际贸易有限公司 一种乙酰胺类化合物及其制备方法和应用
CN108707114B (zh) * 2018-05-03 2021-07-23 上海泰禾国际贸易有限公司 一种乙酰胺类化合物及其制备方法和应用
JPWO2020149295A1 (fr) * 2019-01-18 2020-07-23
WO2020149295A1 (fr) * 2019-01-18 2020-07-23 国立研究開発法人科学技術振興機構 Inhibiteur de l'activité de la v-atpase, agent antibactérien, médicament, procédé antibactérien et procédé de criblage
CN113286582A (zh) * 2019-01-18 2021-08-20 国立研究开发法人科学技术振兴机构 V－ATPase活性抑制剂、抗菌剂、药物以及抗菌方法和筛选方法
JP7428387B2 (ja) 2019-01-18 2024-02-06 国立研究開発法人科学技術振興機構 Ｖ－ＡＴＰａｓｅ活性阻害剤、抗菌剤、医薬及び抗菌方法並びにスクリーニング方法

Also Published As

Publication number Publication date
BR102013006007A2 (pt) 2014-11-11

Similar Documents

Publication Publication Date Title
Chan et al. Discovery of s taphylococcus aureus sortase a inhibitors using virtual screening and the relaxed complex scheme
Laudadio et al. Natural alkaloid berberine activity against Pseudomonas aeruginosa MexXY-mediated aminoglycoside resistance: in silico and in vitro studies
Ni et al. Structural insights into plasticity and discovery of remdesivir metabolite GS-441524 binding in SARS-CoV-2 macrodomain
Zhao et al. Quinoline and quinazoline derivatives inhibit viral RNA synthesis by SARS-CoV-2 RdRp
Santana-Romo et al. Innovative three-step microwave-promoted synthesis of N-propargyltetrahydroquinoline and 1, 2, 3-triazole derivatives as a potential factor Xa (FXa) inhibitors: Drug design, synthesis, and biological evaluation
Barbosa da Silva et al. Structure-based optimization of quinazolines as cruzain and Tbr CATL inhibitors
Bastien et al. Fragment-based design of symmetrical bis-benzimidazoles as selective inhibitors of the trimethoprim-resistant, type II R67 dihydrofolate reductase
Asha et al. Synthesis, molecular docking, and in silico ADMET studies of 4-benzyl-1-(2, 4, 6-trimethyl-benzyl)-piperidine: Potential Inhibitor of SARS-CoV2
Hu et al. 3-substituted indole inhibitors against Francisella tularensis FabI identified by structure-based virtual screening
Dhameliya et al. Systematic virtual screening in search of SARS CoV-2 inhibitors against spike glycoprotein: pharmacophore screening, molecular docking, ADMET analysis and MD simulations
Ugbe et al. Theoretical activity prediction, structure-based design, molecular docking and pharmacokinetic studies of some maleimides against Leishmania donovani for the treatment of leishmaniasis
Arévalo et al. An in-silico analysis reveals 7, 7′-bializarin as a promising DNA gyrase B inhibitor on Gram-positive and Gram-negative bacteria
Akash et al. Anti-parasitic drug discovery against Babesia microti by natural compounds: an extensive computational drug design approach
Chakraborty et al. Interaction of constituents of MDT regimen for leprosy with Mycobacterium leprae HSP18: impact on its structure and function
Gupta et al. Repurposing Lansoprazole and Posaconazole to treat Leishmaniasis: Integration of in vitro testing, pharmacological corroboration, and mechanisms of action
Sharma et al. Structure based drug discovery and in vitro activity testing for DNA gyrase inhibitors of Salmonella enterica serovar Typhi
WO2014138833A1 (fr) Composés, utilisation, composition pharmaceutique inhibitrice de réductase dans des micro-organismes, ligand d'inha et procédé d'obtention de ligands d'inha
Mishra et al. Pharmacophore screening to identify natural origin compounds to target RNA-dependent RNA polymerase (RdRp) of SARS-CoV2
Yepes et al. Chalcone‐quinoline conjugates as potential T. Cruzi cruzipain inhibitors: docking studies, molecular dynamics and evaluation of drug‐likeness
Yepes et al. Biologically Active Quinoline‐Hydrazone Conjugates as Potential Trypanosoma cruzi DHFR‐TS Inhibitors: Docking, Molecular Dynamics, MM/PBSA and Drug‐Likeness Studies
Ashraf-Uz-Zaman et al. Quinazolinone compounds have potent antiviral activity against Zika and dengue virus
Khade et al. Design, synthesis, biological evaluation and molecular dynamic simulation studies of diphenyl ether derivatives as antitubercular and antibacterial agents
Ghosh et al. Computational studies to identify the common type‐I and type‐II inhibitors against the CDK8 enzyme
Kant et al. In silico screening, molecular dynamic simulations, and in vitro activity of selected natural compounds as an inhibitor of Leishmania donovani 3-mercaptopyruvate sulfurtransferase
Zhang et al. Virtual screening of novel mTOR inhibitors for the potential treatment of human colorectal cancer

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14765627

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14765627

Country of ref document: EP

Kind code of ref document: A1