- Anti-inflammatory, analgesic and COX-2 inhibitory activity of novel thiadiazoles in irradiated rats
-
In this work, novel series of pyran, thiophene and thienopyrimidine derivatives based on 2-acetamide-thiadiazole scaffold were designed and synthesized for evaluation as selective COX-2 inhibitors in-vitro and investigated in-vivo as anti-inflammatory and analgesic agents against carrageenan-induced rat paw oedema model in irradiated rats, since its well-known that ionizing radiation plays an important role in exaggerating the inflammatory responses and in enhancing the release of inflammatory mediators in experimental animals. Toxicological studies were carried out to evaluate the ulcerogenic activity, acute toxicity and kidney and liver functions for the most potent compounds. In order to understand the binding mode of the synthesized compounds into the active site of COX-2, docking study was performed. Most of the tested compounds showed high inhibitory ability to COX-2. Among them, thiadiazole derivatives bearing thiophene and thienopyrimidine moieties were the most active derivatives, compound 26 showed extremely high selectivity index (SI) of >?555.5?μM which is nearly two folds better than celecoxib (>?277.7?μM), in addition to compounds 3, 16, 17, 21 and 26 with SI in the range of >?308.6- >?384.6?μM. The 4-chlorothieno[2.3-d]pyrimidine derivative of thiadiazole 21 showed the highest anti-inflammatory activity in this study having 24.49% of oedema compared to celecoxib (18.61%) in addition to compounds 17 and 26 with 24.70 and 25.40% of oedema, respectively, while the thiadiazol-2-acetamide derivative 2 was the most potent analgesic compound with the highest nociceptive threshold (85.72?g) very close to that of celecoxib (90.23?g). These compounds showed high safety margin on gastric mucosa with no ulceration effect. Also the most active in-vivo anti-inflammatory compounds 17, 21 and 26 were found to be non-toxic in experimental rats with normal kidney and liver functions. Docking study of the synthesized compounds showed similar orientation as celecoxib within the active site of COX-2 enzyme and similar ability to emerge deeply in the additional pocket and binding with Arg513 and His90 the key amino acids responsible for selectivity.
- Ragab, Fatma A.,Heiba, Helmi I.,El-Gazzar, Marwa G.,Abou-Seri, Sahar M.,El-Sabbagh, Walaa A.,El-Hazek, Reham M.
-
-
Read Online
- Synthesis of novel 2-acetamide-5-phenylthio-1,3,4-thiadiazole-containing phenyl urea derivatives as potential VEGFR-2 inhibitors
-
A novel series of 2-acetamide-5-phenylthio-1,3,4-thiadiazol derivatives containing a phenyl urea warhead were synthesized and evaluated as antiproliferative agents. The cytotoxic activities of the newly synthesized compounds were evaluated toward three human cancer cell lines, including HT-29, A431, and PC3, as well as normal HDF cells, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. The biological results revealed the highest degree of cytotoxic effects for the 4-chloro-containing compound 9e against the A431 cell line. Further assessment by Western blot analysis assay confirmed the induction of apoptosis by compound 9e, with upregulation of Bax and downregulation of Bcl-2 proteins in A431 cancer cells. In addition, compound 9e inhibited the phosphorylation of vascular endothelial growth factor and its receptor (VEGFR-2) in A431 cancer cells while the total level of actin protein was unchanged. These results were confirmed by a three-dimensional cell culture method using the hanging drop technique.
- Ayati, Adileh,Fathi, Parnian,Foroumadi, Alireza,Foroumadi, Roham,Ketabforoosh, Shima H. M. E.,Moghimi, Setareh,Safari, Fatemeh,Salarinejad, Somayeh,Toolabi, Mahsa
-
-
- Key intermediate aqiang 2-acetyl-5-chlorosulfonyl -1, 3, 4-thiadiazole method for preparing the non-chlorine (by machine translation)
-
The invention discloses a preparation method of non-chlorine gas of acetazolamide key intermediate 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole. The preparation method comprises the steps of firstly adding hydrochloric acid into a reactor and then dropwise adding hydrogen peroxide to perform reaction so as to obtain a reaction solution; adding 2-acetamido-5-sulfydryl-1, 3, 4-thiadiazole into the obtained reaction solution in batch to perform reaction and obtaining a reactant after reaction is completed; directly conducting suction filtration, washing and drying on the reactant and performing drying to obtain the intermediate 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole. The preparation method is more moderate in operate and more environment-friendly, and the obtained intermediate 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole is good in color and luster and high in purity.
