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The discovery of antibiotics has created a turning point in medical interventions to pathogenic infections, but unfortunately, each discovery was consistently followed by the emergence of resistance. The rise of multidrug-resistant bacteria has generated a great challenge to treat infections caused by bacteria with the available antibiotics. Today, research is active in finding new treatments for multidrug-resistant pathogens. In a step to guide the efforts, the WHO has published a list of the most dangerous bacteria that are resistant to current treatments and requires the development of new antibiotics for combating the resistance. Among the list are various Gram-positive bacteria that are responsible for serious healthcare and community-associated infections. Methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and drug-resistant Streptococcus pneumoniae are of particular concern. The resistance of bacteria is an evolving phenomenon that arises from genetic mutations and/or acquired genomes. Thus, antimicrobial resistance demands continuous efforts to create strategies to combat this problem and optimize the use of antibiotics. This article aims to provide a review of the most critical resistant Gram-positive bacterial pathogens, their mechanisms of resistance, and the new treatments and approaches reported to circumvent this problem. [ABSTRACT FROM AUTHOR]

Bacterial resistance to present antibiotics is emerging at a high pace that makes the development of new treatments a must. At the same time, the development of novel antibiotics for resistant bacteria is a slow-paced process. Amid the massive need for new drug treatments to combat resistance, time and effort preserving approaches, like the prodrug approach, are most needed. Prodrugs are pharmacologically inactive entities of active drugs that undergo biotransformation before eliciting their pharmacological effects. A prodrug strategy can be used to revive drugs discarded due to a lack of appropriate pharmacokinetic and drug-like properties, or high host toxicity. A special advantage of the use of the prodrug approach in the era of bacterial resistance is targeting resistant bacteria by developing prodrugs that require bacterium-specific enzymes to release the active drug. In this article, we review the up-to-date implementation of prodrugs to develop medications that are active against drug-resistant bacteria. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance represents an enormous global health crisis and one of the most serious threats humans face today. Some bacterial strains have acquired resistance to nearly all antibiotics. Therefore, new antibacterial agents are crucially needed to overcome resistant bacteria. In 2017, the World Health Organization (WHO) has published a list of antibiotic-resistant priority pathogens, pathogens which present a great threat to humans and to which new antibiotics are urgently needed the list is categorized according to the urgency of need for new antibiotics as critical, high, and medium priority, in order to guide and promote research and development of new antibiotics. The majority of the WHO list is Gram-negative bacterial pathogens. Due to their distinctive structure, Gram-negative bacteria are more resistant than Gram-positive bacteria, and cause significant morbidity and mortality worldwide. Several strategies have been reported to fight and control resistant Gram-negative bacteria, like the development of antimicrobial auxiliary agents, structural modification of existing antibiotics, and research into and the study of chemical structures with new mechanisms of action and novel targets that resistant bacteria are sensitive to. Research efforts have been made to meet the urgent need for new treatments; some have succeeded to yield activity against resistant Gram-negative bacteria by deactivating the mechanism of resistance, like the action of the β-lactamase Inhibitor antibiotic adjuvants. Another promising trend was by referring to nature to develop naturally derived agents with antibacterial activity on novel targets, agents such as bacteriophages, DCAP(2-((3-(3,6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl)amino)-2(hydroxymethyl)propane1,3-diol, Odilorhabdins (ODLs), peptidic benzimidazoles, quorum sensing (QS) inhibitors, and metal-based antibacterial agents. [ABSTRACT FROM AUTHOR]

Background: The design and development of prodrugs is the most common and effective strategy to overcome pharmacokinetic and pharmacodynamic drawbacks of active drugs. A respected number of prodrugs have been reached the drugs market throughout history and the recent years have witnessed a significant increase in the use of prodrugs as a replacement of their parent drugs for an efficient treatment of various ailment. Methods: A Scan conducted to find recent approved prodrugs and prodrugs in development. Results: Selected prodrugs were reported and categorized in accordance to their target systems. Conclusions: the prodrug approach has shown many successes and still remains a viable and effective approach to deliver new active agents. This conclusion is supported by the recent approved prodrugs and the scan of clinical trials conducted between 2013–2018. [ABSTRACT FROM AUTHOR]

A respected number of drugs suffer from bitter taste which results in patient incompliance. With the aim of solving the bitterness of guaifenesin, dimethyl maleate, maleate, glutarate, succinate, and dimethyl succinate prodrugs were designed and synthesized. Molecular orbital methods were utilized for the design of the ester prodrugs. The density functional theory (DFT) calculations revealed that the hydrolysis efficiency of the synthesized prodrugs is significantly sensitive to the pattern of substitution on C=C bond and distance between the nucleophile and the electrophile. The hydrolysis of the prodrugs was largely affected by the pH of the medium. The experimental t1/2 for the hydrolysis of guaifenesin dimaleate ester prodrugs in 1N HCl was the least and for guaifenesin dimethyl succinate was the highest. Functional heterologous expression of TAS2R14, a broadly tuned bitter taste receptor responding to guaifenesin, and experiments using these prodrugs revealed that, while some of the prodrugs still activated the receptor similarly or even stronger than the parent substance, succinate derivatization resulted in the complete loss of receptor responses. The predicted binding modes of guaifenesin and its prodrugs to the TAS2R14 homology model suggest that the decreased activity of the succinate derivatives may be caused by a clash with Phe247. A number of novel bitterless ester guaifenesin prodrugs were designed, synthesized, and characterized. The prodrugs have shown sufficient stability at neutral pH values and rapid release under low pH conditions (stomach). Using bitter taste receptor assays, it was confirmed that the most promiscuous human bitter taste receptor responsible for the bitter perception of many drugs, the TAS2R14, is not activated by some of the prodrugs. We conclude that our approach could be used to mask the bitterness of other similar drugs. [ABSTRACT FROM AUTHOR]

