73027-79-9Relevant articles and documents
Synthesis and SAR studies of novel 1,2,4-oxadiazole-sulfonamide based compounds as potential anticancer agents for colorectal cancer therapy
Abid, Mohammad,Alajmi, Mohamed F.,Garrison, Jered,Hasan, Phool,Hussain, Afzal,Imtaiyaz Hassan, Md,Khan, Parvez,King, Hannah M.,Queen, Aarfa,Rana, Sandeep,Rizvi, M. Moshahid Alam,Shamsi, Farheen,Zahid, Muhammad,Zeya, Bushra
, (2020/03/23)
A diverse series of 1,2,4-oxadiazoles based substituted compounds were designed, synthesized and evaluated as anticancer agents targeting carbonic anhydrase IX (CAIX). Initial structure-activity analysis suggested that the thiazole/thiophene-sulfonamide conjugates of 1,2,4-oxadiazoles exhibited potent anticancer activities with low μM potencies. Compound OX12 exhibited antiproliferative activity (IC50 = 11.1 μM) along with appreciable inhibition potential for tumor-associated CAIX (IC50 = 4.23 μM) isoform. Therefore, OX12 was structurally optimized and its SAR oriented derivatives (OX17-27) were synthesized and evaluated. This iteration resulted in compound OX27 with an almost two-fold increase in antiproliferative effect (IC50 = 6.0 μM) comparable to the clinical drug doxorubicin and significantly higher potency against CAIX (IC50 = 0.74 μM). Additionally, OX27 treatment decreases the expression of CAIX, induces apoptosis and ROS production, inhibited colony formation and migration of colon cancer cells. Our studies provide preclinical rational for the further optimization of identified OX27 as a suitable lead for the possible treatment of CRC.
Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors
Bhide, Rajeev S.,Keon, Alec,Weigelt, Carolyn,Sack, John S.,Schmidt, Robert J.,Lin, Shuqun,Xiao, Hai-Yun,Spergel, Steven H.,Kempson, James,Pitts, William J.,Carman, Julie,Poss, Michael A.
, p. 4908 - 4913 (2017/09/27)
The identification of small molecule inhibitors of IRAK4 for the treatment of autoimmune diseases has been an area of intense research. We discovered novel 4,6-diaminonicotinamides which potently inhibit IRAK4. Optimization efforts were aided by X-ray crystal structures of inhibitors bound to IRAK4. Structure activity relationship (SAR) studies led to the identification of compound 29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay.
Quinolone amides as antitrypanosomal lead compounds with In Vivo activity
Hiltensperger, Georg,Hecht, Nina,Kaiser, Marcel,Rybak, Jens-Christoph,Hoerst, Alexander,Dannenbauer, Nicole,Müller-Buschbaum, Klaus,Bruhn, Heike,Esch, Harald,Lehmann, Leane,Meinel, Lorenz,Holzgrabe, Ulrike
supporting information, p. 4442 - 4452 (2016/08/02)
Human African trypanosomiasis (HAT) is a major tropical disease for which few drugs for treatment are available, driving the need for novel active compounds. Recently, morpholino-substituted benzyl amides of the fluoroquinolone-type antibiotics were identified to be compounds highly active against Trypanosoma brucei brucei. Since the lead compound GHQ168 was challenged by poor water solubility in previous trials, the aim of this study was to introduce structural variations to GHQ168 as well as to formulate GHQ168 with the ultimate goal to increase its aqueous solubility while maintaining its in vitro antitrypanosomal activity. The pharmacokinetic parameters of spray-dried GHQ168 and the newly synthesized compounds GHQ242 and GHQ243 in mice were characterized by elimination half-lives ranging from 1.5 to 3.5 h after intraperitoneal administration (4 mice/compound), moderate to strong human serum albumin binding for GHQ168 (80%) and GHQ243 (45%), and very high human serum albumin binding (>99%) for GHQ242. For the lead compound, GHQ168, the apparent clearance was 112 ml/h and the apparent volume of distribution was 14 liters/kg of body weight (BW). Mice infected with T. b. rhodesiense (STIB900) were treated in a stringent study scheme (2 daily applications between days 3 and 6 postinfection). Exposure to spray-dried GHQ168 in contrast to the control treatment resulted in mean survival durations of 17 versus 9 days, respectively, a difference that was statistically significant. Results that were statistically insignificantly different were obtained between the control and the GHQ242 and GHQ243 treatments. Therefore, GHQ168 was further profiled in an early-treatment scheme (2 daily applications at days 1 to 4 postinfection), and the results were compared with those obtained with a control treatment. The result was statistically significant mean survival times exceeding 32 days (end of the observation period) versus 7 days for the GHQ168 and control treatments, respectively. Spray-dried GHQ168 demonstrated exciting antitrypanosomal efficacy.
