Antirheumatic Agents:  Novel Methotrexate Derivatives Bearing a Benzoxazine or Benzothiazine Moiety

Abstract

Novel methotrexate (MTX) derivatives bearing dihydro-2H-1,4-benzothiazine or dihydro-2H-1,4-benzoxazine were synthesized and tested for in vitro antiproliferative activities against human synovial cells (hSC) and human peripheral blood mononuclear cells (hPBMC) obtained from patients with rheumatoid arthritis and healthy volunteers, respectively. In vivo antiarthritic activities of these derivatives were also evaluated in a rat adjuvant arthritis model. N-[[4-[(2,4-Diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzothiazin-7-yl]carbonyl]-L-glutamic acid (3c) exhibited more potent antiproliferative activities in hSC and hPBMC than MTX in vitro. Antiproliferative activities of N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzoxazin-7-yl]carbonyl]-L-homoglutamic acid (3b) and N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzothiazin-7-yl]carbonyl]-L-homoglutamic acid (3d) (MX-68) were comparable to that of MTX in these in vitro assays. Compounds 3b,d (MX-68) significantly suppressed progression of the adjuvant arthritis in a dose-dependent manner ranging from 0.5 to 2.5 mg/kg (po). In addition, 3d (MX-68) completely suppressed this progression at the dose of 2.5 mg/kg (po). Importantly, 3d (MX-68) having benzothiazine and homoglutamate, as expected, did not undergo polyglutamation, a process which may be responsible for the associated side effects of MTX. These results suggest that 3d (MX-68) is a potent and safe candidate antirheumatic agent, absent of the side effects of MTX.

Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

“…is an analog of methotrexate chemically designed not to undergo intracellular polyglutamation (4). Like methotrexate, MX-68 has a high affinity for the enzyme dihydrofolate reductase and inhibits the proliferation of human peripheral blood mononuclear cells, endothelial cells, and synovial fibroblasts in vitro (5).…”

Design, synthesis and biological evaluation of new Mannich products using ethyl ammonium nitrate as reusable ionic liquid

“…Ampicillin and Chloramphenicol, at a concentration 500 g/mL, were used as standard against bacteria and Greseofulvin is used as standered drug for fungi, respectively. Test results are shown in (Table 1, Figure 2) for antibacterial and (Table 2 & Figure 3) for antifungal activity from the data, it is clear that compounds HB 9 & HB 10 possess excellent activity, while compounds HB 7, HB 11 and HB 12 possess good activity.…”

“…Isoniazide was used as a reference drug. MIC of compounds (HB [8][9][10][11] ) was determined against M. tuberculosis H 37 Rv strain by using L.J. Medium conventional method and only HB 9 and HB 10 shows moderate activity as compared to isoniazide.…”

“…MIC of compounds (HB [8][9][10][11] ) was determined against M. tuberculosis H 37 Rv strain by using L.J. Medium conventional method and only HB 9 and HB 10 shows moderate activity as compared to isoniazide. The MIC is defined as the lowest concentration affecting a reduction in fluorescence of 90 % relative to controls.…”

“…In which there is a reaction between compounds containing at least one active hydrogen atom condense with aldehyde and primary or secondary amines [1][2]. It is also reports as a variety of natural products containing 1,3-amino-oxygenated functional groups act as potential drugs, as antibiotic [3], antitumor [4], antimalarial [5], antianginal [6], antihypertensive [7], antirheumatics [8] and HIV protease inhibitors [9]. The bradycardiac effects of these motifs have also been reported [10].…”