In this study, the removal of selected pharmaceuticals including ibuprofen, diclofenac sodium, indomethacin, chlorpheniramine maleate, and paracetamol from water using natural Jordanian zeolite was studied. The influence of pH, contact time, adsorbent dosage, and initial pharmaceutical concentration on the adsorption process was investigated using batch and column methods. The optimal pH for the removal of all selected pharmaceuticals was found to be 2 except for diclofenac sodium where the optimal pH was 6. The optimum adsorption time was found to be 80 min. The percentage removal increased as the initial concentration of the pharmaceuticals increased from 10.0 to 50.0 mg/L except for indomethacin where the removal decreased as the initial concentration increased. After optimization, the highest removal was found to be 88.3, 30.1, 59.0, 85.8, and 12.7% for ibuprofen, diclofenac sodium, indomethacin, chlorpheniraminemaleate, and paracetamol, respectively. Langmuir and Freundlich isotherm models were used to evaluate the adsorption efficiencies of the investigated pharmaceuticals. The results demonstrated that Langmuir isotherm fits the experimental data for diclofenac sodium, indomethacin and paracetamol with adsorption capacity (Qmax) of 4.8, 26.6, and 55.6 mg/g, respectively, whereas Freundlich isotherm fits the experimental data for both ibuprofen and chlorpheniramine maleate. Continues flow experiment was performed on ibuprofen under constant influent concentration and fixed flow rate. Equal eluted fractions of 100 mL were collected and analyzed for ibuprofen content. The results indicated that percentage removal of ibuprofen on zeolite was found to be the highest after fraction 9 with 78% removal. [ABSTRACT FROM AUTHOR]

The article presents research briefs related to medicinal chemistry, as of January 2018. Topics include a study on an allosteric inhibitor with the most complex mode of action to combat tuberculosis; use of selective indazole ether-based glucocorticoid receptor modulators for treating asthma and chronic obstructive pulmonary disease; and developing potent proteolysis-targeting chimeras (protacs) in anticancer drug discovery.

: Background: Parkinson's disease is an aggressive and progressive neurodegenerative disorder that depletes dopamine (DA) in the central nervous system. Dopamine replacement therapy, mainly through actual dopamine and its original prodrug L-dopa (LD), faces many challenges such as poor blood brain barrier penetration and decreased response to therapy with time. Methods: The prodrugs described herein are ester, amide, dimeric amide, carrier-mediated, peptide transport-mediated, cyclic, chemical delivery systems and enzyme-models prodrugs designed and made by chemical means, and their bioavailability was studied in animals. Results: A promising ester prodrug for intranasal delivery has been developed. LD methyl ester is currently in Phase III clinical trials. A series of amide prodrugs were synthesized with better stability than ester prodrugs. Both amide and dimeric amide prodrugs offer enhanced blood brain barrier (BBB) penetration and better pharmacokinetics. Attaching LD to sugars has been used to exploit glucose transport mechanisms into the brain. Conclusions: Till now, no DA prodrug has reached the pharmaceutical market, nevertheless, the future of utilizing prodrugs for the treatment of PD seems to be bright. For instance, LD ester prodrugs have demonstrated an adequate intranasal delivery of LD, thus enabling the absorption of therapeutic agents to the brain. Most of the amide, cyclic, peptidyl or chemical delivery systems of DA prodrugs demonstrated enhanced pharmacokinetic properties. [ABSTRACT FROM AUTHOR]

Background: Poor pharmacokinetic profiles and resistance are the main two drawbacks from which currently used antiviral agents suffer, thus make them excellent targets for research, especially in the presence of viral pandemics such as HIV and hepatitis C. Methods: The strategies employed in the studies covered in this review were sorted by the type of drug synthesized into ester prodrugs, targeted delivery prodrugs, macromolecular prodrugs, other nucleoside conjugates, and non-nucleoside drugs. Results: Utilizing the ester prodrug approach a novel isopropyl ester prodrug was found to be potent HIV integrase inhibitor. Further, employing the targeted delivery prodrug zanamivir and valine ester prodrug was made and shown a sole delivery of zanamivir. Additionally, VivaGel, a dendrimer macromolecular prodrug, was found to be very efficient and is now undergoing clinical trials. Conclusions: Of all the strategies employed (ester, targeted delivery, macromolecular, protides and nucleoside analogues, and non-nucleoside analogues prodrugs), the most promising are nucleoside analogues and macromolecular prodrugs. The macromolecular prodrug VivaGel works by two mechanisms: envelope mediated and receptor mediated disruption. Nucleotide analogues have witnessed productive era in the recent past few years. The era of non-interferon based treatment of hepatitis (through direct inhibitors of NS5A) has dawned. [ABSTRACT FROM AUTHOR]

For thousands of years, Cannabis sativa has been utilized as a medicine and for recreational and spiritual purposes. Phytocannabinoids are a family of compounds that are found in the cannabis plant, which is known for its psychotogenic and euphoric effects; the main psychotropic constituent of cannabis is Δ9-tetrahydrocannabinol (Δ9-THC). The pharmacological effects of cannabinoids are a result of interactions between those compounds and cannabinoid receptors, CB1 and CB2, located in many parts of the human body. Cannabis is used as a therapeutic agent for treating pain and emesis. Some cannabinoids are clinically applied for treating chronic pain, particularly cancer and multiple sclerosis-associated pain, for appetite stimulation and anti-emesis in HIV/AIDS and cancer patients, and for spasticity treatment in multiple sclerosis and epilepsy patients. Medical cannabis varies from recreational cannabis in the chemical content of THC and cannabidiol (CBD), modes of administration, and safety. Despite the therapeutic effects of cannabis, exposure to high concentrations of THC, the main compound that is responsible for most of the intoxicating effects experienced by users, could lead to psychological events and adverse effects that affect almost all body systems, such as neurological (dizziness, drowsiness, seizures, coma, and others), ophthalmological (mydriasis and conjunctival hyperemia), cardiovascular (tachycardia and arterial hypertension), and gastrointestinal (nausea, vomiting, and thirst), mainly associated with recreational use. Cannabis toxicity in children is more concerning and can cause serious adverse effects such as acute neurological symptoms (stupor), lethargy, seizures, and even coma. More countries are legalizing the commercial production and sale of cannabis for medicinal use, and some for recreational use as well. Liberalization of cannabis laws has led to increased incidence of toxicity, hyperemesis syndrome, lung disease cardiovascular disease, reduced fertility, tolerance, and dependence with chronic prolonged use. This review focuses on the potential therapeutic effects of cannabis and cannabinoids, as well as the acute and chronic toxic effects of cannabis use on various body systems. [ABSTRACT FROM AUTHOR]

