Syahrul Imran

Synthesis of novel inhibitors of α-glucosidase based on the benzothiazole skeleton containing benzohydrazide moiety and their molecular docking studies

In an effort to design and synthesize a new class of α-glucosidase inhibitor, we synthesized benzothiazole hybrid having benzohydrazide moiety (5). Compound 5 was reacted with various substituted aryl aldehyde to generate a small library of compounds 6-35. Synthesis of compounds was confirmed by the spectral information. These compounds were screened for their α-glucosidase activity. They showed a varying degree of α-glucosidase inhibition with IC50 values ranging between 5.31 and 53.34 μM. Compounds 6, 7, 9-16, 19, 21-30, 32-35 showed superior activity as compared to standard acarbose (IC50 = 906 ± 6.3 μM). This has identified a new class of α-glucosidase inhibitors. The predicted physico-chemical properties indicated the drug appropriateness for most of these compounds, as they obey Lipinskis rule of five (RO5). A hybrid B3LYP density functional theory (DFT) was employed for energy, minimization of 3D structures for all synthetic compounds using 6-311 + G(d,p) basis sets followed by molecular docking to explore their interactions with human intestinal C- and N-terminal domains of α-glucosidase. All compounds bind to the prospective allosteric site of the C- terminal domain, and consequently, may be considered as mixed inhibitors. It was hypothesized that both the dipole moment and H-bond interactions govern the biological activation of these compounds.

Synthesis of novel derivatives of oxindole, their urease inhibition and molecular docking studies

We synthesized a series of novel 5-24 derivatives of oxindole. The synthesis started from 5-chlorooxindole, which was condensed with methyl 4-carboxybezoate and result in the formation of benzolyester derivatives of oxindole which was then treated with hydrazine hydrate. The oxindole benzoylhydrazide was treated with aryl acetophenones and aldehydes to get target compounds 5-24. The synthesized compounds were evaluated for urease inhibition; the compound 5 (IC50 = 13.00 ± 0.35 μM) and 11 (IC50 = 19.20 ± 0.50 μM) showed potent activity as compared to the standard drug thiourea (IC50 = 21.00 ± 0.01 μM). Other compounds showed moderate to weak activity. All synthetic compounds were characterized by different spectroscopic techniques including (1)H NMR, (13)C NMR, IR and EI MS. The molecular interactions of the active compounds within the binding site of urease enzyme were studied through molecular docking simulations.

Identification of bisindolylmethane–hydrazone hybrids as novel inhibitors of β-glucuronidase, DFT, and in silico SAR intimations

The present study involves the synthesis of bisindolylmethane–hydrazone hybrids, 1–30, in a three-step reaction sequence, followed by evaluation against β-glucuronidase enzyme. The IC50 values for the potent compounds were in the range from 0.10 to 83.50 μM. Compound, a trihydroxy analog was found to be the most potent derivative, having an IC50 value of 0.10 ± 0.001 μM. Molecular docking revealed that the active compounds could fit perfectly into the binding groove of β-D-glucuronidase. The presence of hydroxyl groups on the aromatic side chain proved to be the single most important factor that contributed toward the inhibitory potential of these compounds. On the other hand, the imino group of the hydrazone linkage displayed interactions with the side chain carboxyl oxygen (Oe2) of Asp207. The high inhibitory potential of these compounds could be associated with these strong hydrogen bonds. Structures of all the synthesized compounds were confirmed using modern spectroscopic methods.

Synthesis of benzimidazole derivatives as potent β-glucuronidase inhibitors.

Twenty five 4, 6-dichlorobenzimidazole derivatives (1-25) have been synthesized and evaluated against β-glucuronidase inhibitory activity. The compounds which actively inhibit β-glucuronidase activity have IC50 values ranging between 4.48 and 46.12 μM and showing better than standard d-saccharic acid 1,4 lactone (IC50=48.4 ± 1.25 μM). Molecular docking provided potential clues to identify interactions between the active molecules and the enzyme which further led us to identify plausible binding mode of all the benzimidazole derivatives. This study confirmed that presence of hydrophilic moieties is crucial to inhibit the human β-glucuronidase.

Synthesis, biological evaluation, and docking studies of novel thiourea derivatives of bisindolylmethane as carbonic anhydrase II inhibitor.

This article describes discovery of 29 novel bisindolylmethanes consisting of thiourea moiety, which had been synthesized through three steps. These novel bisindolylmethane derivatives evaluated for their potential inhibitory activity against carbonic anhydrase (CA) II. The results for in vitro assay of carbonic anhydrase II inhibition activity showed that some of the compounds are capable of suppressing the activity of carbonic anhydrase II. Bisindoles having halogen at fifth position showed better inhibitory activity as compared to unsubstituted bisindoles. Derivatives showing inhibition activity docked to further, understand the binding behavior of these compounds with carbonic anhydrase II. Docking studies for the active compound 3j showed that nitro substituent at para position fits into the core of the active site. The nitro substituent of compound 3j is capable of interacting with Zn ion. This interaction believed to be the main factor causing inhibition activity to take place.

