Amjad M. Qandil

Prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), More Than Meets the Eye: A Critical Review

The design and the synthesis of prodrugs for nonsteroidal anti-inflammatory drugs (NSAIDs) have been given much attention by medicinal chemists, especially in the last decade. As a therapeutic group, NSAIDs are among the most widely used prescribed and over the counter (OTC) medications. The rich literature about potential NSAID prodrugs clearly shows a shift from alkyl, aryalkyl or aryl esters with the sole role of masking the carboxylic acid group, to more elaborate conjugates that contain carefully chosen groups to serve specific purposes, such as enhancement of water solubility and dissolution, nitric oxide release, hydrogen sulfide release, antioxidant activity, anticholinergic and acetylcholinesterase inhibitory (AChEI) activity and site-specific targeting and delivery. This review will focus on NSAID prodrugs that have been designed or were, later, found to possess intrinsic pharmacological activity as an intact chemical entity. Such intrinsic activity might augment the anti-inflammatory activity of the NSAID, reduce its side effects or transform the potential therapeutic use from classical anti-inflammatory action to something else. Reports discussed in this review will be those of NO-NSAIDs, anticholinergic and AChEI-NSAIDs, Phospho-NSAIDs and some miscellaneous agents. In most cases, this review will cover literature dealing with these NSAID prodrugs from the year 2006 and later. Older literature will be used when necessary, e.g., to explain the chemical and biological mechanisms of action.

Pyrrolizidine alkaloids from Echium glomeratum (Boraginaceae).

The methanolic extract of the whole plant of Echium glomeratum Poir. (Boraginaceae) has afforded five pyrrolizidine alkaloids, three that were (7S, 8R)-petranine (1), (7S, 8S)-petranine (2), and (7R, 8R)-petranine (3a) or (7R, 8S)-petranine (3b), comprising a tricyclic pyrrolizidine alkaloids subclass; and two that were known but to the species: 7-angeloylretronecine (4) and 9-angeloylretronecine (5). All compounds were tested against a human tumor panel for cytotoxicity; no activity was observed (EC50 values>20microg/ml).

Discovery of New Antifungal Leads via Pharmacophore Modeling and QSAR Analysis of Fungal N‐Myristoyl Transferase Inhibitors Followed by In Silico Screening

N‐Myristoyl transferase is an essential enzyme for fungal growth and survival. The continuous interest in the development of new antifungal agents prompted recent interest in developing new potent inhibitors of fungal N‐myristoyl transferase. In this context, we combined pharmacophore and QSAR modeling to explore the structural requirements for potent N‐myristoyl transferase inhibitors employing 55 known N‐myristoyl transferase ligands. Four binding pharmacophore models emerged in the optimal QSAR equations ( = 0.81–0.83, F‐statistic = 47.89–58.83,  = 0.77–0.80, against 11 external test inhibitors = 0.61–0.71). The successful pharmacophores were complemented with exclusion spheres to optimize their receiver operating characteristic curve profiles. The QSAR equations and their associated pharmacophore models were validated by the identification and experimental evaluation of new promising antifungal leads retrieved from the NCI database and our in‐house‐built database of established drugs and agrochemicals.

Virtual lead identification of farnesyltransferase inhibitors based on ligand and structure-based pharmacophore techniques.

Farnesyltransferase enzyme (FTase) is considered an essential enzyme in the Ras signaling pathway associated with cancer. Thus, designing inhibitors for this enzyme might lead to the discovery of compounds with effective anticancer activity. In an attempt to obtain effective FTase inhibitors, pharmacophore hypotheses were generated using structure-based and ligand-based approaches built in Discovery Studio v3.1. Knowing the presence of the zinc feature is essential for inhibitor’s binding to the active site of FTase enzyme; further customization was applied to include this feature in the generated pharmacophore hypotheses. These pharmacophore hypotheses were thoroughly validated using various procedures such as ROC analysis and ligand pharmacophore mapping. The validated pharmacophore hypotheses were used to screen 3D databases to identify possible hits. Those which were both high ranked and showed sufficient ability to bind the zinc feature in active site, were further refined by applying drug-like criteria such as Lipiniski’s “rule of five” and ADMET filters. Finally, the two candidate compounds (ZINC39323901 and ZINC01034774) were allowed to dock using CDOCKER and GOLD in the active site of FTase enzyme to optimize hit selection.

Chemical and in vitro enzymatic stability of newly synthesized celecoxib lipophilic and hydrophilic amides.

Five celecoxib (CXB) acylamide sodium salts, MP-CXB, Cy-CXB, Bz-CXB, CBz-CXB and FBz-CXB were synthesized and characterized. Two simple, fast and validated RP-HPLC methods were developed for simultaneous quantitative determination of the amides and celecoxib in aqueous and biological samples and LOD and LOQ were ≤13.6 and ≤40ng/mL, respectively. The solubility and logP(app) of the amides, in relevant media, were determined. The chemical hydrolysis, at 60, 70 and 80°C, of MP-CXB was studied at GIT-relevant pH (1.2, 6.8 and 7.4) and of CY-CXB was studied at skin relative pH (5.4 and 7.4). Significant hydrolysis was observed for MP-CXB at pH 1.2 only with half-lives 28.28, 11.64 and 3.53h at 60, 70 and 80°C, respectively, with extrapolated half-lives of 2060 and 443h at 25 and 37°C, respectively. The hydrolysis of all amides was studied in rat live homogenate and only Cy-CXB was hydrolyzed with half-life of 3.79h. The hydrolysis of MP-CXB and Cy-CXB was studied in human plasma and neither was hydrolyzed. It is finally suggested that hydrophobic interactions plays a role in the binding of susceptible acylamides to the hepatic hydrolyzing enzyme since only amides with saturated hydrocarbon chains underwent hydrolysis.