New InhA Inhibitors Provided by Fragment-Based Drug Design Highlighted by Josef Jampilek and CongBao Kang Fragment-based drug design (FBDD), despite its youth, has provided marketed drugs and others in clinical trials. However, a recent report [[21]] suggests that resistance is inevitable for KRAS SP G12C sp inhibitors since the cancer cells develop a heterogeneous response to the inhibitors and bypass inhibition by producing new active KRAS SP G12C sp that does not bind the inhibitor, indicating that the challenge to develop efficient inhibitors and achieve complete responses in the clinic continues. An NMR Drug Screening Approach in Human Cells as a New Tool for Drug Potency Early Assess... Highlighted by Tiziano Tuccinardi and Iola F. Duarte A classical drug development workflow usually starts by screening the activity of multiple ligands against the selected target. Among other potential compounds, the c-Jun N-terminal kinase inhibitor SU3327 (halicin) was identified as a potent I E. coli i growth inhibitor. Glucuronide Prodrug, PEGylation, Albumin Binder, Self-Immolative Linker, and a Potent Tox... Highlighted by Jarkko Rautio and Diego Muñoz-Torrero Zelikin's group [[56]] have reported efficient suppression of tumor growth by enzyme prodrug therapy, which takes advantage of noncovalent albumin binding and, subsequently, delivery of the prodrug to the tumor as well as the endogenous enzymatic repertoire of the tumor. [Extracted from the article]

Commercial non-steroidal anti-inflammatory drugs (NSAIDs) are considered as toxic to the environment since they induce side effects when consumed by humans or aquatic life. Ibuprofen is a member of the NSAID family and is widely used as an anti-inflammatory and painkiller agent. Photolysis is a potentially important method of degradation for several emerging contaminants, and individual compounds can undergo photolysis to various degrees, depending on their chemical structure. The efficiency oftitanium dioxide (TiO2) and photocatalysis was investigated for the removal of ibuprofen from the aquatic environment, and the performance of these different processes was evaluated. In heterogeneous photocatalysis, two experiments were carried out using TiO2 as (i) dispersed powder, and (ii) TiO2 immobilized on the active surface of commercial coated glass. The kinetics of each photoreaction was determined, and the identification of the photoproducts was carried out by liquid chromatography coupled with Fourier-transform ion cyclotron resonance mass spectrometry (LC-FTICR MS). The overall results suggest that the TiO2 active thin layer immobilized on the glass substrate can avoid recovery problems related to the use of TiO2 powder in heterogeneous photocatalysis and may be a promising tool toward protecting the environment from emerging contaminants such as ibuprofen and its derivatives. [ABSTRACT FROM AUTHOR]

The growing incidence of microorganisms that resist antimicrobials is a constant concern for the scientific community, while the development of new antimicrobials from new chemical entities has become more and more expensive, time-consuming, and exacerbated by emerging drug-resistant strains. In this regard, many scientists are conducting research on plants aiming to discover possible antimicrobial compounds. The secondary metabolites contained in plants are a source of chemical entities having pharmacological activities and intended to be used for the treatment of different diseases. These chemical entities have the potential to be used as an effective antioxidant, antimutagenic, anticarcinogenic and antimicrobial agents. Among these pharmacologically active entities are the alkaloids which are classified into a number of classes, including pyrrolizidines, pyrrolidines, quinolizidines, indoles, tropanes, piperidines, purines, imidazoles, and isoquinolines. Alkaloids that have antioxidant properties are capable of preventing a variety of degenerative diseases through capturing free radicals, or through binding to catalysts involved indifferent oxidation processes occurring within the human body. Furthermore, these entities are capable of inhibiting the activity of bacteria, fungi, protozoan and etc. The unique properties of these secondary metabolites are the main reason for their utilization by the pharmaceutical companies for the treatment of different diseases. Generally, these alkaloids are extracted from plants, animals and fungi. Penicillin is the most famous natural drug discovery deriving from fungus. Similarly, marines have been used as a source for thousands of bioactive marine natural products. In this review, we cover the medical use of natural alkaloids isolated from a variety of plants and utilized by humans as antibacterial, antiviral, antifungal and anticancer agents. An example for such alkaloids is berberine, an isoquinoline alkaloid, found in roots and stem-bark of Berberis asculin P. Renault plant and used to kill a variety of microorganisms. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses articles in the issue on topics including Antiplatelet Drug Could Emerge as a Potent Antibacterial Agent; and Therapeutic Strategy to Combat Residual Inflammatory Risk in Patients with Ischaemic Heart Disease.

The necessity for the discovery of innovative antimicrobials to treat life-threatening diseases has increased as multidrug-resistant bacteria has spread. Due to antibiotics' availability over the counter in many nations, antibiotic resistance is linked to overuse, abuse, and misuse of these drugs. The World Health Organization (WHO) recognized 12 families of bacteria that present the greatest harm to human health, where options of antibiotic therapy are extremely limited. Therefore, this paper reviews possible new ways for the development of novel classes of antibiotics for which there is no pre-existing resistance in human bacterial pathogens. By utilizing research and technology such as nanotechnology and computational methods (such as in silico and Fragment-based drug design (FBDD)), there has been an improvement in antimicrobial actions and selectivity with target sites. Moreover, there are antibiotic alternatives, such as antimicrobial peptides, essential oils, anti-Quorum sensing agents, darobactins, vitamin B6, bacteriophages, odilorhabdins, 18β-glycyrrhetinic acid, and cannabinoids. Additionally, drug repurposing (such as with ticagrelor, mitomycin C, auranofin, pentamidine, and zidovudine) and synthesis of novel antibacterial agents (including lactones, piperidinol, sugar-based bactericides, isoxazole, carbazole, pyrimidine, and pyrazole derivatives) represent novel approaches to treating infectious diseases. Nonetheless, prodrugs (e.g., siderophores) have recently shown to be an excellent platform to design a new generation of antimicrobial agents with better efficacy against multidrug-resistant bacteria. Ultimately, to combat resistant bacteria and to stop the spread of resistant illnesses, regulations and public education regarding the use of antibiotics in hospitals and the agricultural sector should be combined with research and technological advancements.

SARS-CoV-2, the coronavirus disease-2019 (COVID-19), and the cause of the pandemic is extremely contagious among people and has spread around the world. Antivirals, immunomodulators, and other medications, such as antibiotics, stem cells, and plasma therapy, have all been utilized in the treatment of COVID-19. To better understand the clinical efficacy of these agents and to aid in the selection of effective COVID-19 therapies in various countries, this study reviewed the effectiveness of the various pharmacologic agents that have been used for COVID-19 therapy globally by summarizing the clinical outcomes that have been obtained from the clinical trials published on each drug related to COVID-19 infection. The Food and Drug Administration (FDA) has authorized the use of remdesivir, paxlovid, molnupiravir, baricitinib, tixagevimab-cilgavimab, and bebtelovimab for the management of COVID-19. On the other hand, most research advises against using chloroquine and hydroxychloroquine to treat COVID-19 patients because they are not beneficial. Although the FDA has given emergency use authorization for some monoclonal antibodies, including bamlanivimab, etesevimab, casirivimab, and imdevimab for managing COVID-19, they are not currently approved for use because the Omicron variant has significantly reduced their in vitro susceptibility. In this study, we also included a wide range of alternative therapy strategies that effectively treat COVID-19 patients, although further randomized studies are necessary to support and assess their applicability.

