nan Zaheer-ul-Haq

Synthesis of novel inhibitors of β-glucuronidase based on benzothiazole skeleton and study of their binding affinity by molecular docking.

Benzothiazole derivatives 1-26 have been synthesized and their in vitro β-glucuronidase potential has been evaluated. Compounds 4 (IC(50)=8.9 ± 0.25 μM), 5 (IC(50)=36.1 ± 1.80 μM), 8 (IC(50)=8.9 ± 0.38 μM), 13 (IC(50)=19.4 ± 1.00 μM), 16 (IC(50)=4.23 ± 0.054 μM), and 18 (IC(50)=2.26 ± 0.06 μM) showed β-glucuronidase activity potent than the standard (d-saccharic acid 1,4-lactone, IC(50)=48.4 ± 1.25 μM). Compound 9 (IC(50)=94.0 ± 4.16 μM) is found to be the least active among the series. All active analogs were also evaluated for cytotoxicity and none of the compounds showed any cytotoxic effect. Furthermore, molecular docking studies were performed using the gold 3.0 program to investigate the binding mode of benzothiazole derivatives. This study identifies a novel class of β-glucuronidase inhibitors.

Identification of Novel Urease Inhibitors by High-Throughput Virtual and in Vitro Screening

Ureases are important in both agriculture and human health. Bacterial ureases are directly involved in many farm-field problems and pathological conditions. Here, we report a structure-based virtual screening of an in-house compound bank of about 6000 molecular entities by computational docking and binding free energy calculations followed by in vitro screening. Applied protocol leads to the identification of novel urease inhibitors, which can serve as starting points for structural optimization.

Cholinesterase inhibitory and spasmolytic potential of steroidal alkaloids.

A new steroidal alkaloid, isosarcodine (1) along with four known bases, sarcorine (2), sarcodine (3), sarcocine (4) and alkaloid-C (5) were isolated from the MeOH extract of Sarcococca saligna. The structures of these alkaloids were identified by spectral data interpretation. These compounds were subjected to acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition studies, and were found to be noncompetitive inhibitors of AChE (Ki = 21.8, 90.3, 32.2, 16.0 and 50.0 microM, respectively) and uncompetitive or noncompetitive inhibitors of BChE (Ki = 8.3, 7.5, 15.6, 5.0 and 12.0 microM, respectively). The compounds (2-5) also showed dose-dependent spasmolytic activity in the rabbit jejunum intestinal preparations and also relaxed the high K+ (80 mM)-induced contraction, indicative of a calcium channel-blocking mechanism. Structure-activity relationship suggested that the nitrogen substituents at C-3 and/or C-20 of steroidal skeleton and the hydrophobic properties of the pregnane skeleton are the key structural features contributed to the inhibitory potency of these steroidal alkaloids against AChE and BChE.

New pregnane-type steroidal alkaloids from Sarcococca saligna and their cholinesterase inhibitory activity

Five new steroidal alkaloids, 5,14-dehydro-N(a)-demethylsaracodine [3beta-N(a)-methyl-20S-N(b)-acetyl-N(b)-methylamino-pregn-5,14-diene] (1), 14-dehydro-N(a)-demethylsaracodine [3beta-N(a)-methyl-20S-N(b)-acetyl-N(b)-methylamino-5alpha-pregn-14-ene] (2), 16-dehydrosarcorine [(20S)-20-(N,N-dimethylamino)-3beta-(N(a)-acetylamido)-5alpha-pregn-16-ene] (3), 2,3-dehydrosarsalignone [(20S)-20-(N,N-dimethylamino)-3beta-(tigloylamino)-pregn-2,5-diene-4-one] (4), and 14,15-dehydrosarcovagine-D [(20S)-20-(N,N-dimethylamino)-3beta-(tigloylamino)-5alpha-pregn-2,14-diene-4-one] (5), were isolated from the ethanolic extract of Sarcococca saligna, along with two known bases, sarcovagenine-C (6) and salignarine-C (7). Their structures were elucidated on the basis of spectroscopic methods. All seven compounds were found to possess cholinesterase inhibitory potential in a concentration-dependent manner with the IC50 values ranging from 12.5 to 200 microM against acetylcholinesterase and from 1.25 to 32.2 microM against butyrylcholinesterase.

Pregnane-Type Steroidal Alkaloids of Sarcococca saligna: a New Class of Cholinesterase Inhibitors

Phytochemical investigation of Sarcococca saligna by extensive bioassay-guided fractionation resulted in the isolation of the pregnane-type steroidal alkaloids 1–15, i.e. of the five new compounds 1–5 and the ten known alkaloids 6–15. The structures of the new alkaloids salignenamide C (1), salignenamide D (2), 2β-hydroxyepipachysamine D (3), salignenamide E (4), and salignenamide F (5) were elucidated with the help of modern spectroscopic techniques, while the known alkaloids axillarine C (6), axillarine F (7), sarcorine (8), N3-demethylsaracodine (9), saligcinnamide (10), salignenamide A (11), vaganine A (12), axillaridine A (13), sarsalignone (14), and sarsalignenone (15) were identified by comparing their spectral data with those reported earlier. Inhibition of electric-eel acetylcholinesterase (EC 3.1.1.7) and horse-serum butyrylcholinesterase (EC 3.1.1.8) by alkaloids 1–15 were investigated. These new cholinesterase inhibitors may act as potential leads in the discovery of clinically useful inhibitors for nervous-system disorders, particularly by reducing memory deficiency in Alzheimers disease patients by potentiating and effecting the cholinergic transmission process. These compounds were found to inhibit both enzymes in a concentration-dependent fashion with the IC50 values ranging from 5.21–227.92 μM against acetylcholinesterase and 2.18–38.36 μM against butyrylcholinesterase.

