- Screening of NOS activity and selectivity of newly synthesized acetamidines using RP-HPLC
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Nitric Oxide Synthase (NOS) inhibitors could play a powerful role in inflammatory and neurodegenerative diseases. In this work, novel acetamidine derivatives of NOS were synthesized and the inhibitor activity was evalued. To screen the activity and selectivity, the l-citrulline residue, after the enzymatic NOS assay, was derivatized with o-phthaldialdehyde/N-acetyl cysteine (OPA/NAC) and then evaluated by RP-HPLC method with fluorescence detection.All compounds did not affect the activity of endothelial and neuronal isoforms, while nine of them possessed a percentage of iNOS activity at 10 μM lower than 50%, and were selected for IC50 evaluation. Among them, a compound emerged as a very potent (IC50 of 53 nM) and selective iNOS inhibitor.
- Fantacuzzi, Marialuigia,Maccallini, Cristina,Di Matteo, Mauro,Ammazzalorso, Alessandra,Bruno, Isabella,De Filippis, Barbara,Giampietro, Letizia,Mollica, Adriano,Amoroso, Rosa
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p. 419 - 424
(2016/02/16)
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- Mechanism of inactivation of inducible nitric oxide synthase by amidines. Irreversible enzyme inactivation without inactivator modification
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Nitric oxide synthases (NOS) are hemoproteins that catalyze the reaction of L-arginine to L-citrulline and nitric oxide. N-(3-(Aminomethyl)benzyl) acetamidine (1400W) was reported to be a slow, tight-binding, and highly selective inhibitor of iNOS in vitr
- Zhu, Yaoqiu,Nikolic, Dejan,Van Breemen, Richard B.,Silverman, Richard B.
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p. 858 - 868
(2007/10/03)
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- Acetamidine derivatives and their use as inhibitors for the nitric oxide synthase
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A class of acetamidine derivatives of general formula (I) STR1 wherein R1 is hydrogen, C1-6 hydrocarbyl group optionally substituted by halo, halo, nitro, cyano or a group XR3 wherein X is oxygen, C(O)m wherein m is 1 or 2, S(O)n wherein n is 0, 1 or 2, or a group NR4 wherein R4 is hydrogen or C1-6 alkyl; and R3 is hydrogen, C1-6 alkyl, or a group NR5 R6 wherein R5 and R6 are independently hydrogen or C1-6 alkyl, provided that R3 is not NR5 R6 when X is oxygen or S(O)n; R1a and R1b are independently selected from hydrogen and halo; R2 is a C1-14 hydrocarbyl group which may optionally contain one or two heteroatoms, the group R2 being optionally substituted by one or more groups independently selected from halo; N3 ; nitro; CF3 ; ZR7 wherein Z is oxygen, C(O)m' wherein m' is 1 or 2, S(O)n' wherein n' is 0, 1 or 2, or a group NR8 wherein R8 is hydrogen or C1-6 alkyl and R7 is hydrogen, C1-6 alkyl or a group NR9 R10 wherein R9 and R10 are independently hydrogen or C1-6 alkyl; or R2 is substituted by a group (a) STR2 wherein R11 has a definition the same as for R1 ; with the proviso that when R1 is a C1-6 alkyl group and R2 is a C1-14 hydrocarbyl substituted by two groups ZR7 wherein one group ZR7 is CO2 H, the other group ZR7 is not NH2; and salts thereof, methods for the manufacture thereof, and therapies, particularly inhibtion of nitric oxide synthase, is disclosed.
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