Multiple sclerosis (MS) is known as an autoimmune disease that damages the neurons in the central nervous system. MS is characterized by its most common symptoms of spasticity, muscle spasms, neuropathic pain, tremors, bladder dysfunction, dysarthria, and some intellectual problems, including memory disturbances. Several clinical studies have been conducted to investigate the effects of cannabis on the relief of these symptoms in MS patients. The efficacy of Cannabis sativa ( C. Sativa ) in the management of MS outcomes such as spasticity, pain, tremors, ataxia, bladder functions, sleep, quality of life, and adverse effects were assessed in this review. Most clinical studies showed the positive effects of cannabinoids with their different routes of administration, such as oromucosal spray and oral form, in reducing most MS symptoms. The oromucosal spray Nabiximols demonstrated an improvement in reducing MS spasticity, pain, and quality of life with a tolerated adverse effect. Oral cannabinoids are significantly effective for treating MS pain and spasticity, while the other symptoms indicate slight improvement and the evidence is quite inconsistent. Oromucosal spray and oral cannabis are mainly used for treating patients with MS and have positive effects on treating the most common symptoms of MS, such as pain and spasticity, whereas the other MS symptoms indicated slight improvement, for which further studies are needed.

Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete. Computational methodologies such as molecular mechanics (MM) and quantum mechanical (QM) methods play an important role in elucidating the detailed mechanisms of enzymatic reactions where experimental research measurements are not possible. Theories invoked by a variety of scientists indicate that enzymes work as structural scaffolds that serve to bring together and orient the reactants so that the reaction can proceed with minimum energy. Enzyme models can be utilized for mimicking enzyme catalysis and the development of novel prodrugs. Prodrugs are used to enhance the pharmacokinetics of drugs; classical prodrug approaches focus on alternating the physicochemical properties, while chemical modern approaches are based on the knowledge gained from the chemistry of enzyme models and correlations between experimental and calculated rate values of intramolecular processes (enzyme models). A large number of prodrugs have been designed and developed to improve the effectiveness and pharmacokinetics of commonly used drugs, such as anti-Parkinson (dopamine), antiviral (acyclovir), antimalarial (atovaquone), anticancer (azanucleosides), antifibrinolytic (tranexamic acid), antihyperlipidemia (statins), vasoconstrictors (phenylephrine), antihypertension (atenolol), antibacterial agents (amoxicillin, cephalexin, and cefuroxime axetil), paracetamol, and guaifenesin. This article describes the works done on enzyme models and the computational methods used to understand enzyme catalysis and to help in the development of efficient prodrugs.

Alzheimer's disease (AD) is a disorder that causes degeneration of the cells in the brain and it is the main cause of dementia, which is characterized by a decline in thinking and independence in personal daily activities. AD is considered a multifactorial disease: two main hypotheses were proposed as a cause for AD, cholinergic and amyloid hypotheses. Additionally, several risk factors such as increasing age, genetic factors, head injuries, vascular diseases, infections, and environmental factors play a role in the disease. Currently, there are only two classes of approved drugs to treat AD, including inhibitors to cholinesterase enzyme and antagonists to N -methyl d-aspartate (NMDA), which are effective only in treating the symptoms of AD, but do not cure or prevent the disease. Nowadays, the research is focusing on understanding AD pathology by targeting several mechanisms, such as abnormal tau protein metabolism, β-amyloid, inflammatory response, and cholinergic and free radical damage, aiming to develop successful treatments that are capable of stopping or modifying the course of AD. This review discusses currently available drugs and future theories for the development of new therapies for AD, such as disease-modifying therapeutics (DMT), chaperones, and natural compounds.

The discovery of antibiotics has created a turning point in medical interventions to pathogenic infections, but unfortunately, each discovery was consistently followed by the emergence of resistance. The rise of multidrug-resistant bacteria has generated a great challenge to treat infections caused by bacteria with the available antibiotics. Today, research is active in finding new treatments for multidrug-resistant pathogens. In a step to guide the efforts, the WHO has published a list of the most dangerous bacteria that are resistant to current treatments and requires the development of new antibiotics for combating the resistance. Among the list are various Gram-positive bacteria that are responsible for serious healthcare and community-associated infections. Methicillin-resistant Staphylococcus aureus , vancomycin-resistant Enterococcus faecium , and drug-resistant Streptococcus pneumoniae are of particular concern. The resistance of bacteria is an evolving phenomenon that arises from genetic mutations and/or acquired genomes. Thus, antimicrobial resistance demands continuous efforts to create strategies to combat this problem and optimize the use of antibiotics. This article aims to provide a review of the most critical resistant Gram-positive bacterial pathogens, their mechanisms of resistance, and the new treatments and approaches reported to circumvent this problem.

This study examines the photocatalytic activity of titanium dioxide (TiO 2 ) semiconductor supported on borosilicate tubes (cut-off 290 nm) towards removal of a mix of persistent organic pollutants (POPs) from water. For this purpose, two widely used analgesic and anti-inflammatory drugs (NSAIDs), ibuprofen (IBU) and mefenamic acid, along with MCPA sodium monohydrate, which is a common herbicide frequently used in the agricultural activities, were selected as a case study. Borosilicate tubes were coated with titanium oxide through two different approaches: sol-gel dip-coating and a hybrid nanoparticle dip-coating and plasma-enhanced chemical vapour deposition (PECVD) process. The photochemical reactor that hosts the titania-coated tubes was designed to permit continuous throughput of liquid feed stream. The photodegradation experiments were performed in laboratory conditions under artificial irradiation simulating solar light. The efficiency of direct photolysis and heterogeneous photocatalysis (TiO 2 ) was investigated, and the performance of each coating method was evaluated. Kinetic studies for each experiment were accomplished, the overall results showed poor efficiency and insufficient removal for NSAIDs through direct photolysis, whereas applying heterogeneous photacatalysis with TiO 2 coated on borosilicate tubes was found to accelerate their degradation rate with complete decomposition. Concomitantly, kinetic experimental results showed a critical difference of performance for the two coating methods used; in particular, the degradation rates of pollutants by the sol-gel-coated tubes were much faster than the degradation by the nanoparticle/PECVD-coated tubes. Using TiO 2 supported on borosilicate tubes appears to be a promising alternative to conventional TiO 2 suspension and avoid post-separation stages. The results achieved in this study can be used to optimise large-scale applications, and expanding the study to cover a wide range of pollutants will lead to achieve more representative results.

