Peripheral (E)-2-[(4-hydroxybenzylidene)-3,4-dihydronaphthalen-1(2H)-one)]-coordinated phthalocyanines with improved enzyme inhibition properties and photophysicochemical behaviors.

In this study, (E)-4-{4-[(1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl]phenoxy}phthalonitrile (4) and its phthalocyanine derivatives (5-8) were synthesized for the first time. Aggregation behaviors of the novel soluble phthalocyanines in organic solvents were investigated. In addition, the efficiency of 1O2 production of (5) and ZnPc (6) was investigated. The singlet oxygen quantum yields (ΦΔ) for 2HPc (5) and ZnPc (6) were found to be 0.58 and 0.83, respectively. Additionally, novel phthalocyanines (5-8) were investigated for their ability to inhibit enzymes. They exhibited a highly potent inhibition effect on human carbonic anhydrase I and II (hCA I and II) and α-glycosidase (α-Gly) enzymes. Ki values are in the range of 2.60 ± 9.87 to 11.53 ± 6.92 µM, 3.35 ± 0.53 to 15.47 ± 1.20 µM, and 28.60 ± 4.82 to 40.58 ± 7.37 nM, respectively. The calculations of the studied molecule at the B3LYP, HF, and M062X levels in the 6-31G basis sets were made using the Gaussian package program. Afterward, the interactions occurring in the docking calculation against a protein that is the crystal structure of hCA I (PDB ID: 2CAB), the crystal structure of hCA II (PDB ID: 5AML), and the crystal structure of α-Gly (PDB ID: 1R47), were examined. Following that, Protein-Ligand Interaction Profiler (PLIP) analysis was used to look at the interactions that occurred during the docking calculation in further detail.

Bovine carbonic anhydrase (bCA) inhibitors: Synthesis, molecular docking and theoretical studies of bisoxadiazole-substituted sulfonamide derivatives.

This paper describes the in vitro inhibition potential of bisoxadiazole-substituted sulfonamide derivatives (6a-t) against bovine carbonic anhydrase (bCA) after they were designed through computational analyses and evaluated the predicted interaction via molecular docking. First, in silico ADMET predictions and physicochemical property analysis of the compounds provided insights into solubility and permeability, then density functional theory (DFT) calculations were performed to analyse their ionization energies, nucleophilicity, in vitro electron affinity, dipole moments and molecular interactions under vacuum and dimethyl sulfoxide (DMSO) conditions. After calculating the theoretical inhibition constants, IC50 values determined from enzymatic inhibition were found between 12.93 and 45.77 µM. Molecular docking evaluation revealed favorable hydrogen bonding and π-interactions of the compounds within the bCA active site. The experimentally most active compound, 6p, exhibited the strongest inhibitory activity with a theoretical inhibition constant value of 9.41 nM and H-bonds with Gln91, Thr198, and Trp4 residues and His63 Pi-cation interactions with His63 residues. Overall, the study reveals promising bCA blocking potential for the synthesized derivatives, similar to acetazolamide.

Novel spiroindoline derivatives targeting aldose reductase against diabetic complications: Bioactivity, cytotoxicity, and molecular modeling studies.

Despite significant developments in therapeutic strategies, Diabetes Mellitus remains an increasing concern, leading to various complications, e.g., cataracts, neuropathy, retinopathy, nephropathy, and several cardiovascular diseases. The polyol pathway, which involves Aldose reductase (AR) as a critical enzyme, has been focused on by many researchers as a target for intervention. On the other hand, spiroindoline-based compounds possess remarkable biological properties. This guided us to synthesize novel spiroindoline oxadiazolyl-based acetate derivatives and investigate their biological activities. The synthesized molecules' structures were confirmed herein, using IR, NMR (1H and 13C), and Mass spectroscopy. All compounds were potent inhibitors with KI constants spanning from 0.186 ± 0.020 µM to 0.662 ± 0.042 µM versus AR and appeared as better inhibitors than the clinically used drug, Epalrestat (EPR, KI: 0.841 ± 0.051 µM). Besides its remarkable inhibitory profile compared to EPR, compound 6k (KI: 0.186 ± 0.020 µM) was also determined to have an unusual pharmacokinetic profile. The results showed that 6k had less cytotoxic effect on normal mouse fibroblast (L929) cells (IC50 of 569.58 ± 0.80 µM) and reduced the viability of human breast adenocarcinoma (MCF-7) cells (IC50 of 110.87 ± 0.42 µM) more than the reference drug Doxorubicin (IC50s of 98.26 ± 0.45 µM and 158.49 ± 2.73 µM, respectively), thus exhibiting more potent anticancer activity. Moreover, molecular dynamic simulations for 200 ns were conducted to predict the docked complex's stability and reveal significant amino acid residues that 6k interacts with throughout the simulation.

Novel beta-lactam substituted benzenesulfonamides: in vitro enzyme inhibition, cytotoxic activity and in silico interactions.