- -
-
Paragraph 0027; 0028
(2017/01/02)
-
- Synthesis and biological evaluation of nonsymmetrical aromatic disulfides as novel inhibitors of acetohydroxyacid synthase
-
46 Novel nonsymmetrical aromatic disulfides containing [1,3,4]thiadiazole or [1,3,4]oxadiazole groups were synthesized and their biological activities were evaluated as inhibitors of acetohydroxyacid synthase (AHAS, EC 2.2.1.6). Besides their strong in vitro inhibition against plant AHAS, compounds 3e and 3f also display 80-100% post-emergence herbicidal activities in greenhouse bioassay at 1500 g/ha dosage. The assay of exogenous branched-chain amino acids supplementation on rape root growth of 3e suggests that the herbicidal activity has relationship with AHAS inhibition.
- Li, Zai-Shun,Wang, Wei-Min,Lu, Wei,Niu, Cong-Wei,Li, Yong-Hong,Li, Zheng-Ming,Wang, Jian-Guo
-
supporting information
p. 3723 - 3727
(2013/07/25)
-
- Acetazolamide-based fungal chitinase inhibitors
-
Chitin is an essential structural component of the fungal cell wall. Chitinases are thought to be important for fungal cell wall remodelling, and inhibition of these enzymes has been proposed as a potential strategy for development of novel anti-fungals. The fungal pathogen Aspergillus fumigatus possesses two distinct multi-gene chitinase families. Here we explore acetazolamide as a chemical scaffold for the inhibition of an A. fumigatus 'plant-type' chitinase. A co-crystal structure of AfChiA1 with acetazolamide was used to guide synthesis and screening of acetazolamide analogues that yielded SAR in agreement with these structural data. Although acetazolamide and its analogues are weak inhibitors of the enzyme, they have a high ligand efficiency and as such are interesting leads for future inhibitor development.
- Schüttelkopf, Alexander W.,Gros, Ludovic,Blair, David E.,Frearson, Julie A.,Van Aalten, Daan M.F.,Gilbert, Ian H.
-
experimental part
p. 8334 - 8340
(2011/02/28)
-
- GIAO/DFT 13C NMR Chemical Shifts of 1,3,4-thiadiazoles
-
1H, 13C and 15N NMR spectra of 2-acetylamino-1,3,4-thiadiazole and its 5-substituted derivatives have been measured and assigned based on reference data, as well as homo- and heteronuclear 2 D NMR experiments. In addition, the GIAO/DFT approach at the B3LYP level of theory using the 6-311G basis set was used to calculate the 13C NMR chemical shifts. Although this method gives reliable results for 2-arylhydrazones of 1,3-diphenylpropanetrione, 2-phenacylpyridines, (Z)-2-(2-hydroxy-2-phenylvinyl)pyridines, 4-fluoroanilines, (1Z,3Z)-1,4-di(pyridin-2-yl)buta-1,3-dienediols and their tautomeric forms, the calculated chemical shifts for the 1,3,4-thiadiazoles studied are less satisfactory. Presence of the sulfur atom(s) seems to be responsible for such behavior.
- Loghmani-Khouzani, Hossein,Rauckyte, Teresa,Osmialowski, Borys,Gawinecki, Ryszard,Kolehmainen, Erkki
-
p. 2217 - 2225
(2008/02/10)
-
- Synthesis, antibacterial and?antitubercular activities of?some?7-[4-(5-amino-[1,3,4]thiadiazole-2-sulfonyl)-piperazin -1-yl] fluoroquinolonic derivatives
-
In the present study, a series of 7-[4-(5-amino-1,3,4 thiadiazole-2-sulfonyl)]-1-piperazinyl fluoroquinolonic derivatives VIIa-d were synthesized in good yields and characterized by IR, 1H-NMR, 13C-NMR, FAB Mass spectral and elemental analyses. The compounds were evaluated for their preliminary in vitro antibacterial activity against some Gram-positive and Gram-negative bacteria and selected compounds VIIa, b were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain by broth dilution assay method. The antibacterial data of the tested N-sulfonylfluoroquinolones VIIa-d indicated that all the synthesized compounds showed better activity against Gram-positive bacteria S.?aureus, E.?faecelis, Bacillus sp. (MIC = 1-5?μg?ml-1, respectively) compared to reference drugs. The MIC values of tested derivatives connotes that the sparfloxacin and gatifloxacin derivatives VIIc, d were most active against the tested Gram-positive bacterial strains (MIC = 1-5?μg?ml-1). All the tested compounds VIIa-d showed poor activity against the Gram-negative bacteria. The in vitro antitubercular activity reports of selected compounds VIIa, b against M.?tuberculosis strain H37Rv showed moderate activity at MIC of 10?μg?ml-1.
