ABSTRACT
A series of 13 new 3-substituted 5-(5-nitro-2-furyl)-1,2,4-oxadiazoles was synthesized from different aminonitriles. All compounds were screened in the disc diffusion test at a 100 µg/mL concentration to determine the bacterial growth inhibition zone presence and diameter, and then the minimum inhibitory concentrations (MICs) were determined for the most active compounds by serial dilution. The compounds showed antibacterial activity against ESKAPE bacteria, predominantly suppressing the growth of 5 species out of the panel. Some compounds had similar or lower MICs against ESKAPE pathogens compared to ciprofloxacin, nitrofurantoin, and furazidin. In particular, 3-azetidin-3-yl-5-(5-nitro-2-furyl)-1,2,4-oxadiazole (2h) inhibited S. aureus at a concentration lower than all comparators. Compound 2e (5-(5-nitro-2-furyl)-3-[4-(pyrrolidin-3-yloxy)phenyl]-1,2,4-oxadiazole) was active against Gram-positive ESKAPE pathogens as well as M. tuberculosis. Differences in the molecular periphery led to high selectivity for the compounds. The induced-fit docking (IFD) modeling technique was applied to in silico research. Molecular docking results indicated the targeting of compounds against various nitrofuran-associated biological targets.
Subject(s)
Anti-Bacterial Agents , Microbial Sensitivity Tests , Molecular Docking Simulation , Nitrofurans , Nitrofurans/pharmacology , Nitrofurans/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Drug Design , Structure-Activity Relationship , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Molecular Structure , Staphylococcus aureus/drug effectsABSTRACT
A series of 21 new 7'H-spiro[azetidine-3,5'-furo [3,4-d]pyrimidine]s substituted at the pyrimidine ring second position were synthesized. The compounds showed high antibacterial in vitro activity against M. tuberculosis. Two compounds had lower minimum inhibitory concentrations against Mtb (H37Rv strain) compared with isoniazid. The novel spirocyclic scaffold shows excellent properties for anti-tuberculosis drug development.
Subject(s)
Antitubercular Agents , Azetidines , Microbial Sensitivity Tests , Mycobacterium tuberculosis , Nitrofurans , Spiro Compounds , Mycobacterium tuberculosis/drug effects , Antitubercular Agents/pharmacology , Antitubercular Agents/chemistry , Antitubercular Agents/chemical synthesis , Azetidines/chemistry , Azetidines/pharmacology , Nitrofurans/pharmacology , Nitrofurans/chemistry , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Spiro Compounds/chemical synthesis , Structure-Activity Relationship , Molecular StructureABSTRACT
A series of eight 5-nitrofuran-tagged oxazolyl tetrahydropyrazolopyridines (THPPs) has been prepared in six stages with excellent regioselectivity. The testing of these compounds against pathogens of the ESKAPE panel showed a good activity of lead compound 1-(2-methoxyethyl)-5-(5-nitro-2-furoyl)-3-(1,3-oxazol-5-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c] pyridine (13g), which is superior to nitrofurantoin. These results confirmed the benefit of combining a THPP scaffold with a nitrofuran warhead. Certain structure-activity relationships were established in the course of this study which were rationalized by the induced-fit docking experiments in silico.
Subject(s)
Nitrofurans , Nitrofurans/pharmacology , Pyrazoles , Nitrofurantoin , Structure-Activity RelationshipABSTRACT
The previously reported as well as newly synthesized derivatives of the 1-oxa-9-azaspiro[5.5]undecane were employed in the synthesis of thirty-six derivatives of ciprofloxacin using commercially available 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and the literature protocol involving the preparation of boron chelate complex to facilitate nucleophilic aromatic substitution. All new fluoroquinolone derivatives were tested against two gram-positive as well as three gram-negative strains of bacteria. With the activity spectrum of the new derivatives being substantially narrower than that of ciprofloxacin, compounds were distinctly active against two of the five strains: gram-negative Acinetobacter baumannii 987® and gram-positive Bacillus cereus 138®. Towards these two strains, a large group of compounds displayed equal or higher potency than ciprofloxacin.
Subject(s)
Anti-Bacterial Agents , Ciprofloxacin , Anti-Bacterial Agents/pharmacology , Bacteria , Ciprofloxacin/pharmacology , Fluoroquinolones , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
Ribavirin analogs substituted at position 5 of the heterocyclic base are interesting for their biological activity. This protocol describes a synthetic route to several such ribavirin analogs with a wide range of substituents.© 2021 Wiley Periodicals LLC. Basic Protocol 1: Synthesis and purification of 5-substituted ethyl 1,2,4-triazole-3-carboxylates - synthetic precursors of nucleobases Basic Protocol 2: Synthesis and purification of protected 1,2,4-triazole nucleoside analogs Basic Protocol 3: Synthesis and purification of 5-substituted ribavirin analogs.