Novel quinoline derivatives as potent in vitro α-glucosidase inhibitors: in silico studies and SAR predictions

A new series of quinoline derivatives 6–30 was identified as potent α-glucosidase inhibitors. These analogs exhibited inhibitory potentials (IC50 values) in the ranges between 2.60 and 102.12 μM. Among the series, compounds 24 (2.60 ± 0.01 μM), 27 (2.60 ± 0.01 μM) and 20 (2.86 ± 0.01 μM) were found to be exceptionally potent (>14 times the standard) inhibitors of α-glucosidase when compared to the standard acarbose (IC50 = 38.25 ± 0.12 μM). Molecular docking studies on the two most active compounds 24 and 27 corroborated that compound 24 adopted a linear position to optimally fit into the binding site of α-glucosidase. Observations for the best position of compound 24 showed a total of four interactions towards catalytically active site residues of α-glucosidase involving amino acid residues such as Phe-177 and Asp-214. The oxadiazole ring of compound 24 interacted with His-279. Compound 27 formed one hydrogen bond interaction (N-methylacetamide) and three arene–arene interactions (quinoline and 1,3,4-oxadiazole moiety). The quinoline moiety of compound 27 formed two π-interactions with Phe-157. All compounds were tested for cytotoxicity, but none of them was found to be cytotoxic.

Synthesis of novel benzohydrazone–oxadiazole hybrids as β-glucuronidase inhibitors and molecular modeling studies

A series of compounds consisting of 25 novel oxadiazole-benzohydrazone hybrids (6-30) were synthesized through a five-step reaction sequence and evaluated for their β-glucuronidase inhibitory potential. The IC50 values of compounds 6-30 were found to be in the range of 7.14-44.16μM. Compounds 6, 7, 8, 9, 11, 13, 18, and 25 were found to be more potent than d-saccharic acid 1,4-lactone (48.4±1.25μM). These compounds were further subjected for molecular docking studies to confirm the binding mode towards human β-d-glucuronidase active site. Docking study for compound 13 (IC50=7.14±0.30μM) revealed that it adopts a binding mode that fits within the entire pocket of the binding site of β-d-glucuronidase. Compound 13 has the maximum number of hydrogens bonded to the residues of the active site as compared to the other compounds, that is, the ortho-hydroxyl group forms hydrogen bond with carboxyl side chain of Asp207 (2.1Å) and with hydroxyl group of Tyr508 (2.6Å). The other hydroxyl group forms hydrogen bond with His385 side chain (2.8Å), side chain carboxyl oxygen of Glu540 (2.2Å) and Asn450 side-chains carboxamide NH (2.1Å).

Synthesis of novel inhibitors of β-glucuronidase based on the benzothiazole skeleton and their molecular docking studies

A series of benzothiazole based oxadiazole analogs 1–20 was synthesized by reacting intermediate sulfite adducts with 2-aminothiophenol and refluxing in DMF for 12 h to afford ester analog I which, on further refluxing in methanolic hydrazine hydrate solution, afforded compound II. Compound II was then condensed with different aromatic carboxylic acids in POCl3 to synthesize novel benzothiazole based oxadiaxole derivatives 1–20 in good yields. All compounds were screened for β-glucuronidase inhibitory potential. Compounds 7, 14, 8 and 17 were found to be the most active analogs among the series with micromolar activities (IC50 = 2.16, 4.38, 7.20 and 8.56 μM, respectively). While compounds 5, 10, 18, 16, 1, 2, 15, 11, and 20 showed moderate activity with (IC50 values ranging between 14.12–75.14 μM), whereas compounds 3, 12, 13, and 19 were found to be inactive. Further studies showed that they do not possess any cytotoxic properties. Molecular docking studies were done to reveal the binding modes of the synthetic benzothiazole derivatives 1–20 targeting the active site of β-glucuronidase (PDB code: 1BHG).

Synthesis, In vitro and Docking Studies of New Flavone Ethers as α-Glucosidase Inhibitors

We report herein the synthesis, α‐glucosidase inhibition and docking studies for a series of 3–15 new flavones. A simple nucleophilic substitution reaction takes place between 3′hydroxyflavone (2) with halides to afford the new flavones. Chalcone (1), 3′hydroxyflavone (2) and the newly synthesized flavones (3–15) were being evaluated for their ability to inhibit activity of α‐glucosidase. Compounds 2, 3, 5, 7–10 and 13 showed good inhibitory activity with IC50 values ranging between 1.26 and 36.44 μm as compared to acarbose (IC50 = 38.25 ± 0.12 μm). Compounds 5 (5.45 ± 0.08 μm), 7 (1.26 ± 0.01 μm) and 8 (8.66 ± 0.08 μm) showed excellent inhibitory activity, and this may be due to trifluoromethyl substitution that is common for these compounds. Compound 7, a 2,5‐trifluoromethyl‐substituted compound, recorded the highest inhibition activity, and it is thirty times better than the standard drug. Docking studies for compound 7 suggest that both trifluoromethyl substituents are well positioned in a binding pocket surrounded by Phe300, Phe177, Phe157, Ala278, Asp68, Tyr71 and Asp214. The ability of compound 7 to interact with Tyr71 and Phe177 is extremely significant as they are found to be important for substrates recognition by α‐glucosidase.

Novel thiosemicarbazide–oxadiazole hybrids as unprecedented inhibitors of yeast α-glucosidase and in silico binding analysis

Compounds 1–18, new oxadiazole–thiosemicarbazide hybrids, were synthesized using a five-step reaction sequence in excellent yields. All the synthesized analogs exhibited exceptional α-glucosidase inhibitory potentials in the range of 0.4–38.1 μM. Among the current series, it was observed that the fluoro-substituted analogues were exceptionally potent inhibitors of α-glucosidase. The study provides a proof of concept that inductively strong electron withdrawing groups result in enhanced inhibitory potentials. The binding interactions of these compounds were analyzed in silico for possible prediction and identification of the improved inhibitory potential.