716-94-9Relevant articles and documents
New glycine derived peptides bearing benzenesulphonamide as an antiplasmodial agent
Ugwuja, Daniel Izuchukwu,Okoro, Uchechukwu,Soman, Shubhanji,Ibezim, Akachukwu,Ugwu, David,Soni, Rina,Obi, Bonaventure,Ezugwu, James,Ekoh, Ogechi
, p. 3660 - 3674 (2021/03/03)
In the tropics, malaria is among the most serious infectious diseases in developing countries. The discovery of the artemesinin antimalarial drug not too long ago was a major breakthrough in the effort to combat the malaria disease. However, recent reports of resistance even to combination therapy involving artemisinin are very worrisome and have led to the search for new chemical agents to sustain the fight against malaria. The carboxamide functionality has been shown to be an important pharmacophore in over 25% of commercial chemotherapeutic agents. Three benzensulphonamides (3a-c) were prepared from the reaction of the appropriate benzensulphonyl chloride (1a-c) and alanine (2) in aqueous basic medium. Eight tert-butylamino-oxo-ethylcarbamates (5a-h) were also prepared from reacting commercially available boc-glycine (4) and different amines using peptide coupling reagents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBt), with triethyl amine and dichloromethane (DCM) as solvents. The target compounds were prepared by reacting compounds 3a-c with compounds 5a-h in the presence of coupling reagents to get twenty four (24) different compounds. The compounds were characterized and evaluated for their antiplasmodial activity. Computed molecular descriptors and assessed biochemical parameters showed that the compounds were drug-like and safe. All the compounds had favourable binding interactions with residues at the PABA binding site of homologically modeled P. falciparum dihydropteroate synthase and henceforward the in vitro and in vivo antiplasmodial activities were evaluated. Compounds 7a-7x showed activity against P. falciparum (W2 strain) at MIC values ranging from 3.52 to 0.09 μM. Moreover, seven of the compounds (7c, 7d, 7i, 7j, 7p, 7r and 7s) showed better activity than quinine (MIC = 0.72 μM). In addition, 16 of the 24 compounds were found to clear more than 50 percent of P. berghei (NK-65 strain) from the blood of infected mice at 12 days post-infection. The percentages of parasites cleared by 20 mg kg-1 of the three most effective compounds (7g, 7n and 7r) were 74.98, 74.98 and 74.07, respectively. In conclusion, 7r (MIC 0.71 μM) from this class of glycine derived sulfonamides has the ability to clear 74.07% of P. berghei from blood of infected mice at 20 mg kg-1 and an interesting pharmacokinetic profile (MW = 430.31 Da, HBA = 7, HBD = 3, log?P = 2.56, NRB = 9 and TPSA = 104.37 ?2), which is in agreement with the Lipinski rule of 5 for a compound to be qualified as a drug candidate. 7r could serve as a lead in developing new antiplasmodial agents. This journal is
Active site mapping of trypsin, thrombin and matriptase-2 by sulfamoyl benzamidines
Dosa, Stefan,Stirnberg, Marit,Luelsdorff, Verena,Haeussler, Daniela,Maurer, Eva,Guetschow, Michael
supporting information, p. 6489 - 6505,17 (2012/12/11)
The benzamidine moiety, a well-known arginine mimetic, has been introduced in a variety of ligands, including peptidomimetic inhibitors of trypsin-like serine proteases. According to their primary substrate specificity, the benzamidine residue interacts with the negatively charged aspartate at the bottom of the S1 pocket of such enzymes. Six series of benzamidine derivatives (1-73) were synthesized and evaluated as inhibitors of two prototype serine proteases, that is, bovine trypsin and human thrombin. As a further target, human matriptase-2, a recently discovered type II transmembrane serine protease, was investigated. Matriptase-2 represents an important regulatory protease in iron homeostasis by down-regulation of the hepcidin expression. Compounds 1-73 were designed to contain a fixed sulfamoyl benzamidine moiety as arginine mimetic and a linker-connected additional substructure, such as a tert-butyl ester, carboxylate or second benzamidine functionality. A systematic mapping approach was performed with these inhibitors to scan the active site of the three target proteases. In particular, bisbenzamidines, able to interact with both the S1 and S3/S4 binding sites, showed notable affinity. In branched bisbenzamidines 66-73 containing a third hydrophobic residue, opposite effects of the stereochemistry on trypsin and thrombin inhibition were observed.
