Benzimidazolone-piperazine/triazole/thiadiazole/furan/thiophene conjugates: Synthesis, in vitro urease inhibition, and in silico molecular docking studies.

This study describes the synthesis, in vitro urease inhibition, and molecular docking studies of benzimidazolone derivatives incorporating the piperazine, triazole, thiadiazole, furan, thiophene, and thiosemicarbazide moieties. All newly synthesized compounds demonstrated varying degrees of urease inhibitory activity, with IC50 values ranging between 0.64 ± 0.099 and 0.11 ± 0.017 µM, when compared with the standard drug thiourea (IC50 value of 0.51 ± 0.028 µM). To confirm the experimental urease inhibition results and elucidate the mode of interaction of the synthesized compounds with the binding site of the urease enzyme, molecular docking studies were performed using the Schrödinger Suite package. Molecular docking studies showed that compounds with high in vitro urease inhibition interacted with key residues of the urease active site such as His221, Glu222, Asp223, His322, Arg338, and Ni2+ cations via hydrogen bonding, metal coordination, salt bridge, π-π stacking, and π-cation interactions.

Synthesis, in vitro urease inhibition and molecular docking studies of some novel quinazolin-4(3H)-one derivatives containing triazole, thiadiazole and thiosemicarbazide functionalities.

A new series of quinazolinone derivatives containing triazole, thiadiazole, thiosemicarbazide functionalities was synthesized and then screened for their in vitro urease inhibition properties. Most of the compounds showed excellent activity with IC50 values ranging between 1.88 ±â€¯0.17 and 6.42 ±â€¯0.23 µg/mL, compared to that of thiourea (IC50 = 15.06 ±â€¯0.68) and acetohydroxamic acid (IC50 = 21.03 ±â€¯0.94), as reference inhibitors. Among the synthesized molecules, compounds 5c, 5e and 5a showed the best inhibitory effect against urease enzyme with IC50 values of 1.88 ±â€¯0.17 µg/mL, 1.90 ±â€¯0.10 and 1.96 ±â€¯0.07 µg/mL, respectively. Moreover in order to give better understanding of the inhibitory activity of synthesized compounds, molecular docking studies were applied at the target sites of jack bean urease enzyme (JBU). Their binding poses and energy calculations were analyzed using induced fit docking (IFD) and prime-MMGBSA tool. Binding poses of studied compounds were determined using induced fit docking (IFD) algorithms.

Synthesis and molecular docking study of some novel 2,3-disubstituted quinazolin-4(3H)-one derivatives as potent inhibitors of urease.

A new series of 2,3-disubstituted quinazolin-4(3H)-one compounds including oxadiazole and furan rings was synthesized. Their inhibitory activities on urease were assessed in vitro. All newly synthesized compounds exhibited potent urease inhibitory activity in the range of IC50 = 1.55 ±â€¯0.07-2.65 ±â€¯0.08 µg/mL, when compared with the standard urease inhibitors such as thiourea (IC50 = 15.08 ±â€¯0.71 µg/mL) and acetohydroxamic acid (IC50 = 21.05 ±â€¯0.96 µg/mL). 2,3-Disubstituted quinazolin-4(3H)-one derivatives containing furan ring (3a-e) were found to be the most active inhibitors when compared with the compounds 2a-e bearing oxadiazole ring. Compound 3a, bearing 4-chloro group on phenyl ring, was found as the most effective inhibitor of urease with the IC50 value of 1.55 ±â€¯0.11 µg/mL. The molecular docking studies of the newly synthesized compounds were performed to identify the probable binding modes in the active site of the Jack bean urease (JBU) enzymes.

Synthesis of some novel quinazolin-4(3H)-one hybrid molecules as potent urease inhibitors.

A new series of quinazolinone hybrid molecules containing coumarin, furan, 1,2,4-triazole and 1,2,4-thiadiazole rings was designed, synthesized, and screened for their urease inhibition activities. All newly synthesized compounds showed outstanding urease inhibitory potentials with IC50 values ranging between 1.26 ± 0.07 and 7.35 ± 0.31 µg/mL. Among the series, coumarin derivatives (10a-d) exhibited the best inhibitory effect against urease in the range of IC50 = 1.26 ± 0.07 to 1.82 ± 0.10 µg/mL, when compared to standard urease inhibitors such as acetohydroxamic acid and thiourea (IC50 = 21.05 ± 0.96 and 15.08 ± 0.71 µg/mL, respectively). Molecular docking studies were also performed to analyze the binding mode of compound 10b, and supported the experimental results.

Characterization and inhibition studies of carbonic anhydrase from gill of Russian Sturgeon Fish (Acipenser gueldenstaedtii).

An α-carbonic anhydrase (CA, EC 4.2.1.1) was purified and characterized kinetically from gill of Acipenser gueldenstaedtii as an endangered sturgeon species. The carbonic anhydrase was purified 66-folds with yield 20.7% by Sepharose-4B-l-tyrosine-sulfanilamide affinity column and the specific activity was determined as 222.2 EU/mg protein. Km and Vmax kinetic values for gill carbonic anhydrase were calculated by a Lineweaver-Burk graph using p-nitrophenol acetate (p-NPA) as a substrate, and was defined as 2.5 mM and 5 × 10(6 )µM/min, respectively. It was observed that CA from the sturgeon gill in the presence of the sulfanilamide and acetazolamide as an inhibitor had very low IC50 values such as 13.0 and 0.1 µM, respectively. In addition, it was determined that the enzyme was inhibited by Fe(2+,) Co(2+,) Ni(2+), and Zn(2+)-Ba(2+) with the IC50 values of 0.2, 1.7, 1.2, and 1.1 mM, respectively.

Inhibition of mammalian carbonic anhydrase isoforms I-XIV with a series of phenolic acid esters.

A series of phenolic acid esters incorporating caffeic, ferulic, and p-coumaric acid, and benzyl, m/p-hydroxyphenethyl- as well as p-hydroxy-phenethoxy-phenethyl moieties were investigated for their inhibitory effects against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Many of the mammalian isozymes of human (h) or murine (m) origin, hCA I-hCA XII, mCA XIII and hCA XIV, were inhibited in the submicromolar range by these derivatives (with KIs of 0.31-1.03 µM against hCA VA, VB, VI, VII, IX and XIV). The off-target, highly abundant isoforms hCA I and II, as well as hCA III, IV and XII were poorly inhibited by many of these esters, although the original phenolic acids were micromolar inhibitors. These phenols, like others investigated earlier, possess a CA inhibition mechanism distinct of the sulfonamides/sulfamates, clinically used drugs for the treatment of a multitude of pathologies, but with severe side effects due to hCA I/II inhibition. Unlike the sulfonamides, which bind to the catalytic zinc ion, phenols are anchored at the Zn(II)-coordinated water molecule, binding more externally within the active site cavity, and making contacts with amino acid residues at the entrance of the active site. As this is the region with the highest variability between the many CA isozymes found in mammals, this class of compounds shows isoform-selective inhibitory profiles, which may be exploited for obtaining pharmacological agents with less side effects compared to other classes of inhibitors.