Carbonic Anhydrase Inhibition Activities of Schiff's Bases Based on Quinazoline-Linked Benzenesulfonamide.

Human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII were investigated for their inhibitory activity with a series of new Schiff's bases based on quinazoline scaffold 4-27. The hCA I isoform was efficiently inhibited by Schiff's bases 4-6, 10-19, 22-27 and had an inhibition constant (Ki) value of 52.8-991.7 nM compared with AAZ (Ki, 250 nM). Amongst the quinazoline derivatives, the compounds 2, 3, 4, 10, 11, 16, 18, 24, 26, and 27 were proven to be effective hCA II inhibitors, with Ki values of 10.8-52.6 nM, measuring up to AAZ (Ki, 12 nM). Compounds 2-27 revealed compelling hCA IX inhibitory interest with Ki values of 10.5-99.6 nM, rivaling AAZ (Ki, 25.0 nM). Quinazoline derivatives 3, 10, 11, 13, 15-19, and 24 possessed potent hCA XII inhibitory activities with KI values of 5.4-25.5 nM vs. 5.7 nM of AAZ. Schiff's bases 7, 8, 9, and 21 represented attractive antitumor hCA IX carbonic anhydrase inhibitors (CAIs) with KI rates (22.0, 34.8, 49.2, and 45.3 nM, respectively). Compounds 5, 7, 8, 9, 14, 18, 19, and 21 showed hCA I inhibitors on hCA IX with a selectivity index of 22.46-107, while derivatives 12, 14, and 18 showed selective hCA I inhibitors on hCA XII with a selectivity profile of 45.04-58.58, in contrast to AAZ (SI, 10.0 and 43.86). Compounds 2, 5, 7-14, 19-23, and 25 showed a selectivity profile for hCA II inhibitors over hCA IX with a selectivity index of 2.02-19.67, whereas derivatives 5, 7, 8, 13, 14, 15, 17, 20, 21, and 22 showed selective hCA II inhibitors on hCA XII with a selectivity profile of 4.84-26.60 balanced to AAZ (SI, 0.48 and 2.10).

Synthesis, antitumor, and apoptosis-inducing activities of novel 5-arylidenethiazolidine-2,4-dione derivatives: Histone deacetylases inhibitory activity and molecular docking study.

The antitumor activity of the newly synthesized 5-arylidenethiazolidine-2,4-dione derivatives 18a-f and 19a-f was investigated, compared to doxorubicin (IC50 = 4.17-8.87 µM) and SAHA (IC50 = 2.70-7.11 µM). Among the tested molecules, compounds 18b, 18c, 18f, 19d, and 19e displayed the highest antitumor activity against cancer cell lines (IC50 = 3.16-28.94 µM). Further, compounds 18b, 18c, 18f, and 19d were tested as Histone deacetylases (HDACs) inhibitors compared with Entinostat (IC50 = 0.093-0.75 µM). Compounds 18b, 18c, 18f, and 19d inhibited HDAC1, HDAC2, HDAC8, and HDAC6 enzymes with IC50 values ranging from 0.144 to 1.741 µM. In addition, compound 18b caused apoptosis via a mitochondrial-mediated pathway and led to cell cycle arrest at the G1 phase. It also increased caspases-3 and caspases-7 by 5.2-3.9 and 9.1-3.7 folds, respectively. The molecular docking analysis of compounds 18b and 18c revealed that they could bind to the active sites of HDAC1, HDAC2, HDAC8, and HDAC6 like co-crystallized inhibitors.

Synthesis, antitumor and antimicrobial activity of some new 6-methyl-3-phenyl-4(3H)-quinazolinone analogues: in silico studies.

Some new derivatives of substituted-4(3H)-quinazolinones were synthesized and evaluated for their in vitro antitumor and antimicrobial activities. The results of this study demonstrated that compound 5 yielded selective activities toward NSC Lung Cancer EKVX cell line, Colon Cancer HCT-15 cell line and Breast Cancer MDA-MB-231/ATCC cell line, while NSC Lung Cancer EKVX cell line and CNS Cancer SF-295 cell line were sensitive to compound 8. Additionally, compounds 12 and 13 showed moderate effectiveness toward numerous cell lines belonging to different tumor subpanels. On the other hand, the results of antimicrobial screening revealed that compounds 1, 9 and 14 are the most active against Staphylococcus aureus ATCC 29213 with minimum inhibitory concentration (MIC) of 16, 32 and 32 µg/mL respectively, while compound 14 possessed antimicrobial activities against all tested strains with the lowest MIC compared with other tested compounds. In silico study, ADME-Tox prediction and molecular docking methodology were used to study the antitumor activity and to identify the structural features required for antitumor activity.