- Talath,Gadad
-
p. 918 - 924
(2007/10/03)
-
- Discovery of aminothiazole inhibitors of cyclin-dependent kinase 2: Synthesis, x-ray crystallographic analysis, and biological activities
-
High throughput screening identified 2-acetamido-thiazolylthio acetic ester 1 as an inhibitor of cyclin-dependent kinase 2 (CDK2). Because this compound is inactive in cells and unstable in plasma, we have stabilized it to metabolic hydrolysis by replacing the ester moiety with a 5-ethyl-substituted oxazole as in compound 14. Combinatorial and parallel synthesis provided a rapid analysis of the structure-activity relationship (SAR) for these inhibitors of CDK2, and over 100 analogues with IC50 values in the 1-10 nM range were rapidly prepared. The X-ray crystallographic data of the inhibitors bound to the active site of CDK2 protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues displayed potent and broad spectrum antiproliferative activity across a panel of tumor cell lines in vitro. In addition, A2780 ovarian carcinoma cells undergo rapid apoptosis following exposure to CDK2 inhibitors of this class. Mechanism of action studies have confirmed that the phosphorylation of CDK2 substrates such as RB, histone H1, and DNA polymerase α (p70 subunit) is reduced in the presence of compound 14. Further optimization led to compounds such as water soluble 45, which possesses a favorable pharmacokinetic profile in mice and demonstrates significant antitumor activity in vivo in several murine and human models, including an engineered murine mammary tumor that overexpresses cyclin E, the coactivator of CDK2.
- Kim, Kyoung Soon,Kimball, S. David,Misra, Raj N.,Rawlins, David B.,Hunt, John T.,Xiao, Hai-Yun,Lu, Songfeng,Qian, Ligang,Han, Wen-Ching,Shan, Weifang,Mitt, Toomas,Cai, Zhen-Wei,Poss, Michael A.,Zhu, Hong,Sack, John S.,Tokarski, John S.,Chang, Chieh Ying,Pavletich, Nikola,Kamath, Amrita,Humphreys, William G.,Marathe, Punit,Bursuker, Isia,Kellar, Kristen A.,Roongta, Urvashi,Batorsky, Roberta,Mulheron, Janet G.,Bol, David,Fairchild, Craig R.,Lee, Francis Y.,Webster, Kevin R.
-
p. 3905 - 3927
(2007/10/03)
-
- Synthesis and investigation of inhibition effects of new carbonic anhydrase inhibitors
-
Three new derivatives of 2-substituted 1,3,4-thiadiazole-5-sulfonamide have been synthesized. These compounds are 2-(3-chloropropionylamino)- 1,3,4-thiadiazole-5-sulfonamide (1); 2-(2,2-dichloroacetylamino)-1,3,4-thiadiazole-5-sulfonamide (2); and 2-(3-phenylpropionylamino)-1,3,4-thiadiazole-5-sulfonamide (3). Inhibition effects of these compounds on carbonic anhydrase I and II have been investigated. By comparing 150 and K(i) values of the compounds, it has been found that compound 1 is a more potent inhibitor than acetazolamide (b) on carbonic anhydrase II.
- Arslan, Oktay,Kuefrevioglu, Oe. Irfan,Nalbantoglu, Barbaros
-
p. 515 - 518
(2007/10/03)
-
- Aminosulfonylthiadiazolylureas
-
Disclosed are compounds of the formula STR1 wherein R1 is alkyl, R2 is selected from the group consisting of hydrogen and alkyl; or R1 and R2 together with the nitrogen atom form a cyclic ring structure having 4 or 5 carbon atoms; m is the integer 0 or 1; when m is 1, R4 and R5 are each independently selected from the group consisting of hydrogen and alkyl or up to 3 carbon atoms; when m is 0, R4 is hydrogen and R5 is the same as defined above; R3, R6, R7, R8, R9 are each independently selected from the group consisting of hydrogen and alkyl; n is an integer from 0 to 2; and Z1 and Z2 are each independently selected from the group consisting of oxygen and sulfur. These compounds are useful as herbicides.
- -
-
-