Introduction: Ample efforts have been carried out to improve the efficacy of a variety of drugs. The prodrugs approach was found to be a safe haven for providing medications with improved pharmacokinetic and pharmacodynamic properties. Areas covered: Herein, several selected successful prodrugs are reported and categorized. These include prodrugs for the treatment of the cardiovascular system, the central nervous system, the gastrointestinal tract, ophthalmology, the immune system, and oncology. In addition, some successful antiviral, antibacterial, antifungal, antiprotozoal, and several other miscellaneous prodrugs are documented. Further, a number of failed prodrugs are reported followed by those potentially promising prodrugs of the future. Expert opinion: The molecular revolution and accumulation of knowledge on the chemistry of enzymes and transporters has opened the door widely to novel successful prodrugs. For example, newer platelet aggregation inhibitors could signal the end of the warfarin era with their demanding treatment follow-up. The discovery of prodrugs can significantly improve the quality of patient care. Future attention should be focused towards directed enzyme prodrug therapy (DEPT). This strategy employs the design of artificial enzymes to activate prodrugs at specific sites. Agents designed for use in DEPT medicine can be directed at antibodies, genes, viruses, and clostridia.

Background : Parkinson's disease is an aggressive and progressive neurodegenerative disorder that depletes dopamine (DA) in the central nervous system. Dopamine replacement therapy, mainly through actual dopamine and its original prodrug l-dopa (LD), faces many challenges such as poor blood brain barrier penetration and decreased response to therapy with time. Methods : The prodrugs described herein are ester, amide, dimeric amide, carrier-mediated, peptide transport-mediated, cyclic, chemical delivery systems and enzyme-models prodrugs designed and made by chemical means, and their bioavailability was studied in animals. Results: A promising ester prodrug for intranasal delivery has been developed. LD methyl ester is currently in Phase III clinical trials. A series of amide prodrugs were synthesized with better stability than ester prodrugs. Both amide and dimeric amide prodrugs offer enhanced blood brain barrier (BBB) penetration and better pharmacokinetics. Attaching LD to sugars has been used to exploit glucose transport mechanisms into the brain. Conclusions : Till now, no DA prodrug has reached the pharmaceutical market, nevertheless, the future of utilizing prodrugs for the treatment of PD seems to be bright. For instance, LD ester prodrugs have demonstrated an adequate intranasal delivery of LD, thus enabling the absorption of therapeutic agents to the brain. Most of the amide, cyclic, peptidyl or chemical delivery systems of DA prodrugs demonstrated enhanced pharmacokinetic properties., Competing Interests: The authors of this review have no conflict of interest to declare.

Background: Intensive efforts have been implemented to improve the efficacy of platinum complexes especially with emerging cisplatin resistance and elevated cancer deaths. Platinum(IV) agents show better pharmacokinetics and decreased side effects compared to Platinum(II) agents., Methods: This review aims to summarize and categorize the strategies being employed to improve the efficacy of Platinum-based anticancer agents in recent years., Results: Nanoparticles and nanoplatforms offer a vast variety of strategies in targeting specific tumor types and delivering one or two lethal drugs simultaneously. Theranostic agents are being developed to achieve enhanced imaging and provide further insight into the activity of platinum containing chemotherapy. Moreover, photoactivation of Pt(IV) prodrugs specifically at the tumor site is gaining attention due to a controlled activity. A platinum agent formulated as large multi-activity complex is the most common strategy being employed., Conclusion: Platinum(IV) agents offer great potential in targeting, increasing efficacy, and decreasing toxicity of Platinum-based anticancer agents. The strategies being employed are aiming to increase specificity and targeting as well as provide more potent agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Kinetic studies on the stability of the pain killer paracetamol in Al-Quds activated sludge demonstrated that paracetamol underwent biodegradation within less than one month to furnish p-aminophenol in high yields. Characterizations of bacteria contained in Al-Quds sludge were accomplished. It was found that Pseudomonas aeruginosa is the bacterium most responsible for the biodegradation of paracetamol to p-aminophenol and hydroquinone. Batch adsorptions of paracetamol and its biodegradation product (p-aminophenol) by activated charcoal and a composite micelle (octadecyltrimethylammonium)-clay (montmorillonite) were determined at 25°C. Adsorption was adequately described by a Langmuir isotherm, and indicated better efficiency of removal by the micelle-clay complex. The ability of bench top reverse osmosis (RO) plant as well as advanced membrane pilot plant to remove paracetamol was also studied at different water matrixes to test the effect of organic matter composition. The results showed that at least 90% rejection was obtained by both plants. In addition, removal of paracetamol from RO brine was investigated by using photocatalytic processes; optimal conditions were found to be acidic or basic pH, in which paracetamol degraded in less than 5 min. Toxicity studies indicated that the effluent and brine were not toxic except for using extra low energy membrane which displayed a half maximal inhibitory concentration (IC-50) value of 80%.

Sensing potentially harmful bitter substances in the oral cavity is achieved by a group of (˜) 25 receptors, named TAS2Rs, which are expressed in specialized sensory cells and recognize individual but overlapping sets of bitter compounds. The receptors differ in their tuning breadths ranging from narrowly to broadly tuned receptors. One of the most broadly tuned human bitter taste receptors is the TAS2R14 recognizing an enormous variety of chemically diverse synthetic and natural bitter compounds, including numerous medicinal drugs. This suggests that this receptor possesses a large readily accessible ligand binding pocket. To allow probing the accessibility and size of the ligand binding pocket, we chemically modified cognate agonists and tested receptor responses in functional assays. The addition of large functional groups to agonists was usually possible without abolishing agonistic activity. The newly synthesized agonist derivatives were modeled in the binding site of the receptor, providing comparison to the mother substances and rationalization of the in vitro activities of this series of compounds., (© 2016 John Wiley & Sons A/S.)

