Robust therapeutic potential of carbazole-triazine hybrids as a new class of urease inhibitors: A distinctive combination of nitrogen-containing heterocycles.

The inhibition of urease enzyme is very important as it plays a key role in the treatment of several urinary and gastrointestinal tract infections. This enzyme provides a suitable environment for Helicobacter pylori at the low pH of the stomach, a causative agent of gastric and peptic ulcer that may lead to cancer. In agriculture, the high urease content causes environmental and economic problems. In this pursuit, given the well-established importance of integrated pharmacophores in medicinal chemistry and to explore new inhibitors of urease featuring two distinct heterocyclic functionalities, we herein report a facile synthesis of carbazole-triazine hybrids (3a-j). These new propeller-shaped chemical scaffolds were evaluated for their urease inhibitory potential in order to identify suitable leads. The initial structure-activity survey work guided through in vitro bioactivity results recognized 3e and 3f as new starting point hits incorporating bulky iodo (3e) and strong electron-withdrawing nitro (3f) groups at the para-position of aryl amine component. The potent compounds (3e &3f) exhibited the highest activity with IC50 values of 5.6 and 6.7 µM, respectively. In the molecular docking analysis, these compounds depicted excellent binding interactions with the active site residues. The key interactions observed include hydrogen bonding, π-π interactions, π-cation and nickel atom coordination to the triazine nitrogen of both inhibitors.

Developing new hybrid scaffold for urease inhibition based on carbazole-chalcone conjugates: Synthesis, assessment of therapeutic potential and computational docking analysis.

Although a diverse range of chemical entities offering striking therapeutic potential against urease enzyme has been reported, the key challenges (toxicity and safety) associated with these inhibitors create a large unmet medical need to unveil new, potent and safe inhibitors of urease enzyme. In this pursuit, the present study demonstrates the successful synthesis of carbazole-chalcone hybrids (4a-n) in good yields. The evaluation of the preliminary in vitro biological results showed that selected members of the investigated library of hybrid compounds possess excellent urease inhibitory efficacy. In particular, compounds 4c and 4k were the most potent inhibitors with lowest IC50 values of 8.93 ±â€¯0.21 and 6.88 ±â€¯0.42 µM, respectively. Molecular docking analysis of the most potent inhibitor 4k suggests that the compound is fitted neatly at the active site interface and mediates interaction with both nickel atoms present in the active site. Several other obvious interactions including metal-carbonyl contact, hydrogen bonding and hydrophobic interactions were also observed, playing a crucial part in the stabilization of 4k in the active site of urease.

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.

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.

Generation and electrophile trapping of N-Boc-2-lithio-2-azetine: synthesis of 2-substituted 2-azetines.

s-BuLi-induced α-lithiation-elimination of LiOMe from N-Boc-3-methoxyazetidine and further in situ α-lithiation generates N-Boc-2-lithio-2-azetine which can be trapped with electrophiles, either directly (carbonyl or heteroatom electrophiles) or after transmetalation to copper (allowing allylations and propargylations), providing a concise access to 2-substituted 2-azetines.

1,1'-(9-Octyl-9H-carbazole-3,6-di-yl)diethanone.

The central structural element of the title compound, C(24)H(29)NO(2), is a carbazole unit substituted with two acetyl residues and an octyl chain. The acetyl residues are nearly coplanar [dihedral angles = 5.37 (14) and 1.0 (3)°] with the carbazole unit which is essentially planar (r.m.s. deviation for all non-H atoms = 0.025 Å). The octyl chain adopts an all-trans conformation. The crystal packing is stabilized by C-H⋯O hydrogen bonds.