Utilization of transition metal fluoride-based solid support catalysts for the synthesis of sulfonamides: carbonic anhydrase inhibitory activity and in silico study.

The applications of solid support catalysts in catalyzing organic reactions are well-evident. In the present study, we explored a transition metal fluoride (FeF3) adsorbed on molecular sieves (4 Å) as a solid support catalyst for the preparation of sulfonamides 3a-3o. The solid support catalyst was characterized via X-ray diffraction and AFM analysis. The catalyst was further explored for the synthesis of indoles 6a-h, 1H-tetrazoles and 1,4-dihydropyridines. The sulfonamides prepared herein were investigated for their potential to inhibit carbonic anhydrase (hCA II, hCA IX and hCA XII). All compounds were found to be active inhibitors with IC50 values in the low micromolar range. Some compounds were even found to be highly selective inhibitors. Compound 3i only inhibited hCA II (IC50 = 2.76 ± 1.1 µM) and had <27% inhibition against hCA IX and hCA XII. Similarly, 3e (IC50 = 0.63 ± 0.14 µM) only inhibited hCA XII and showed <31% inhibition against hCA II and hCA IX. Molecular docking studies were carried out to rationalize the ligand-binding site interactions. Given the lack of selective CA inhibitors, compounds 3e and 3i can provide significant leads for the further development of highly selective CA inhibitors.

Citrus flavonoids as potential therapeutic agents: A review.

The plants Rutaceae family are known to have contributed a lot toward food and medicine. The most important metabolites of the family are flavonoids. A systematic review was conducted to collect chemical and pharmacological information of flavonoids isolated from family Rutaceae till 2018. A plethora of flavonoids have been isolated and studied systematically for various bioactivities, including anticancer, antibacterial, antiviral, analgesic, antioxidant, antidiabetic, antiinflammatory, in bronchitis, ulcers, and so on. The important groups of flavonoids isolated are naringin, poncirin, rhoifolin, marmesin, hesperidin, tangeretin, nobiletin, glychalcone, glyflavanone, lemairone, acacetin 3,6-di-C-glucoside, vicenin-2, lucenin-2 4'-methyl ether, narirutin 4'-O-glucoside, apigenin 8-C-neohesperidoside, phloretin 3',5'-di-C-glucoside, rutin, rhamnetin, dihydrokaempferol, dihydrokaempferol 3-O-rhamnoside (engeletin) and kaempferol, excavaside A and B, myricetin 3-O-ß-D-rutinoside, myricetin 3,3'-di-α-l-rhamnopyranoside, myricetin 3'-α-l-rhamnopyranoside, and others. The flavonoids isolated from the citrus family need to be considered from a nutraceutical, therapeutic, and pharmaceutical point of view for future medicine.

Sulfonate and sulfamate derivatives possessing benzofuran or benzothiophene nucleus as potent carbonic anhydrase II/IX/XII inhibitors.

In the current work, we report the discovery of new sulfonate and sulfamate derivatives of benzofuran- and benzothiophene as potent inhibitors of human carbonic anhydrases (hCAs) II, IX and XII. A set of derivatives, 1a-t, having different substituents on the fused benzofuran and benzothiophene rings (R = alkyl, cyclohexyl, aryl, NH2, NHMe, or NMe2) was designed and synthesized. Most of the derivatives exhibited higher potency than acetazolamide as inhibitors of the purified hCAII, IX and XII isoforms. The most potent inhibitors for hCAII, hCAIX and hCAXII were 1g, 1b and 1d with an IC50 ±â€¯SEM values of 0.14 ±â€¯0.03, 0.13 ±â€¯0.03 and 0.17 ±â€¯0.06 µM, respectively. In addition, compounds 1d and 1n exerted preferential inhibitory effect against hCAXII isozyme with good potencies. Some selected compounds were docked within the active pocket of these isozymes and binding of the molecules revealed that sulfonate and sulfamate rings were located towards the active cavity and compounds coordinated to zinc ions.

Enzymes inhibitors from natural sources with antidiabetic activity: A review.

Natural products have been extensively investigated for antidiabetic therapy. Many of the natural products have direct or indirect effect in diabetes pathways as enzyme inhibitors. The most involved mechanisms are inhibition of intestinal alpha-glucosidase and alpha-amylase, lens aldose reductase, oxidative stress protection, inhibition of formation of advanced glycation end products, inhibition of aldose reductase, lowering plasma glucose levels, altering enzyme activity of hexokinases and glucose-6-phosphate, synthesizing and releasing of insulin, postprandial hyperglycemia inhibition, stimulation of GLUT-4, decreasing activity of G6P, lowering the level of skeletal hexokinases, etc. The following medicinal plants products or extracts showed promising effects as enzyme inhibitors: Abelmoschus moschatus, Alangium salvifolium, Azadirachta indica, Bidens pilosa, Boerhaavia diffusa, Capsicum frutescens, Cassia alata, Eclipta alba, Embellica officinalis, Ficus carica, Gentiana Olivier, Glycyrrhiza glabra, Gymnema sylvestre, Hordeum vulgare, Ipomoea aquatica, Juniperus communis, Mangifera indica, Momordica charantia, Ocimum sanctum, Punica granatum, and Zingiber officinale. Some of the group of phytochemicals isolated with enzyme inhibition activities are Alkaloids, sesquiterpene and saponins, polysaccharides, flavonoids, dietary fibers, ferulic acid, tannins, limonene, and oleuropeoside. This review will provide very useful material to enhance the efficiency of rational antidiabetic drug design.