G protein-coupled receptors (GPCRs) are seven transmembrane (TM) proteins that play a key role in human physiology. The GPCR superfamily comprises about 800 members, classified into several classes, with rhodopsin-like Class A being the largest and most studied thus far. A huge component of the human repertoire consists of the chemosensory GPCRs, including ∼400 odorant receptors, 25 bitter taste receptors (TAS2Rs), which are thought to guard the organism from consuming poisons, and sweet and umami TAS1R heteromers, which indicate the nutritive value of food. The location of the binding site of TAS2Rs is similar to that of Class A GPCRs. However, most of the known bitter ligands are agonists, with only a few antagonists documented thus far. The agonist-to-antagonist ratios of Class A GPCRs vary, but in general are much lower than for TAS2Rs. For a set of well-studied GPCRs, a gradual change in agonists-to-antagonists ratios is observed when comparing low (10 μM)- and high (10 nM)-affinity ligand sets from ChEMBL and the DrugBank set of drugs. This shift reflects pharmaceutical bias toward the therapeutically desirable pharmacology for each of these GPCRs, while the 10 μM sets possibly represent the native tendency of the receptors toward either agonists or antagonists. Analyzing ligand-GPCR interactions in 56 X-ray structures representative of currently available structural data, we find that the N-terminus, TM1 and TM2 are more involved in binding of antagonists than of agonists. On the other hand, ECL2 tends to be more involved in binding of agonists. This is of interest, since TAS2Rs harbor variations on the typical Class A sequence motifs, including the absence of the ECL2-TM3 disulfide bridge. This suggests an alternative mode of regulation of conformational states for TAS2Rs, with potentially less stabilized inactive state. The comparison of TAS2Rs and Class A GPCRs structural features and the pharmacology of the their ligands highlights the intricacies of GPCR architecture and provides a framework for rational design of new ligands., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Utilizing the prodrug approach as a method to overcome various pharmaceutical and pharmacokinetic barriers to drug delivery is significantly accelerating and achieving successes. In contrast to the older traditional prodrugs which suffer from decreased bioavailability and a high profile of side effects, due to activation at undesired sites, the targeted prodrug approach utilizes delivery systems to improve delivery for a wide range of therapeutics including anti-cancer, anti-bacterial and anti-inflammatory drugs., Areas Covered: Recent updates in utilization of prodrugs in drug delivery between 2013 and 2015 are discussed. Targeted prodrugs against cancer, solid tumors, microbial infections, inflammation and other diseases using advanced delivery systems such as theranostic approaches, siRNA, DOX immunoconjugate, C 60-ser carrier vector, biotinylated prodrug, human serum albumin (HSA) carrier and others are presented., Expert Opinion: Recent research efforts have been directed at developing targeted prodrugs to replace the classical prodrugs. The use of this approach has accelerated following the emergence of encouraging results from several studies on targeted prodrugs that have highlighted their higher efficiency and improved safety profiles. Targeted prodrug delivery is now considered more than a chemical modification method. It is an applicable and promising approach and, in the future, better knowledge and wide application of this approach may be attained which may pave the way for more forward-thinking and creative techniques.

Stability and removal of dexamethasone sodium phosphate (DSP) from wastewater produced at Al-Quds University Campus were investigated. Kinetic studies in both pure water and wastewater coming from secondary treatment (activated sludge) demonstrated that the anti-inflammatory DSP underwent degradation to its hydrolytic derivative, dexamethasone, in both media. The first-order hydrolysis rate of DSP in activated sludge at 25 degrees C (3.80 x 10(-6) s-1) was about 12-fold larger than in pure water (3.25 x 10(-7) s-1). The overall performance of the wastewater treatment plant (WWTP) installed in the University Campus was also assessed showing that 90% of spiked DSP was removed together with its newly identified metabolites by the ultra-filtration (UF) system, which consists of a UF hollow fibre (HF) with a 100-kDa cutoff membrane as the pre-polishing stage for the UF spiral wound with a 20-kDa cutoffmembrane. In testing other technologies, the effectiveness of adsorption and filtration by micelle-clay (MC) preparation for removing DSP was ascertained in comparison with activated charcoal. Batch adsorption in aqueous suspensions of the MC composite and activated carbon was well described by Langmuir isotherms showing the best results for MC material. Filtration of DSP water solutions demonstrated a significant advantage of columns filled in with a mixture of sand and MC complex in comparison with activated carbon/sand filters.

DFT molecular orbital calculations at B3LYP 6-31G (d,p) and B3LYP/311+G (d,p) levels and molecular mechanics (MM2) calculations of kinetic properties for Bruice's systems 1-5 indicate that the rate enhancement in the cyclization of di-carboxylic semi-esters 1-5 is solely the result of strain effects and not proximity orientation 'reactive rotamer effect". Furthermore, it was found that the activation energy in systems 1-5 and atovaquone ProD1- ProD5 is largely dependent on the difference in the strain energies of the tetrahedral intermediates and reactants, and no correlation was found between the cyclization rate and distance between the nucleophile and the electrophile (rGM). Using the experimental t1/2 (the time needed for the conversion of 50% of the reactants to products) value for the cyclization reaction of di-carboxylic semi-ester 1 and the calculated log krel values for prodrugs ATQ ProD1- ProD5 the t1/2 values for the interconversion of ATQ ProD1- ProD5 to the parent drug were calculated. Thet1/2 values were: ATQ ProD3, 22.44 hours; ATQ ProD1, ATQ ProD2 and ATQ ProD4, few seconds and ATQ ProD5 few years. Therefore, the interconversion rate of atovaquone prodrugs to atovaquone can be programmed according to the nature of the prodrug linker.

Based on DFT, MP2, and the density functional from Truhlar group (hybrid GGA: MPW1k) calculations for an acid-catalyzed hydrolysis of nine Kirby's N-alkylmaleamic acids and two atenolol prodrugs were designed. The calculations demonstrated that the amide bond cleavage is due to intramolecular nucleophilic catalysis by the adjacent carboxylic acid group and the rate-limiting step is determined based on the nature of the amine leaving group. In addition, a linear correlation of the calculated and experimental rate values has drawn credible basis for designing atenolol prodrugs that are bitterless, are stable in neutral aqueous solutions, and have the potential to release the parent drug in a sustained release manner. For example, based on the calculated B3LYP/6-31 G (d,p) rates, the predicted t1/2 (a time needed for 50% of the prodrug to be converted into drug) values for atenolol prodrugs ProD 1-ProD 2 at pH 2 were 65.3 hours (6.3 hours as calculated by GGA: MPW1K) and 11.8 minutes, respectively. In vitro kinetic study of atenolol prodrug ProD 1 demonstrated that the t1/2 was largely affected by the pH of the medium. The determined t1/2 values in 1N HCl, buffer pH2, and buffer pH 5 were 2.53, 3.82, and 133 hours, respectively.

