Synthesis of Tetrazoloquinoline‐Based Mono‐ and Bisphosphonate Esters as Potent Anti‐Inflammatory Agents

Abstract

View this article online at wileyonlinelibrary.com.Several new α-alkoxyand α-hydroxyphosphonate derivatives of tetrazole-quinolines were synthesized from the reaction of 2-azidoquinolines 3-carboxaldehyde 1a,b with trialkyl phosphites and dialkyl phosphites. On the other hand, azaphospholes 12a,b were obtained by treating 1a,b with tris(dimethylamino) phosphine. Furthermore, Perkin-type condensation of 1a,b and tetraethyl methylenebisphosphonate provided the corresponding tetrazoloquinoline-based bisphosphonate esters 14a,b. Based on the prediction results (PASS program), the anti-inflammatory activity of the prepared compounds was determined in vivo by the acute carrageenin-induced paw edema in rats. Many of the new compounds exhibit considerable anti-inflammatory properties at a dose of 50 mg/kg body weight. Especially 14a and 14b revealed remarkable activities compared with indomethacin, which was used as a reference standard in this study.

Investigations of the Chemistry of Alkyl Phosphites Toward Nitrogen-Containing Compounds: Efficient Approaches to α-Amino-, β-Amino-, and/or Enaminophosphonates

“…Dialkyl phosphonate analogs 187 (R = H) were isolated from the reactions of 186 with (RO) 2 POH (Scheme 82). [182] N-Phthalonyl-alanylazide 188 reacted with excess of (RO) 3 P via Staudingerphosphoraneimine intermediates to afford the phosphonates 189 (Scheme 83). [183] Conversely, treatment of 188 with ( i PrO) 3 P afforded 189c, together with the vinyl phosphate 190 (Scheme 83).…”

Synthesis and quantitative structure–activity relationship study of substituted imidazophosphor ester based tetrazolo[1,5-b]pyridazines as antinociceptive/anti-inflammatory agents

“…Based on previous reports [24–26] that recognized the pyridazine nucleus is being suitable for anti-inflammatory and antinociceptive agents, and by the fact that ring-fused heterocycles containing more than one nitrogen atom (e.g., tetrazole nuclei [21–23]) are key structures in a large variety of biochemical processes, bioscreening of the synthesized substituted tetrazolo[1,5- b ]pyridazine-phosphor derivatives was carried out. Thus, keeping the tetrazolopyridazine core structure intact, we studied the effect of different phosphorus-containing moieties on their antinociceptive and anti-inflammatory effects.…”

“…As a part of our continued interest in the development of convenient synthetic approaches to β-enamino- and α-aminophosphonates with anti-inflammatory properties [13–20], we recently successfully synthesized a series of mono- and bisphosphonate-based tetrazolo[1,5- a ]quinolines with marked anti-inflammatory properties [21–22]. Following this, synthesis of the target compounds, substituted tetrazolo[1,5- b ]pyridazinphosphor esters, is described herein.…”

“…The anti-inflammatory and the antinociceptive properties of the prepared compounds were screened and the structure–activity relationships were studied. The anti-inflammatory properties of many tetrazole [21–23] and pyridazine derivatives have also led to their clinical application as NSAIDs (e.g. Bucolome) [24].…”

Synthesis of new 2-[2-(dialkyl(diaryl)-phosphoryl)-2-methylpropyl]quinoline-4-carboxylic acids

“…Quinoline derivatives exhibit various types of biological effects, including antibacterial, [1][2][3][4] tuberculostatic, [5][6][7] antimalarial, 8 and antitumor activity. 9,10 It was also found that quinoline derivatives containing phosphonate or phosphine oxide fragments 11,12 possess antiinflammatory 13 and antiHIV activity. 14 Besides that, we previously showed that hydrazones of isoniazid and dimephosphone (antacid medication, dimethyl (2-methyl-4-oxopent-2-yl)phosphonate) 15 or its Р,С-analogs, dialkyl (2-methyl-4-oxopentyl)phosphine oxides, 16 are significantly less toxic compared to isoniazid, while maintaining its therapeutic effect.…”