Facile and promising method for michael addition of indole and pyrrole to electron-deficient trans-ß-nitroolefins catalyzed by a hydrogen bond donor catalyst Feist's acid and preliminary study of antimicrobial activity.

The importance of cooperative hydrogen-bonding effects has been demonstrated using novel 3-methylenecyclopropane-1,2-dicarboxylic acid (Feist's acid (FA)) as hydrogen bond donor catalysts for the addition of indole and pyrrole to trans-ß-nitrostyrene derivatives. Because of the hydrogen bond donor (HBD) ability, Feist's acid (FA) has been introduced as a new class of hydrogen bond donor catalysts for the activation of nitroolefin towards nucleophilic substitution reaction. It has effectively catalyzed the Michael addition of indoles and pyrrole to ß-nitroolefins under optimum reaction condition to furnish the corresponding Michael adducts in good to excellent yields (up to 98%). The method is general, atom-economical, convenient, and eco-friendly and could provide excellent yields and regioselectivities. Some newly synthesized compounds were for examined in vitro antimicrobial activity and their preliminary results are reported.

Design, synthesis and antibacterial activity of fluoroquinolones containing bulky arenesulfonyl fragment: 2D-QSAR and docking study.

Here in, we report the design, synthesis, and antibacterial activity of series of bulky arenesulfonamido derivatives using ciprofloxacin and norfloxacin as scaffolds. All the synthesized compounds were investigated in vitro for their antibacterial activities against two Gram-positive and two Gram-negative organisms using dilution broth method. Among the tested compounds examined, compounds 3-7 showed significance difference from the standard drug ciprofloxacin. 2D-QSAR study provides details on the fine relationship linking structure and activity and offers clues for structural modifications that can improve the activity. Docking study of the compound 3b into the active site of the topoisomerase II DNA-gyrase enzymes revealed a similar binding mode to ciprofloxacin with additional classical and nonclassical hydrogen bonds.

Prevalence and genetic characteristics of TEM, SHV, and CTX-M in clinical Klebsiella pneumoniae isolates from Saudi Arabia.

The prevalence and genetic basis of extended-spectrum beta-lactamases (ESBLs) in Klebsiella pneumoniae remains unclear in Saudi Arabia. Therefore, this study was devoted to determine the prevalence and characterize ESBL-producing K. pneumoniae in Al-Qassim area, Saudi Arabia. A total of 430 isolates of K. pneumoniae isolated from clinical samples were collected over 6 months from January to June 2008. These isolates were screened for the presence of ESBLs by double-disk synergy test and re-evaluated by E-test ESBL method. Minimum inhibitory concentrations of 15 antibiotics against ESBL-positive strains were determined by E-test strips. The ß-lactamases involved were characterized by polymerase chain reaction assays and DNA sequencing. Conjugation experiments were done and ISEcp1 elements were tested among CTX-M positive isolates. The prevalence of ESBL was 25.6% (110/430) and all ESBL-positive isolates were sensitive to imipenem and tigecycline; however, the resistance rate to gentamicin, amikacin, and ciprofloxacin was 87.3%, 10%, and 9.1%, respectively. Of these, 89.1% produced SHV, 70.9% produced TEM, and 36.4% were CTX-M-producing strains. The prevalence of ESBL SHV SHV-12 and SHV-5 was of 60% and 18.2%, respectively, and various non-ESBL SHV, including SHV-1 (5.5%), -11 (3.6%), and -85 (1.8%), was detected. However, the prevalence of CTX-M-15 and CTX-M-14 was 34.5% and 1.8%, respectively. ISEcp1 element was detected in 60% of bla(CTX-M-15) genes. All bla(CTX-M) genes were transferable; however, most of bla(SHV-12) and bla(SHV-5) were not transferable. TEM-type ESBLs were not detected in any of the isolates. This is the first description of CTX-M-14, SHV-5, SHV-11, and SHV-85 in Saudi Arabia. We have documented the dominance of K. pneumoniae SHV-12 and highlighted the emergence of CTX-M-15 in Saudi Arabia.