scholarly journals Novel Diamide-Based Benzenesulfonamides as Selective Carbonic Anhydrase IX Inhibitors Endowed with Antitumor Activity: Synthesis, Biological Evaluation and In Silico Insights

2019 ◽  
Vol 20 (10) ◽  
pp. 2484 ◽  
Author(s):  
Mohamed A. Abdelrahman ◽  
Wagdy M. Eldehna ◽  
Alessio Nocentini ◽  
Silvia Bua ◽  
Sara T. Al-Rashood ◽  
...  

In this work, we present the synthesis and biological evaluation of novel series of diamide-based benzenesulfonamides 5a–h as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IX and XII. The target tumor-associated isoforms hCA IX and XII were undeniably the most affected ones (KIs: 8.3–123.3 and 9.8–134.5 nM, respectively). Notably, diamides 5a and 5h stood out as a single-digit nanomolar hCA IX inhibitors (KIs = 8.8 and 8.3 nM). The SAR outcomes highlighted that bioisosteric replacement of the benzylidene moiety, compounds 5a–g, with the hetero 2-furylidene moiety, compound 5h, achieved the best IX/I and IX/II selectivity herein reported with SIs of 985 and 13.8, respectively. Molecular docking simulations of the prepared diamides within CA IX active site revealed the ability of 5h to establish an additional H-bond between the heterocyclic oxygen and HE/Gln67. Moreover, benzenesulfonamides 5a, 5b and 5h were evaluated for their antitumor activity against renal cancer UO-31 cell line. Compound 5h was the most potent derivative with about 1.5-fold more enhanced activity (IC50 = 4.89 ± 0.22 μM) than the reference drug Staurosporine (IC50 = 7.25 ± 0.43 μM). Moreover, 5a and 5h were able to induce apoptosis in UO-31 cells as evidenced by the significant increase in the percent of annexinV-FITC positive apoptotic cells by 22.5- and 26.5-folds, respectively.

Metabolites ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 225
Author(s):  
Pavitra S. Thacker ◽  
Prerna L. Tiwari ◽  
Andrea Angeli ◽  
Danaboina Srikanth ◽  
Baijayantimala Swain ◽  
...  

A series of coumarin-linked 4-anilinomethyl-1,2,3-triazoles (6a–t) was synthesized via a molecular hybridization approach, through carbon C-6 of the coumarin moiety. The synthesized compounds were evaluated for their inhibition of carbonic anhydrase (CA) isoforms I, II, IX and XIII. CAs IX and XIII were selectively inhibited over the off-target isoforms I and II. The best inhibitory profiles against CA IX were shown by compounds 6a, 6e and 6f (Ki < 50 nM), with compound 6e displaying the best inhibition with a Ki value of 36.3 nM. Compounds 6a, 6b, 6j, 6o and 6q exhibited the best inhibitory profiles against CA XIII (Ki < 100 nM). These compounds can be further explored for the discovery of potent and effective CA IX and CA XIII inhibitors.


2017 ◽  
Vol 14 (2) ◽  
pp. 80-85 ◽  
Author(s):  
Hayriye Genc ◽  
Busra Ceken ◽  
Cigdem Bilen ◽  
Zubeyde Sackes ◽  
Nahit Gencer ◽  
...  

MedChemComm ◽  
2017 ◽  
Vol 8 (5) ◽  
pp. 1000-1006 ◽  
Author(s):  
Ibrahim Bin Sayeed ◽  
V. Lakshma Nayak ◽  
Mohd Adil Shareef ◽  
Neeraj Kumar Chouhan ◽  
Ahmed Kamal

A library of imidazopyridine–propenone conjugates (8a–8u) were synthesized and evaluated for their antitumor activity against four human cancer cell lines.


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