- Design, synthesis and in vitro evaluation studies of sulfonyl-amino-acetamides as small molecule BACE-1 inhibitors
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The identification of a series of sulfonyl-amino-acetamides as BACE-1 (β-secretase) inhibitors for the treatment of Alzheimer's disease is reported. The derivatives were designed based on the docking simulation study, synthesized and assessed for BACE-1 inhibition in vitro. The designed ligands revealed desired binding interactions with the catalytic aspartate dyad and occupance of S1 and S2′ active site regions. These in silico results correlated well with in vitro activity. Out of 33 compounds synthesized, 12 compounds showed significant inhibition at 10 μM concentration. The most active compound 2.17S had IC50 of 7.90 μM against BACE-1, which was concomitant with results of in silico docking study.
- Jain, Priti,Wadhwa, Pankaj K.,Gunapati, Sinduri,Jadhav, Hemant R.
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p. 2567 - 2575
(2016/05/10)
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- Synthesis and in vitro antimicrobial activity of some newer quinazolinone-sulfonamide linked hybrid heterocyclic entities derived from glycine
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A novel series of 4-(amino or acetamido)-N-{[3-(substituted aryl)-4-oxo-3,4-dihydroquinazolin-2-yl]-methyl}benzenesulfonamide derivatives (1-19) were designed to assimilate 4-quinazolone and sulfonamide moieties in a single molecular framework. To derive entitled hybrid entities with structural diversity, an efficient multi-step synthetic approach initiated from glycine was developed, which involves milder conditions for emphasizing steps viz., reaction in aqueous-media, phosphazo-method of condensation, base mediated selective ester-cleavage, along with key-step, rapid and improved Grimmel's hetero-cyclization method. The structure of the synthesized compounds was confirmed by physico-chemical characteristics and spectroscopic investigations. All these compounds were screened for their in vitro antimicrobial activity. The minimum inhibitory concentrations of the synthesized compounds against various bacteria (S. aureus, B. cereus, E. coli, K. pneumonia, P. aeruginosa) and fungus (A. niger, C. albicans) was measured by broth microdilution assay. Further, results on the preliminary biological activity indicated that most of the screened compounds have displayed varied degree of inhibitory actions.
- Vanparia, Satish F.,Patel, Tarosh S.,Dixit, Ritu B.,Dixit, Bharat C.
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p. 5184 - 5196
(2013/12/04)
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- Sulfonylamino acid derivatives
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The present invention is related to: (i) matrix metalloproteinase inhibitors containing sulfonylamino acid derivatives of the formula (Ia): wherein R1is hydrogen, C1-4 alkyl; R is hydrogen, C1-8 alkyl etc.; E is —CONR3—, in which R3is hydrogen, C1-4 alkyl etc., —NR3CO—, —CO—O—, —O—CO— etc.; A is hydrogen, C1-8 alkyl, C3-7 cycloalkyl, or Ar; J is bond, C2-4 alkylene etc.; G is —(CH2)m— in which m is 2, 3 or 4, or in which R6and R7is hydrogen, C1-8 alkyl etc.; and non-toxic salts thereof, (ii) novel sulfonylamino acid derivatives of the formula (Ib): wherein all the symbols are the same meaning as (i); and non-toxic salts thereof, and (iii) process for the preparation of the compound of the formula (Ib). The compounds of the formula (Ia) are useful for prevention and/or treatment of diseases induced by overexpression and excess activity of MMP. The diseases such as above, for example, are rheumatoid, arthrosteitis, unusual bone resorption, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, metastasis of, invasion of or growth of tumor cell, autoimmune disease (Crohn's disease, Sjogren's syndrome etc.), disease caused by vascular emigration or infiltration of leukocytes, arterialization.
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- Protease inhibitors - Part 5. Alkyl/arylsulfonyl- and arylsulfonylureido-/arylureido- glycine hydroxamate inhibitors of Clostridium histolyticum collagenase
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Reaction of alkyl/arylsulfonyl halides with glycine afforded a series of derivatives which were first N-benzylated by treatment with benzyl chloride, and then converted to the corresponding hydroxamic acids with hydroxylamine in the presence of carbodiimide derivatives. Other derivatives were obtained by reaction of N-benzyl-glycine with aryl isocyanates, arylsulfonyl isocyanates or benzoyl isothiocyanate, followed by conversion of their COOH group into the CONHOH moiety, as mentioned above. The 90 new compounds reported here were assayed as inhibitors of the Clostridium histolyticum collagenase (EC 3.4.24.3), a zinc enzyme which degrades triple helical regions of native collagen. The prepared hydroxamate derivatives were generally 100-500 times more active than the corresponding carboxylates. In the series of synthesized hydroxamates, substitution patterns leading to the best inhibitors were those involving perfluoroalkylsulfonyl- and substituted- arylsulfonyl moieties, such as pentafluorophenylsulfonyl, 3- and 4- carboxyphenylsulfonyl-, 3-trifluoromethyl-phenylsulfonyl or 1- and 2-naphthyl among others. Thus, it seems that similarly to the matrix metalloproteinase (MMP) hydroxamate inhibitors, Clostridium histolyticum collagenase inhibitors should incorporate hydrophobic moieties at the P1, and P2, sites, whereas the α-carbon substituent may be a small and compact moiety (such as H. for the Gly derivatives reported here). Such compounds might lead to the design of collagenase inhibitor-based drugs useful as anti-cancer, anti-arthritis or anti-bacterial agents for the treatment of corneal keratitis. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
- Scozzafava, Andrea,Supuran, Claudiu T.
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p. 299 - 307
(2007/10/03)
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- Diazonium salt for bilirubin assay
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Diazonium salts which are useful in an assay for bilirubin are disclosed. The novel salts have the structural formula: STR1 wherein X- is a stabilizing anion, Y is CO-- or SO2 --; and R1 and R2 are independently
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