Ahmed Elkerdawy

Abstract Novel benzenesulfonamide derivatives linked to diverse functionalized thiouracils through a flexible N-ethyl acetamide linker were designed and synthesized as carbonic anhydrase (CA) inhibitors. The synthesized candidates demonstrated a potent inhibitory activity against four different CA isoforms in the nanomolar range. Compound 10d showed more than twofold higher potency than the reference AAZ against CA II with Ki of 5.65 and 12?nM, respectively. Moreover, compounds 10d and 20 revealed potent activity against CA IX with Ki of 18.1 and 14.2?nM, respectively. In addition, 10c, 10d, 11b, 11c, and 20 demonstrated high potency against the CA XII isozyme with a Ki range of 4.18?4.8?nM. Most of the synthesized derivatives displayed preferential selectivity toward the CA IX and CA XII isoforms over CA I and CA II. Compounds 11a and 20 exhibited favorable selectivity toward CA IX over CA II with a selectivity index (SI) of 14.36 and 16.62, respectively, and toward CA XII over CA II with SI of 71.01 and 51.19, respectively. Molecular docking simulations showed that the synthesized conjugates adopted comparable binding modes in the CA I, CA II, CA IX, and CA XII isoforms, involving the deep fitting of the sulfonamide moiety in the base of the CA active site via chelation of the Zn2+ ion and H-bond interaction with the key amino acids Thr199 and/or Thr200. Moreover, the N-ethyl acetamide flexible linker enables the substituted thiouracils and fused thiouracil tail to achieve multiple interactions with the surrounding hydrophobic and hydrophilic regions.

A dual-tail approach was applied to the design of a novel series of 2-thiopyrimidine–benzenesulfonamides as carbonic anhydrase (CA) inhibitors. The design strategy is based on the hybridization between a benzenesulfonamide moiety as Zn2+ binding group and 2,4-disubstituted thiopyridimidine as a tail. Among the synthesized compounds, 14h displayed the highest potency (Ki = 1.72 nM) and selectivity for CA II over the isoforms CA IX and CA XII with selectivity indexes of 50 and 5.26, respectively. Meanwhile, compounds 14a and 14l displayed a potent inhibitory activity against CA IX (Ki = 7.4 and 7.0 nM, respectively) compared with the reference drug acetazolamide (AAZ) (Ki = 25 nM), and compound 14l showed higher potency (Ki = 4.67 nM) than AAZ (Ki = 5.7 nM) against the tumor-associated isoform CA XII. Evaluation of the antiproliferative activity in NCI single-dose testing of selected hybrids revealed a pronounced potency of the selective CA II inhibitor 14h against most of the tested NCI cancer cell lines. Moreover, compound 14h demonstrated an IC50 values ranging from 2.40 to 4.50 μM against MCF-7, T-47D, MDA-MB-231, HCT-116, HT29 and SW-620. These results demonstrate that CA II inhibition can be an alternative therapeutic target for cancer treatment. A cell cycle analysis of MCF-7 and MDA-MB-231 showed that treatment with 14h arrested both cell lines at the G2/M phase with significant accumulation of cells in the pre-G1 phase. Moreover, compound 14h showed a noticeable induction of late apoptosis and necrotic cell death of both cell lines compared with untreated cells as a control. A molecular docking study suggested that the sulfonamide moiety accommodates deeply in the CA active site and interacts with the Zn2+ ion while the dual-tail extension interacts with the surrounding amino acids via several hydrophilic and hydrophobic interactions, which affects the potency and selectivity of the hybrids.

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A new series of pyrazolo[3,4-b]pyridine compounds (3a,b–9a-c) was synthesized starting with 2-oxo-6-phenyl-1,2-dihydropyridine-3-carbonitriles 1a,b which converted to their 2- chloro analogues 2a,b. By further treatment of of 2a,b with hydrazine hydrate, the key intermediates 3-amino-pyrazolopyridine derivatives 3a,b were afforded. Whereas, the target 3-substituted-pyrazolopyridine derivatives (4a-d–9a-c) were obtained through treatment of 3a,b with different reagents. All the new compounds were evaluated as antimicrobial agents against six bacterial and six fungal strains. The most potent antimicrobial activity was showed by compounds (3a, 3b, 4a, 4d, 6a, 6c, 9a and 9c) with MIC values range (2-32) μg/mL. Moreover, the most active compounds were selected to be evaluated for their inhibition activity against the resistant bacteria methicillin-resistant Staphylococcus aureus (MRSA). In addition, the inhibitory activity of the potent compounds against dihydrofolate reductase (DHFR) was evaluated compared with Trimethoprim (TMP) as a reference DHFR inhibitor. The most potent inhibition of the target enzyme was also showed by compounds 4d, 6c and 9c of IC50 values 0.72, 0.95 and 1.09 µM, compared with the IC50 value 5.54 µM of TMP. Also, molecular docking study showed that compounds 4d, 6c and 9c having the most binding affinity in DHFR active site.