A new entry into the portfolio of α-glucosidase inhibitors as potent therapeutics for type 2 diabetes: Design, bioevaluation and one-pot multi-component synthesis of diamine-bridged coumarinyl oxadiazole conjugates.

Diabetes mellitus (DM), a chronic multifarious metabolic disorder resulting from impaired glucose homeostasis has become one of the most challenging diseases with severe life threat to public health. The inhibition of α-glucosidase, a key carbohydrate hydrolyzing enzyme, could serve as one of the effective methodology in both preventing and treating diabetes through controlling the postprandial glucose levels and suppressing postprandial hyperglycemia. In this context, three series of diamine-bridged bis-coumarinyl oxadiazole conjugates were designed and synthesized by one-pot multi-component methodology. The synthesized conjugates (4a-j, 5a-j, 6a-j) were evaluated as potential inhibitors of glucosidases. Compound 6f containing 4,4'-oxydianiline linker was identified as the lead and selective inhibitor of α-glucosidase enzyme with an IC50 value of 0.07 ±â€¯0.001 µM (acarbose: IC50 = 38.2 ±â€¯0.12 µM). This inhibition efficacy was ∼545-fold higher compared to the standard drug. Compound 6f was also emerged as the lead molecule against intestinal maltase-glucoamylase with good inhibition strength (IC50 = 0.04 ±â€¯0.02 µM) compared to acarbose (IC50 = 0.06 ±â€¯0.01 µM). Against ß-glucosidase enzyme, compound 6 g was noted as the lead inhibitor with IC50 value of 0.08 ±â€¯0.002 µM. Michaelis-Menten kinetic experiments were performed to explore the mechanism of inhibition. Molecular docking studies of the synthesized library of hybrid structures against glucosidase enzyme were performed to describe ligand-protein interactions at molecular level that provided an insight into the biological properties of the analyzed compounds. The results suggested that the inhibitors could be stabilized in the active site through the formation of multiple interactions with catalytic residues in a cooperative fashion. In addition, strong binding interactions of the compounds with the amino acid residues were effective for the successful identification of α-glucosidase inhibitors.

2-Substituted 7-trifluoromethyl-thiadiazolopyrimidones as alkaline phosphatase inhibitors. Synthesis, structure activity relationship and molecular docking study.

Alkaline Phosphatases (APs) play a key role in maintaining a ratio of phosphate to inorganic pyrophosphate (Pi/PPi) and thus regulate extracellular matrix calcification during bone formation and growth. Among different isozymes of AP, aberrant increase in the level of tissue non-specific alkaline phosphatase (TNAP) is strongly associated with vascular calcification and end-stage renal diseases. In this context, we synthesized a novel series of fluorinated pyrimidone derivatives, i.e., 2-bromo-7-trifluoromethyl-5-oxo-5H-1,3,4-thiadiazolepyrimidones. The bromine functionality was further used for derivatisation by nucleophilic aromatic substitution using amines as nucleophiles as well as by Palladium catalysed Suzuki-Miyaura reactions. The synthesized derivatives were found potent but non-selective inhibitors of both isozymes of AP. Arylated thiadiazolopyrimidones exhibited stronger inhibitory activities than 2-amino-thiadiazolopyrimidones. The binding modes and possible interactions of the most active inhibitor within the active site of the enzyme were observed by molecular docking studies.

Exploration of aroyl/heteroaroyl iminothiazolines featuring 2,4,5-trichlorophenyl moiety as a new class of potent, selective, and in vitro efficacious glucosidase inhibitors.

A series of iminothiazolines (4a-j) featuring 2,4,5-trichlorophenyl moiety and aroyl/heteroaroyl substituents has been prepared from readily accessible thioureas. In-vitro screening against glucosidase enzymes showed highly specific inhibition of α-glucosidase with a marked dependence of the potency upon the nature of the aroyl/heteroaroyl substituents. The most potent representatives, bearing ortho-tolyl and bulky naphthyl groups displayed the highest inhibitory potential with IC50 value of 0.15±0.01µM compared to standard drug acarbose (IC50=38.2±0.12µM). Several other derivatives (4c, 4d, 4i and 4j) were also significantly powerful and selective inhibitors of α-glucosidase. Binding interactions of potent compounds 4b, 4c, 4h and 4i with α-glucosidase were explored by molecular docking simulation. These results clearly identified a new class of structural leads which can be further investigated for the development of promising α-glucosidase inhibitors for the prevention of diabetes mellitus.