In this study, a library of twelve beta-lactam-substituted benzenesulfonamides (5a-l) was synthesized using the tail-approach method. The compounds were characterized using IR, 1H NMR, 13C NMR and elemental analysis techniques. These newly synthesized compounds were tested for their ability to inhibit the activity of two carbonic anhydrases (hCA) isoforms, I and II, and acetylcholinesterase (AChE) in vitro. The results showed that the synthesized compounds were potent inhibitors of hCA I, with KIs in the low nanomolar range (66.60-278.40 nM) than the reference drug acetazolamide (AAZ), which had a KI of 439.17 nM. The hCA II was potently inhibited by compounds 5a, 5d-g and 5l, with KIs of 69.56, 39.64, 79.63, 74.76, 78.93 and 74.94 nM, respectively (AAZ, KI of 98.28 nM). Notably, compound 5a selectively inhibited hCA II with a selectivity of > 4-fold over hCA I. In terms of inhibition of AChE, the synthesized compounds had KIs ranging from 30.95 to 154.50 nM, compared to the reference drug tacrine, which had a KI of 159.61 nM. Compounds 5f, 5h and 5l were also evaluated for their ability to inhibit the MCF-7 cancer cell line proliferation and were found to have promising anticancer activity, more potent than 5-fluorouracil and cisplatin. Molecular docking studies suggested that the sulfonamide moiety of these compounds fits snugly into the active sites of hCAs and interacts with the Zn2+ ion. Furthermore, molecular dynamics simulations were performed for 200 ns to assess the stability and dynamics of each enzyme-ligand complex. The acceptability of the compounds based on Lipinski's and Jorgensen's rules was also estimated from the ADME/T results. These results indicate that the synthesized molecules have the potential to be developed into effective and safe inhibitors of hCAs and AChE and could be lead agents.Communicated by Ramaswamy H. Sarma.

Exploration of 1,2,3-triazole linked benzenesulfonamide derivatives as isoform selective inhibitors of human carbonic anhydrase.

A novel series of 1,2,3-triazole benzenesulfonamide substituted 1,3-dioxoisoindolin-5-carboxylate (7a-l) inhibitors of human α-carbonic anhydrase (hCA) was designed using a tail approach. The design method relies on the hybridization of a benzenesulfonamide moiety with a tail of 1,3-dioxoisoindoline-5-carboxylate and a zinc-binding group on a 1,2,3-triazole scaffold. Among the synthesized analogues, 2­iodophenyl (7f, KI of 105.00 nM and SI of 2.98) and 2­naphthyl (7h, KI of 32.11 nM and SI of 3.48) analogues (over off-target hCA I) and phenyl (7a, KI of 50.13 nM and SI of 2.74) and 2,6­dimethylphenyl (7d, KI of 50.60 nM and SI of 3.35) analogues (over off-target hCA II) exhibited a remarkable selectivity for tumor isoforms hCA IX and XII, respectively. Meanwhile, analogue 7a displayed a potent inhibitory effect against the tumor-associated isoform hCA IX (KI of 18.29 nM) compared with the reference drug acetazolamide (AAZ, KI of 437.20 nM), and analogue 7h showed higher potency (KI of 9.22 nM) than AAZ (KI of 338.90 nM) against another tumor-associated isoform hCA XII. However, adding the lipophilic large naphthyl tail to the 1,3-dioxoisoindolin-5-carboxylate analogues increased both the hCA inhibitory and selective activities against the target isoform, hCA XII. Additionally, these analogues (7a-l) showed IC50 values against the human lung (A549) adenocarcinoma cancer cell line ranging from 129.71 to 352.26 µM. The results of the molecular docking study suggested that the sulfonamide moiety fits snugly into the hCAs active sites and interacts with the Zn2+ ion. At the same time, the tail extension engages in various hydrophilic and hydrophobic interactions with the nearby amino acids, which affects the potency and selectivity of the hybrids.

Cytotoxic effect, enzyme inhibition, and in silico studies of some novel N-substituted sulfonyl amides incorporating 1,3,4-oxadiazol structural motif.

The acetylcholinesterase and carbonic anhydrase inhibitors (AChEIs and hCAIs) remain key therapeutic agents for many bioactivities such as anti-Alzheimer and antiobesity antiepileptic, anticancer, antiinfective, antiglaucoma, and diuretic effects. Here, it has been attempted to discover novel multi-target AChEIs and hCAIs that are highly potent, orally bioavailable, may be brain penetrant, and have higher effectiveness at lower doses than tacrine and acetazolamide. After detailed investigations both in vitro and in silico, novel N-substituted sulfonyl amide derivatives (6a-j) were determined to be highly potent inhibitors for AChE and hCAs (KIs are in the range of 23.11-52.49 nM, 18.66-59.62 nM, and 9.33-120.80 nM for AChE, hCA I, and hCA II, respectively). Moreover, according to the cytotoxic effect studies, such as the ADME-Tox, cortex neuron cells, and neuroblastoma SH-SY5Y cell line, compounds 6a, 6d, and 6h, which are the most potent representative versus the target enzymes, were identified as orally bioavailable, highly selective, and brain preferentially distributed AChEIs and hCAIs. The docking studies revealed precise binding modes between 6a, 6d, and 6h and hCA II, hCA I, and AChE, respectively. The results presented here might provide a solid basis for further investigation into more potent AChEIs and hCAIs.

Synthesis and carbonic anhydrase inhibitory properties of new spiroindoline-substituted sulphonamide compounds.

New spiroindoline-substituted sulphonamide compounds were synthesised and their inhibitory effects on the activity of purified human carbonic anhydrase I and II were evaluated. Human carbonic anhydrase isoenzymes (hCA-I and hCA-II) were purified from erythrocyte cells by affinity chromatography. The inhibitory effects of the 14 synthesised sulphonamides (6a-n) on esterase activities of these isoenzymes were studied in vitro. In relation to these activities, the inhibition equilibrium constants (Ki) were determined. The results showed that all the synthesised compounds inhibited the carbonic anhydrase (CA) isoenzyme activity. Among them, 6b was found to be the most active (Ki: 0.042 µM) for hCA I and 6a (Ki: 0.151 µM) for hCA II.