ABSTRACT
In this paper, we describe the synthesis and pharmacological evaluation of a series of 4-aminoquinolines. The compounds were characterised and tested in models of pain and inflammation, using the writhing test with acetic acid, formalin test, peritonitis test by zymosan and arthritis test with Freund's adjuvant complete assay. The results revealed that all of the 4-aminoquinolines that were prepared promoted anti-nociceptive activity as well as acute and chronic anti-inflammatory effects, with marked activity in the derivates labelled with BAQ and 7-CF3-MAQ. After 7 days of treatment, 7-CF3-MAQ did not induce significant hepatotoxicity, gastrotoxicity or nephrotoxicity.
Subject(s)
Aminoquinolines/chemistry , Analgesics/chemical synthesis , Anti-Inflammatory Agents/chemical synthesis , Aminoquinolines/chemical synthesis , Aminoquinolines/therapeutic use , Analgesics/chemistry , Analgesics/therapeutic use , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Arthritis/drug therapy , Arthritis/etiology , Freund's Adjuvant/toxicity , Male , Mice , Pain/chemically induced , Pain/drug therapy , Pain Measurement , Peritonitis/chemically induced , Peritonitis/drug therapy , Rats , Rats, Wistar , Zymosan/toxicityABSTRACT
Different chemotypes are described as anti-inflammatory. Among them the N-acylhydrazones (NAH) are highlighted by their privileged structure nature, being present in several anti-inflammatory drug-candidates. In this paper a series of functionalized 3-aminothiophene-2-acylhydrazone derivatives 5a-i were designed, synthesized and bioassayed. These new derivatives showed great anti-inflammatory and analgesic potency and efficacy. Compounds 5a and 5d stand out in this respect, and were also active in CFA-induced arthritis in rats. After daily treatment for seven days with 5a and 5d (50 µmol/Kg), by oral administration, these compounds were not renal or hepatotoxic nor immunosuppressive. Compounds 5a and 5d also displayed good drug-scores and low risk toxicity calculated in silico using the program OSIRIS Property Explorer.
Subject(s)
Analgesics/chemistry , Anti-Inflammatory Agents/chemistry , Hydrazones/chemistry , Analgesics/therapeutic use , Animals , Anti-Inflammatory Agents/therapeutic use , Arthritis/drug therapy , Male , MiceABSTRACT
In this paper we report the design, synthesis, antinociceptive and anti-inflammatory activities of a series of benzothiazine N-acylhydrazones 14ah, planned by structural modification of piroxicam (1), a non steroidal anti-inflammatory drug. Among the synthesized analogues, compounds 14f (LASSBio-1637) and 14g (LASSBio-1639) were identified as novel antinociceptive and anti-inflammatory prototypes, active by oral administration, acting by a mechanism of action that seems to be different from that of piroxicam, since they were inactive as an inhibitor of cyclooxygenase (COX-1 and COX-2) at concentrations of 10 mM.
Subject(s)
Analgesics , Anti-Inflammatory Agents , Cyclooxygenase Inhibitors/pharmacology , Piroxicam , Administration, Oral , Analgesics/chemical synthesis , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Benzothiadiazines/chemical synthesis , Benzothiadiazines/pharmacology , Cyclooxygenase 1/chemistry , Cyclooxygenase 2/chemistry , Membrane Proteins/chemistry , Mice , Molecular Structure , Piroxicam/analogs & derivatives , Piroxicam/chemical synthesis , Piroxicam/chemistry , Piroxicam/pharmacologyABSTRACT
In this paper, we report the synthesis and pharmacological evaluation of pyrazine N-acylhydrazone (NAH) derivatives (2a-s) designed as novel analgesic and anti-inflammatory drug candidates. This series was planned by molecular simplification of prototype 1 (LASSBio-1018), previously described as a non-selective cyclooxygenase inhibitor. Derivatives 2a-s were evaluated in several animal models of pain and inflammation, standing-out compound 2o (2-N'-[(E)-(3,4,5-trimethoxyphenyl) methylidene]-2-pyrazinecarbohydrazide; LASSBio-1181), that was also active in a murine model of chronic inflammation (i.e., adjuvant-induced arthritis test in rats) and can be considered a new analgesic and anti-inflammatory lead for drug development.
Subject(s)
Analgesics/chemistry , Analgesics/therapeutic use , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Arthritis/drug therapy , Hydrazones/chemistry , Hydrazones/therapeutic use , Pain/drug therapy , Pyrazines/chemistry , Pyrazines/therapeutic use , Analgesics/chemical synthesis , Animals , Anti-Inflammatory Agents/chemical synthesis , Arthritis/chemically induced , Ear/pathology , Edema/chemically induced , Edema/drug therapy , Female , Freund's Adjuvant , Hydrazones/chemical synthesis , Male , Mice , Peritonitis/chemically induced , Peritonitis/drug therapy , Pyrazines/chemical synthesis , Rats , Rats, Wistar , ZymosanABSTRACT
In this paper we report the design, synthesis and pharmacological evaluation of a series of N-phenyl-acetamide sulfonamide derivatives (5a-g), planned by structural modification on the prototype paracetamol (1). In this series (5a-g), compound LASSBio-1300 (5e; ID(50)=5.81 micromol/kg) stands out as a new non-hepatotoxic analgesic drug candidate. The increase of area, volume and electrostatic potential of paracetamol's analogues seems to be beneficial to the analgesic activity. Unlike paracetamol (1) and the other analogues (5a, 5d-g), compounds 5b and 5c presented an important anti-hypernociceptive activity associated to inflammatory pain.
