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

Selective dopamine D(1) receptor ligands: Synthesis of naphthisoquinolines and benzisoquinolines

In an effort to assess the effect of changes of the accessory ring and the nitrogen in the trans-β-dopamine-β-ring pharmacophore, which is proposed to be the optimal pharmacophore for D1-agonist activity, this work reports the synthesis of a series of potential dopamine agonists substituted at the nitrogen and at different positions of the phenyl ring, as modifications to the structure of the potent D1 agonist 8,9-dihydroxy-2,3,7,11b-tetahydro-1H-naphth[1,2,3-de]isoquinoline (dinapsoline). Six members of this series have been synthesized, N-allyl-dinapsoline (1), N-n-propyl-dinapsoline (2), 6-methyl-dinapsoline (3), 4-methyl-dinapsoline (4), N-allyl-4-methyl-dinapsoline (5), and N-n-propyl-4-methyl-dinapsoline (6). The synthesis of compounds 1 and 2 used the same intermediates, and a route was developed that was much improved over the reported synthesis of dinapsoline. Nevertheless, this new approach was complicated by very poor yields at a key cyclization step that employed concentrated sulfinic acid. Attempts to improve this step failed. The synthesis of compounds 3–6 utilized similar intermediates. An important feature of this synthesis involved the optimization of the Suzuki cross-coupling conditions when using vinyl triflates and boronic acids. The synthesis of 3-phenyl benz[h]isoquinolines 7 and 8 was also attempted. However, the chemistry failed when attempts were made to attach the pyridine and the dimethoxyphenyl ring. Compounds 1–6 will be evaluated pharmacologically to test the effect of these structural modifications on D1 and D2 receptor binding affinity and on behavioral effects

Synthesis and Spectroscopic Analysis of Novel 1<em>H</em>-Benzo[<em>d</em>]imidazoles Phenyl Sulfonylpiperazines

A group of benzimidazole analogs of sildenafil, 3-benzimidazolyl-4-methoxy-phenylsulfonylpiperazines <strong>2</strong><strong>–4 </strong>and 3-benzimidazolyl-4-methoxy-<em>N,N</em>-dimethyl- benzenesulfonamide (<strong>5</strong>),<strong> </strong>were efficiently synthesized. Compounds <strong>2</strong><strong>–5</strong> were characterized by NMR and MS and contrary to the reported mass spectra of sildenafil, the spectra of the piperazine-containing compounds <strong>2</strong><strong>–4</strong> showed a novel fragmentation pattern leading to an <em>m/z</em> = 316. A mechanism for the formation of this fragment was proposed

Qandil, A.M., Synthesis and Spectroscopic Analysis of Novel 1H-Benzo[d]imidazolylphenylsulfonylpiperazines. Pharmaceuticals 2012, 5, 460-468

We have found the following errors in the title of this article which was recently published in Pharmaceuticals [1]

Design and Synthesis of a Series of 3Aminobenzenesulfonamide Derivatives and Their Screening for Antimicrobial and Cytotoxic

ABSTRACT A series of 3-aminobenzenesulfonamide derivatives with a 3-N-substituted side chains that contain ureas, thioureas or cyclic amines was designed, synthesized and assayed for antibacterial, anti-candidal and cytotoxic activity. The synthesized compounds exhibited minimal antibacterial activity but showed good anti-candidal activity, especially compounds 2a, 2d, 2e, 3a, 3d, 4b, 4c, 4d, 4j, 4k, 4l and 4m with MIC values ranging from 16-64 µg/mL. The thiourea and urea (compounds 2a-f and 3a-d), but not the cyclic amine derivatives (compounds 4a-m), exhibited significant cytotoxic activity against brine shrimp

Depolymerization of High Molecular Weight into a Predicted Low Molecular Weight Chitosan and Determination of the Degree of Deacetylation Coupled with Other Tests to Guarantee its Quality for Research Use