This review provides the reader a concise overview of the majority of prodrug approaches with the emphasis on the modern approaches to prodrug design. The chemical approach catalyzed by metabolic enzymes which is considered as widely used among all other approaches to minimize the undesirable drug physicochemical properties is discussed. Part of this review will shed light on the use of molecular orbital methods such as DFT, semiempirical and ab initio for the design of novel prodrugs. This novel prodrug approach implies prodrug design based on enzyme models that were utilized for mimicking enzyme catalysis. The computational approach exploited for the prodrug design involves molecular orbital and molecular mechanics (DFT, ab initio, and MM2) calculations and correlations between experimental and calculated values of intramolecular processes that were experimentally studied to assign the factors determining the reaction rates in certain processes for better understanding on how enzymes might exert their extraordinary catalysis., (© 2013 John Wiley & Sons A/S.)

Removal of Cr(VI) from aqueous solutions under different conditions was investigated using either clay (montmorillonite) or micelle-clay complex, the last obtained by adsorbing critical micelle concentration of octadecyltrimethylammonium ions onto montmorillonite. Batch experiments showed the effects of contact time, adsorbent dosage, and pH on the removal efficiency of Cr(VI) from aqueous solutions. Langmuir adsorption isotherm fitted the experimental data giving significant results. Filtration experiments using columns filled with micelle-clay complex mixed with sand were performed to assess Cr(VI) removal efficiency under continuous flow at different pH values. The micelle-clay complex used in this study was capable of removing Cr(VI) from aqueous solutions without any prior acidification of the sample. Results demonstrated that the removal effectiveness reached nearly 100% when using optimal conditions for both batch and continuous flow techniques.

DFT calculations at B3LYP/6-31G(d,p) for intramolecular proton transfer in Kirby's enzyme models 1-7 demonstrated that the reaction rate is dependent on the distance between the two reacting centers, rGM, and the hydrogen bonding angle, α, and the rate of the reaction is linearly correlated with rGM and α. Based on these calculation results three simvastatin prodrugs were designed with the potential to provide simvastatin with higher bioavailability. For example, based on the calculated log EM for the three proposed prodrugs, the interconversion of simvastatin prodrug ProD 3 to simvastatin is predicted to be about 10 times faster than that of either simvastatin prodrug ProD 1 or simvastatin ProD 2. Hence, the rate by which the prodrug releases the statin drug can be determined according to the structural features of the promoiety (Kirby's enzyme model).

Based on density functional theory (DFT) calculations for the acid-catalyzed hydrolysis of several maleamic acid amide derivatives four tranexamic acid prodrugs were designed. The DFT results on the acid catalyzed hydrolysis revealed that the reaction rate-limiting step is determined on the nature of the amine leaving group. When the amine leaving group was a primary amine or tranexamic acid moiety, the tetrahedral intermediate collapse was the rate-limiting step, whereas in the cases by which the amine leaving group was aciclovir or cefuroxime the rate-limiting step was the tetrahedral intermediate formation. The linear correlation between the calculated DFT and experimental rates for N-methylmaleamic acids 1-7 provided a credible basis for designing tranexamic acid prodrugs that have the potential to release the parent drug in a sustained release fashion. For example, based on the calculated B3LYP/6-31G(d,p) rates the predicted t1/2 (a time needed for 50 % of the prodrug to be converted into drug) values for tranexamic acid prodrugs ProD 1-ProD 4 at pH 2 were 556 h [50.5 h as calculated by B3LYP/311+G(d,p)] and 6.2 h as calculated by GGA: MPW1K), 253 h, 70 s and 1.7 h, respectively. Kinetic study on the interconversion of the newly synthesized tranexamic acid prodrug ProD 1 revealed that the t1/2 for its conversion to the parent drug was largely affected by the pH of the medium. The experimental t1/2 values in 1 N HCl, buffer pH 2 and buffer pH 5 were 54 min, 23.9 and 270 h, respectively.

DFT calculations for the acid-catalyzed hydrolysis of several maleamic acid amide derivatives revealed that the reaction rate-limiting step is determined on the nature of the amine leaving group. Further, it was established that when the amine leaving group was a secondary amine, acyclovir or cefuroxime moiety the tetrahedral intermediate formation was the rate-limiting step such as in the cases of acyclovir ProD 1- ProD 4 and cefuroxime ProD 1- ProD 4. In addition, the linear correlation between the calculated and experimental rates provided a credible basis for designing prodrugs for masking bitter taste of the corresponding parental drugs which have the potential to release the parent drug in a sustained release fashion. For example, based on the DFT calculated rates the predicted t₁/₂ (a time needed for 50 % of the reactant to be hydrolyzed to products) for cefuroxime prodrugs, cefuroxime ProD 1- ProD 4, were 12 min, 18 min, 200 min and 123 min, respectively.

Density functional theory (DFT) calculations at B3LYP/6-31 G (d,p) and B3LYP/6-311+G(d,p) levels for the substituted pyridine-catalyzed isomerization of monomethyl maleate revealed that isomerization proceeds via four steps, with the rate-limiting step being proton transfer from the substituted pyridinium ion to the C=C double bond in INT1. In addition, it was found that the isomerization rate (maleate to fumarate) is solvent dependent. Polar solvents, such as water, tend to accelerate the isomerization rate, whereas apolar solvents, such as chloroform, act to slow down the reaction. A linear correlation was obtained between the isomerization activation energy and the dielectric constant of the solvent. Furthermore, linearity was achieved when the activation energy was plotted against the pKa value of the catalyst. Substituted-pyridine derivatives with high pKa values were able to catalyze isomerization more efficiently than those with low pKa values. The calculated relative rates for prodrugs 1-6 were: 1 (406.7), 2 (7.6×10(6)), 3 (1.0), 4 (20.7), 5 (13.5) and 6 (2.2×10(3)). This result indicates that isomerizations of prodrugs 1 and 3-5 are expected to be slow and that of prodrugs 2 and 6 are expected to be relatively fast. Hence, prodrugs 2 and 3-5 have the potential to be utilized as prodrugs for the slow release of monomethylfumarate in the treatment of psoriasis and multiple sclerosis.