Subject(s)
Ribavirin , Triazoles , Carboxylic Acids , NucleosidesABSTRACT
A set of 1,3,4-thiadiazole-2-carboxamides bearing a substituted biphenyl in the amide portion was synthesised and tested for agonistic activity towards free fatty acid receptor 1 (FFA1). The observed activity trends were impossible to rationalised based solely on the docking energy scores of Glide SP. On the contrary, when the phospholipid cell membrane bilayer was reconstructed around FFA1, it became apparent that inactive compounds displayed significant strained contacts with the membrane while for active compounds the strain was noticeably lower. These findings justify using the improved docking protocol for modelling GPCR-ligand interactions which uses the crystal structure of the receptor and a reconstructed portion of a cell membrane.
Subject(s)
Hydrazines/pharmacology , Receptors, G-Protein-Coupled/agonists , Small Molecule Libraries/pharmacology , Cell Membrane/drug effects , Dose-Response Relationship, Drug , Humans , Hydrazines/chemical synthesis , Hydrazines/chemistry , Ligands , Molecular Structure , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
This review article is devoted to the so-called fleximer nucleoside analogs, containing two or more planar moieties in the heterocyclic base, connected by a bond that permits rotation. Such analogs have been proposed as molecular probes for detecting enzyme-substrate interactions and studying the transcription and translation of nucleic acids, but subsequently have attracted the interest of researchers by their antiviral and antitumor activity. The methods used in the synthesis of such compounds, along with their structural features and also biological activity are considered in this review.
ABSTRACT
Some 5-substituted ribavirin analogues have a high antiviral and anticancer activity, but their mechanisms of action are obviously not the same as their parent compound. The SAR studies performed on 3 (5)-substituted 1,2,4-triazole nucleosides have shown a high dependency between the structure of the 3 (5)-substituent and the level of antiviral/anticancer activity. The most active substances of the row contain coplanar with the 1,2,4-triazole ring aromatic substituent which is connected by a rigid ethynyl bond. However, the compounds with the trans-vinyl linker also had antiviral activity. We decided to study the antitumor activity of ribavirin analogues with alkyl/aryl vinyl substituents in the 5th position of the 1,2,4-triazole ring. Protected nucleoside analogues with various 5-alkylvinyl substituents were obtained by Horner-Wadsworth-Emmons reaction from the common precursor and converted to the nucleosides. Arylvinyl nucleosides were synthesised according the reported procedures. All compounds did not show significant antiproliferative activity on several tumour cell lines. Coplanar aromatic motif in the 5-substituent for the anticancer activity manifestation was confirmed.
Subject(s)
Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , Nucleosides/pharmacology , Triazoles/pharmacology , Vinyl Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Hepacivirus/drug effects , Humans , Influenza A virus/drug effects , Microbial Sensitivity Tests , Molecular Structure , Nucleosides/chemical synthesis , Nucleosides/chemistry , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry , Vinyl Compounds/chemical synthesis , Vinyl Compounds/chemistryABSTRACT
The chemical ribosylation pathways of 5-substituted-1,2,4-triazole-3-carboxylates are discussed. For the products of the chemical synthesis of the 3(5)-alkyl- or 3(5)-aryl-substituted ribavirin analogues the anomer configuration and isomer composition were determined.
Subject(s)
Carboxylic Acids/chemical synthesis , Ribavirin/analogs & derivatives , Ribavirin/chemical synthesis , Triazoles/chemical synthesis , Catalysis , Isomerism , Molecular Structure , Structure-Activity RelationshipABSTRACT
The novel isosteric ribavirin analogues were synthesized by two different ways. Some of them showed significant antiviral action against hepatitis C virus (HCV), herpes simplex (HCV-1) and influenza A virus comparable to that of ribavirin itself. The data obtained confirm the proposed theory of the ribavirin possible antiviral activity mechanism related with bioisosterism.
Subject(s)
Antiviral Agents/chemical synthesis , Ribavirin/analogs & derivatives , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Survival/drug effects , Chlorocebus aethiops , Hepacivirus/drug effects , Herpesvirus 1, Human/drug effects , Humans , Influenza A virus/drug effects , Ribavirin/chemical synthesis , Ribavirin/pharmacology , Vero CellsABSTRACT
A new pathway to synthesis of arylvinyl ribavirin analogues is developed which makes it possible to obtain not only trans- but also cis-isomers at vinyl bond. By this route eight ribavirin 5-arylvinyl analogues are synthesized and their antiviral activity is evaluated.
Subject(s)
Antiviral Agents/pharmacology , Hepacivirus/drug effects , Nucleosides/pharmacology , Triazoles/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Chlorocebus aethiops , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Nucleosides/chemical synthesis , Nucleosides/chemistry , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry , Vero CellsABSTRACT
Some diacid biodegradable synthesis of aziduthymidine (AZT) were synthesized and applied to production of about 60 different derivatives.