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A variety of hydroxamic acid derivatives have recently been touted for their potential use as inhibitors of hypertension, tumor growth, inflammation, infectious agents, asthma, arthritis, and more. Here we provide a comprehensive review of the basic medicinal chemistry and pharmacology of hydroxamic acid derivatives that have been examined as inhibitors of zinc metalloproteases, matrix metalloproteinases, leukotriene A4 hydrolases, ureases, lipoxigenases, cyclooxygenases, as well as peptide deformilases.

abstract A series of N-substituted 2-[5-(1H-indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]sulfanylacetamides (8a-w) was synthesized in three steps. The first step involved the sequential conversion of 2-(1H-indol-3-yl)acetic acid (1) to ester (2) followed by hydrazide (3) formation and finally cyclization in the presence of CS2 and alcoholic KOH yielded 5-(1H-indole-3-yl-methyl)-1,3,4-oxadiazole-2-thiol (4). In the second step, aryl/aralkyl amines (5a-w) were reacted with 2-bromoacetyl bromide (6) in basic medium to yield 2-bromo-N-substituted acetamides (7a-w). In the third step, these electrophiles (7a-w) were reacted with 4 to afford the target compounds (8a-w). Structural elucidation of all the synthesized derivatives was done by 1H-NMR, IR and EI-MS spectral techniques. Moreover, they were screened for antibacterial and hemolytic activity. Enzyme inhibition activity was well supported by molecular docking results, for example, compound 8q exhibited better inhibitory potential against α-glucosidase, while 8g and 8b exhibited comparatively better inhibition against butyrylcholinesterase and lipoxygenase, respectively. Similarly, compounds 8b and 8c showed very good antibacterial activity against Salmonella typhi, which was very close to that of ciprofloxacin, a standard antibiotic used in this study. 8c and 8l also showed very good antibacterial activity against Staphylococcus aureus as well. Almost all compounds showed very slight hemolytic activity, where 8p exhibited the least. Therefore, the molecules synthesized may have utility as suitable therapeutic agents. resumo Uma série de acetamidas 2-[5-(1H-indol-3-ilmetil)-1,3,4-oxadiazol-2-il]sulfanila N-substituídas (8a-w) foi sintetizada em três fases. A primeira etapa envolveu a conversão sequencial de ácido 2-(1H-indol-3-il)acético (1) a éster (2), seguido por hidrazida (3) e, finalmente, a e ciclização na presença de CS2 e KOH alcoólico produziu 5-(1H-indol-3-il- metil)-1,3,4-oxadiazole-2-tiol (4). Na segunda etapa, aminas arílicas/aralquílicas(5a-w) reagiram com brometo de 2-bromoacetila (6), em meio básico, para se obter acetamidas 2-bromo-N-substituídas (7a-w). Na terceira etapa, estes eletrófilos (7a- w) reagiram com 4, para se obter os compostos alvo (8a-w). A elucidação estrutural de todos os derivados sintetizados foi realizada por 1H-NMR, IR e técnicas de espectrometria de EI-MS. Além disso, eles foram submetidos a triagem de atividade antibacteriana e hemolítica. Análise da inibição enzimática foi bem apoiada pelos resultados de docking molecular. Por exemplo, o composto 8q exibiu melhor potencial inibitório contra α-glicosidase, e os compostos 8g e 8b exibiram, comparativamente, melhor inibição contra butirilcolinesterase (BChE) elipoxigenase (LOX), respectivamente. Do mesmo modo os compostos 8b e 8c mostraram excelente potencial antibacteriano contra SalmonellaTyphi, semelhante ao do ciprofloxacino, antibiótico padrão usado neste estudo. Os compostos 8c e 8l também mostraram excelente potencial antibacteriano contra Staphylococcus aureus . Quase todos os compostos mostraram pequena atividade hemolítica, sendo que o composto 8p apresentou menor atividade. Assim, as moléculas sintetizadas podem ter a sua utilidade como agentes terapêuticos adequados.

The present work summarizes results of isolation and identification of polar constituents of the methanolic extract of Ligustrum vulgare L. leaves and of the evaluation of inhibiting activity of selected isolates on rat lung cytosol fraction lipoxygenase. Six different compounds were isolated from the ethylacetate and butanol portions of the methanolic extract (hydroxytyrosol and its glucoside, ligustroflavon, oleuropein, acteoside, echinacoside). The inhibitory activity of oleuropein, echinacoside and the water infusion of Ligustrum vulgare leaves tested on LOX was expressed as IC50. Kinetic parameters (KM, Vmax) and type of inhibition were determined. As the most effective in competitive inhibition of LOX, oleuropein was proved.

Unlike other nonsteroidal anti‐inflammatory drugs that inhibit formation of cyclooxygenase (COX)‐dependent eicosanoids, acetylation of COX‐2 by aspirin switches eicosanoid biosynthesis from prostaglandin E2 (PGE2) to 15‐epi‐lipoxin A4 (15‐epi‐LXA4 or aspirin‐triggered lipoxin, ATL). ATL formation by activated leukocytes (PMN) requires the intervention of 5‐lipoxygenase (5‐LOX), an enzyme that is involved in leukotriene B4 (LTB4) formation. In the present study, we have examined the role of acetylated COX‐2 and 5‐LOX in modulating antiadhesive effects of aspirin on adhesion of PMN to endotoxin (LPS)‐primed human umbilical endothelial cells (HUVEC). Treating PMN/HUVEC cocultures with aspirin resulted in a concentration‐dependent inhibition of cell‐to‐cell adhesion induced by LPS. Treating HUVEC with selective COX‐2 inhibitors, celecoxib and rofecoxib, caused an ∼70% reversion of antiadhesive effect of aspirin. In contrast, inhibition of neutrophil's 5‐LOX pathway with 1 μM ZD2138, a selective 5‐LOX inhibitor, 1 μM BAY‐X‐1005, a FLAP inhibitor, or 100 μM licofelone, a dual COX/5‐LOX inhibitor, did not affect antiadhesive properties of aspirin. Exposure to celecoxib (100 μM) or rofecoxib (10 μM) completely suppressed ATL formation caused by aspirin without affecting LTB4 levels. ZD2138, licofelone and BAY‐X‐1005 inhibited ATL formation as well as LTB4 generation. Treatment with LXA4 reduced PMN adhesion to HUVEC and counteracted the proadhesive effect of celecoxib. In contrast, exposure to Boc‐1, an LXA4 antagonist, counteracts the antiadhesive activities of aspirin. Exposure to U75302, an LTB4 receptor antagonist, enhances the antiadesive effect of aspirin. Reversal of antiadhesive activities of aspirin by celecoxib was associated with increased expression of LFA‐1 on PMN and E‐selectin on HUVEC. Addition of LXA4, ZD2138 and U75302 inhibited these changes. The present results support the notion that inhibition of ATL formation is mechanistically linked to the reversal of the antiadhesive activity of aspirin caused by selective COX‐1 inhibitors and suggests that the LTB4/ATL balance modulates pro‐ and antiadhesive activity of nonsteroidal anti‐inflammatory drugs at the leukocyte–endothelial cell interface. British Journal of Pharmacology (2003) 139, 1351–1359. doi:10.1038/sj.bjp.0705356