Low molecular weight chitosan (LMWC) is a semi synthetic biopolymer with potential uses as a pharmaceutical excipient, though, consistent and reliable grades of pure LMWC are scarce. Credible and competent preparation and characterization methods are, therefore, of utmost importance to specialized laboratories. Although acid hydrolysis of chitosan is already known, existing protocols produce oligomer mixtures of high polydispersity and fail to predict the ensuing molecular weights. We, herein, optimize a mild acid-catalyzed depolymerization of high molecular weight chitosan (HMWC) of 100kDa and 93% degree of deacetylation, and develop a standardized protocol that enables the predetermination of resultant molecular weight and re-acetylation in the ranges of 1.4-28.1 kDa and 55.1-81.1%, respectively. Molecular weight measurements were extracted and verified based on dynamic viscosity readings and dynamic light scattering. Degree of deacetylation was calculated by H1 NMR. These protocols were found to be efficient, time and cost-effective, reproducible, and gave LMWC with the desired quality and yield for research purposes

Synthesis, Antibacterial Evaluation and QSAR of α-Substituted-N4-Acetamides of Ciprofloxacin and Norfloxacin

Twenty six α-substituted N4-acetamide derivatives of ciprofloxacin (CIPRO) and norfloxacin (NOR) were synthesized and assayed for antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus and Bacillus subtilis. The derivatives were primarily more active against Gram-positive bacteria. The CIPRO derivatives, CD-7 (Ar = 3-chlorophenyl), CD-9 (Ar = 2-pyrimidyl) and CD-10 (α-phenyl, Ar = 2-pyrimidyl), exhibited lower MIC values, 0.4–0.9 μM, against Staphylococcus aureus than CIPRO, while only compound CD-10 exhibited better activity, 0.1 μM, against Bacillus subtilis than CIPRO. In addition, compounds CD-5 (Ar = 2-methoxyphenyl), CD-6 (α-phenyl, Ar = 2-methoxyphenyl), CD-7 (Ar = 3-Chlorophenyl), CD-8 (α-phenyl, Ar = 3-chlorophenyl) and CD-9 (Ar = 2-pyrimidyl) showed MIC values below 1.0 μM against this strain. The NOR derivatives showed lower activity than NOR itself against Staphylococcus aureus, although ND-6 (α-phenyl, Ar = 2-methoxyphenyl) and ND-7 (Ar = 3-chlorophenyl) showed MIC values less than 2 μM. Two NOR derivatives, ND-7 and ND-6, exhibited MIC values of 0.7 and 0.6, respectively, which were comparable to that of NOR against Bacillus subtilis, while compounds ND-8 (α-phenyl, Ar = 3-chlorophenyl) and ND-10 (α-phenyl, Ar = 2-pyrimidyl) exhibited MIC values less than 1.0 μM against the same strain. QSAR revealed that while polarity is the major contributing factor in the potency against Staphylococcus aureus, it is balanced by lipophilicity and electron density around the acetamide group. On the other hand, electron density around the introduced acetamide group is the major determining factor in the activity against Bacillus subtilis, with a lesser and variable effect for lipophilicity

Strategic initiatives to maintain pharmaceutical care and clinical pharmacists sufficiency in Saudi Arabia

Objectives: The shortage of clinical pharmacists in Saudi Arabia has limited the full implementation of pharmaceutical care in most of its hospitals. The National Guard Health Affairs hospitals. This work discussed the Department of Pharmaceutical Care, and the King Saud Bin Abdulaziz University for Health Sciences College of Pharmacy four initiatives that were planned in 2009–2010 to develop and recruit clinical pharmacists, practitioners, or faculty. Methods: The combined initiatives were aimed at (1) instituting a 4-year clinical skills development career ladder, (2) expanding the National Guard Health Affairs postgraduate residency program, (3) offering scholarships to qualified pharmacy graduates to pursue the PharmD degree and a PGY-1 residency training in the United States, and (4) recruiting non-Saudi clinical pharmacists educated and trained in the United States to ameliorate the current shortage of practitioner. Results: The current number of clinical pharmacists practicing at the National Guard Health Affairs at central region is 24, most of whom are Board Certified by the American Pharmacists Association Board of Pharmacy Specialties. Conclusions: The four initiatives, based on current trends, suggest that 60–65 positions will be added by 2017–2018, barring attrition. Saudi Arabia and many developing countries will continue to experience a shortage in clinical pharmacists due to the high demand for clinical pharmacy services. A multifaceted approach is recommended to address the problem