Synthesis, characterization and in vitro hydrolysis of a gemfibrozil-nicotinic acid codrug for improvement of lipid profile.

Combination therapy of fibrates and nicotinic acid has been reported to be synergistic. Herein, we describe a covalent codrug of gemfibrozil (GEM) and nicotinic acid (NA) that was synthesized and characterized by (1)H NMR, (13)C NMR, FT-IR, MS analysis and elemental analysis. A validated HPLC method was developed that allows for the accurate quantitative determination of the codrug and its hydrolytic products that are formed during the in vitro chemical and enzymatic hydrolysis. The physico-chemical properties of codrug were improved compared to its parent drugs in term of water solubility and partition coefficient. The kinetics of hydrolysis of the codrug was studied using accelerated hydrolysis experiments at high temperatures in aqueous phosphate buffer solution in pH 1.2, 6.8 and 7.4. Using the Arrhenius equation, the extrapolated half-life at 37°C were 289 days at pH 1.2 for the codrug and 130 and 20,315 days at pH 6.8 for the codrug and gemfibrozil 2-hydroxyethyl ester (GHEE), respectively. The shortest half-lives were at pH 7.4; 42 days for the codrug and 5837 days for GHEE, respectively. The hydrolysis of the latter was studied, alone, at 80°C and pH 1.2 and compared to its hydrolysis when it is produced from the codrug using similar conditions. The k(obs) was found in both cases to be 1.60×10(-3)h(-1). The half-lives in plasma were 35.24 min and 26.75 h for the codrug and GHEE, respectively. With regard to liver homogenate, the hydrolysis half-lives were 1.96 min and 48.13 min for the codrug and GHEE, respectively. It can be expected that in vivo, the codrug will liberate NA immediately in plasma then GEM will be liberated from its 2-hydroxyethyl ester in the liver.

Medication Adherence among Adult Patients on Hemodialysis

Medication adherence was assessed in 89 patients on hemodialysis (HD) at the King Abdul Aziz Medical City using an Arabic version of the Morisky Medication Adherence Scale (MASS-8). The results of the study revealed that 31.46% and 40.45% of the participants showed low and medium adherence, respectively, while 28.09% showed high medication adherence. Accordingly, 71.91% of the patients visiting the dialysis unit were considered medication non-adherent. While being of older age (P = 0.012), being married (P = 0.012) increased the level of adherence, being of medium level of education (P = 0.024) decreased adherence levels. On the other hand, gender, presence of a care-giver, number of members in the household and employment status seems to have no effect on the level of medication adherence. These results call upon the practitioners in HD units to develop intervention programs that can increase the level of medication adherence.

Novel N-substituted aminobenzamide scaffold derivatives targeting the dipeptidyl peptidase-IV enzyme

Background The dipeptidyl peptidase-IV (DPP-IV) enzyme is considered a pivotal target for controlling normal blood sugar levels in the body. Incretins secreted in response to ingestion of meals enhance insulin release to the blood, and DPP-IV inactivates these incretins within a short period and stops their action. Inhibition of this enzyme escalates the action of incretins and induces more insulin to achieve better glucose control in diabetic patients. Thus, inhibition of this enzyme will lead to better control of blood sugar levels. Methods In this study, computer-aided drug design was used to help establish a novel N-substituted aminobenzamide scaffold as a potential inhibitor of DPP-IV. CDOCKER software available from Discovery Studio 3.5 was used to evaluate a series of designed compounds and assess their mode of binding to the active site of the DPP-IV enzyme. The designed compounds were synthesized and tested against a DPP-IV enzyme kit provided by Enzo Life Sciences. The synthesized compounds were characterized using proton and carbon nuclear magnetic resonance, mass spectrometry, infrared spectroscopy, and determination of melting point. Results Sixty-nine novel compounds having an N-aminobenzamide scaffold were prepared, with full characterization. Ten of these compounds showed more in vitro activity against DPP-IV than the reference compounds, with the most active compounds scoring 38% activity at 100 μM concentration. Conclusion The N-aminobenzamide scaffold was shown in this study to be a valid scaffold for inhibiting the DPP-IV enzyme. Continuing work could unravel more active compounds possessing the same scaffold.

Colchicinoids from Colchicum crocifolium Boiss. (Colchicaceae)

A new colchicinoid from Colchicum crocifolium Boiss. (Colchicaceae) was isolated and identified as N,N-dimethyl-N-deacetyl-(−)-cornigerine (5), along with four known compounds, but new to the species: (−)-colchicine (1), (−)-demecolcine (2), (−)-N-methyl-(−)-demecolcine (3) and 3-demethyl-N-methyl-(−)-demecolcine (4). All isolated compounds showed potent cytotoxicity against a human cancer cell panel.

Synthesis and Anticandidal Activity of Azole-Containing Sulfonamides

Twenty five benzenesulfonamides containing one imidazole or triazole ring, or two imidazole or triazole rings have been synthesized and evaluated as anticandidal agents. The most active compounds were 5c, 6b, 6c, 6e, and 17b, which exhibited MIC values of 4.55–24.39 mM depending on the clinical isolate. Comparing imidazole to triazole derivatives did not show a clear effect on activity. Compounds containing a N‐benzyl group also showed no clear evidence on activity given the fact that they have an extra aromatic ring. Secondary sulfonamides, 5l, 5m, and 5n showed activities that were proportional to their lipophilicity. The activities of N‐aryl‐substituted derivatives 5j, 5k, 5l, 5m, 5n, and 6j were also proportional to their lipophilicity. Halogenation enhanced the activity as a result of improvement of lipophilicity. The presence of two imidazole or triazole rings in the same compound did not show a clear enhancement of activity.