Molecular modeling-based antioxidant arylidene barbiturates as urease inhibitors.

Previously we have reported arylidene barbiturates 1-18 as a novel class of antioxidants; however, their urease inhibitory potential has not yet been explored. In this communication, molecular docking studies were used to predict the potential ligands from compounds 1-18 which culminated in the identification of certain new urease inhibitors. Ligands were screened in vitro for their urease inhibitory potential. Compound 1, as deduced from modeling studies, was found to be the most active urease inhibitor (13.0 ± 1.2 μM), when compared with the standard thiourea (IC₅₀=21.1 ± 0.3 μM). All of the compounds were found to be nontoxic to Artemia salina in brine shrimp lethality bioassay.

New Steroidal Alkaloids From Sarcococca Saligna

Two new steroidal alkaloids, salonine-A [(20S)-20-(N,N-dimethylamino)-3β-(tigloylamino)-5α-pregn-14-en-2β,4β-diol] (1), and salonine-B [(20S)-20-(N,N-dimethylamino)-3β-methoxy-pregn-5,16-diene] (2), were isolated from the MeOH extract of Sarcococca saligna, along with a known base, alkaloid-C (3). Their structures were elucidated on the basis of spectroscopic methods. All three compounds were found to be cholinesterase inhibitors.

Structure based 3D-QSAR studies of Interleukin-2 inhibitors: Comparing the quality and predictivity of 3D-QSAR models obtained from different alignment methods and charge calculations.

Interleukin-2 is an essential cytokine in an innate immune response, and is a promising drug target for several immunological disorders. In the present study, structure-based 3D-QSAR modeling was carried out via Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) methods. Six different partial charge calculation methods were used in combination with two different alignment methods to scrutinize their effects on the predictive power of 3D-QSAR models. The best CoMFA and CoMSIA models were obtained with the AM1 charges when used with co-conformer based substructure alignment (CCBSA) method. The obtained models posses excellent correlation coefficient value and also exhibited good predictive power (for CoMFA: q(2)=0.619; r(2)=0.890; r(2)Pred=0.765 and for CoMSIA: q(2)=0.607; r(2)=0.884; r(2)Pred=0.655). The developed models were further validated by using a set of another sixteen compounds as external test set 2 and both models showed strong predictive power with r(2)Pred=>0.8. The contour maps obtained from these models better interpret the structure activity relationship; hence the developed models would help to design and optimize more potent IL-2 inhibitors. The results might have implications for rational design of specific anti-inflammatory compounds with improved affinity and selectivity.

In vitro and in silico exploration of IL-2 inhibition by small drug-like molecules

Interleukin-2 (IL-2) is an immunoregulatory cytokine produced by T lymphocytes in response to antigen. It is a potent growth and differentiation factor for several cell-types and is structurally related to the four-helix bundle family of cytokines. Here, we report IL-2 inhibitory potential and computational studies on different series of chalcones, benzothiazepines, semicarbazones, and dihydropyrimidines. These compounds were synthesized in wet lab and were then tested for their potency as IL-2 inhibitors through in vitro T cell proliferation, IL-2 cytokine production as well as their effect on oxidative burst. Compounds that showed significant suppressive activity were further evaluated for their cytotoxicity on normal two cell lines. Most of the chalcones were found to have a powerful inhibitory effect on T-lymphocytes proliferation and cytokine production. Among the aza heterocycles benzothiazepines, benzoxazepines, and benzodiazepinones were found to be the strongest IL-2 inhibitors. Molecular docking and MD simulation studies were carried out to correlate experimental and theoretical results whereby a good correlation was observed which indicated that computational studies could provide an alternate tool for the identification and designing of more potent IL-2 inhibitors.

Erratum to: Three-dimensional quantitative structure–activity relationship (CoMSIA) analysis of bis-coumerine analogues as urease inhibitors

As a basis for predicting structural features that may lead to the design of more potent and selective inhibitors of urease, the three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were carried out on a series of 30 bis-coumerine analogs, which are known urease inhibitors. Five different properties: steric, electrostatic, hydrophobic, H-bond donor, and H-bond acceptor, assumed to cover the major contributions to ligand binding, were used to generate the 3D-QSAR model. A significant cross-validated correlation coefficient q2 (0.51), r2 (0.962) for CoMSIA were obtained, indicating the statistical significance of this class of compounds. Actual urease inhibitory activities of this class, and the predicted values were in good agreement with the experimental results. This model offer insight into the structural requirements for activity of bis-coumerine analogues as urease inhibitors, since there is only speculative knowledge of their target in protein.