Based on stability studies on the drugs atenolol and propranolol and some of their derivatives it is believed that increasing the lipophilicity of the drug will lead to an increase in the stability of its aqueous solutions and will provide a prodrug system with the potential for releasing atenolol in a controlled manner. Using DFT theoretical calculations we have calculated an intramolecular acid catalyzed hydrolysis in nine maleamic (4-amino-4-oxo-2butenoic) acids (Kirby's N-alkylmaleamic acids), 1-9. The DFT calculations confirmed that the acid-catalyzed hydrolysis mechanism in these systems involves: (1) a proton transfer from the hydroxyl of the carboxyl group to the adjacent amide carbonyl carbon, (2) an approach of the carboxylate anion toward the protonated amide carbonyl carbon to form a tetrahedral intermediate; and (3) a collapse of the tetrahedral intermediate into products. Furthermore, DFT calculations in different media revealed that the reaction rate-limiting step depends on the reaction medium. In aqueous medium the rate-limiting step is the collapse of the tetrahedral intermediate whereas in the gas phase the formation of the tetrahedral intermediate is the rate-limiting step. Furthermore, the calculations establish that the acid-catalyzed hydrolysis efficiency is largely sensitive to the pattern of substitution on the carbon-carbon double bond. Based on the experimental t(1/2) (the time needed for the conversion of 50% of the reactants to products) and EM (effective molarity) values for processes 1-9 we have calculated the t(1/2) values for the conversion of the two prodrugs to the parental drug, atenolol. The calculated t(1/2) values for ProD 1-2 are predicted to be 65.3 hours and 11.8 minutes, respectively. Thus, the rate by which atenolol prodrug undergoes cleavage to release atenolol can be determined according to the nature of the linker of the prodrug (Kirby's N-alkylmaleamic acids 1-9).

It is believed that the bitter taste of paracetamol, a pain killer drug, is due to its hydroxyl group. Hence, it is expected that blocking the hydroxy group with a suitable linker could inhibit the interaction of paracetamol with its bitter taste receptor/s and hence masking its bitterness. Using DFT theoretical calculations we calculated proton transfers in ten different Kirby's enzyme models, 1-10. The calculation results revealed that the reaction rate is linearly correlated with the distance between the two reactive centers (r(GM)) and the angle of the hydrogen bonding (α) formed along the reaction pathway. Based on these results three novel tasteless paracetamol prodrugs were designed and the thermodynamic and kinetic parameters for their proton transfers were calculated. Based on the experimental t(1/2) (the time needed for the conversion of 50% of the reactants to products) and EM (effective molarity) values for processes 1-10 we have calculated the t(1/2) values for the conversion of the three prodrugs to the parental drug, paracetamol. The calculated t(1/2) values for ProD 1-3 were found to be 21.3 hours, 4.7 hours and 8 minutes, respectively. Thus, the rate by which the paracetamol prodrug undergoes cleavage to release paracetamol can be determined according to the nature of the linker of the prodrug (Kirby's enzyme model 1-10). Further, blocking the phenolic hydroxyl group by a linker moiety is believed to hinder the paracetamol bitterness.

The goal of this project was to design novel dopamine prodrugs for the treatment of Parkinson's disease that can improve the overall biopharmaceutical profile of the current medications to enhance effectiveness and to ease the use of the medications. Based on Menger's study and other's kinetic studies on the cleavage reactions of some Kemp's acid amides to the corresponding amines and anhydrides, DFT calculations were made to find a candidate to be used as an efficient dopamine prodrug. The proposed dopamine prodrugs have a carboxylic group as a hydrophilic moiety and a hydrocarbon skeleton as a lipophilic moiety, where the combination of both groups ensures a moderate hydrophilic lipophilc balance value. The potential prodrugs are expected to give better bioavailability than the parental drug owing to improved absorption. Furthermore, the proposed prodrugs are believed to be more effective than l-dopa because the latter undergoes decarboxylation in the periphery before reaching the blood-brain barrier. Additionally, the predicted prodrugs can be used in different dosage forms (I.V., S.C., tablets, and others) because of their potential solubility in organic and aqueous media. It is expected that the proposed prodrugs will undergo cleavage reactions to release the parental dopamine drug with half-life time (t(½) ) of 12-20 h., (© 2011 John Wiley & Sons A/S.)

DFT calculation results for intramolecular proton transfer reactions in Kirby's enzyme models 1-7 reveal that the reaction rate is quite responsive to geometric disposition, especially to distance between the two reactive centers, r (GM), and the angle of attack, α (the hydrogen bonding angle). Hence, the study on the systems reported herein could provide a good basis for designing aza nucleoside prodrug systems that are less hydrophilic than their parental drugs and can be used, in different dosage forms, to release the parent drug in a controlled manner. For example, based on the calculated log EM, the cleavage process for prodrug 1ProD is predicted to be about 10¹⁰ times faster than that for prodrug 7ProD and about 10⁴ times faster than prodrug 3ProD: rate( 1ProD ) > rate( 3ProD ) > rate( 7ProD ). Hence, the rate by which the prodrug releases the aza nucleoside drug can be determined according to the structural features of the linker (Kirby's enzyme model).

Density Functional Theory (DFT) and ab initio calculation results for the proton transfer reaction in Kirby's enzyme models 1-6 reveal that the reaction rate is largely dependent on the existence of a hydrogen bonding net in the reactants and the corresponding transition states. Further, the distance between the two reacting centers and the angle of the hydrogen bonding formed along the reaction path has profound effects on the rate. Hence, the study on the systems reported herein could provide a good basis for designing antimalarial (atovaquone) pro-drug systems that can be used to release the parent drug in a controlled manner. For example, based on the calculated log EM, the cleavage process for pro-drug 1Pro may be predicted to be about 10¹¹ times faster than that for a pro-drug 4Pro and about 10⁴ times faster than pro-drug 2Pro: rate (1Pro) > rate (2Pro > rate (4Pro). Thus, the rate by which the pro-drug releases the antimalarial drug can be determined according to the nature of the linker (Kirby's enzyme model 1-6)., (© 2010 John Wiley & Sons A/S.)

This article proposes a model for chemical reactivity that involves singularities ("catastrophes") in the timing of bond-making and bond-breaking events. The common stapler is a good mechanical analogy: As hand-pressure is increased on the machine, the staple hardly changes its configuration until the staple suddenly bends. This is viewed as a singularity or catastrophe, defined classically as an abrupt change resulting from a smooth increase or decrease in external conditions (pressure in the case of a stapler, distance in the case of reactivity). Although experimental observations are provided to support the singularity effect, the model remains a heterodox notion at the present time.