Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (v.15, #1)

Meet our Co-Editor-in-Chief by Simone Carradori (1-1).

Preface by Claudiu T. Supuran (2-2).

Review of Antibiotic and Non-Antibiotic Properties of Beta-lactam Molecules by Ochoa-Aguilar Abraham, Ventura-Martinez Rosa, Sotomayor-Sobrino Marco Antonio, Gómez Claudia, Morales-Espinosa María del Rosario (3-14).
Background: Beta-lactam molecules are a family of drugs commonly used for their antibiotic properties; however, recent research has shown that several members of this group present a large number of other effects such as neuroprotective, antioxidant, analgesic or immunomodulatory capabilities. These properties have been used in both preclinical and clinical studies in different diseases such as hypoxic neuronal damage or acute and chronic pain. The present work briefly reviews the antibiotic effect of these molecules, and will then focus specially on the non-antibiotic effects of three beta-lactam subfamilies: penicillins, cephalosporins and beta lactamase inhibitors, each of which have different molecular structure and pharmacokinetics and therefore have several potential clinical applications.
Methods: A thorough search of bibliographic databases for peer-reviewed research was performed including only classic experiments or high quality reviews for the antibiotic mechanisms of beta-lactam molecules and only experimental research papers where included when the non-antibiotic properties of these molecules were searched. Only published articles from indexed journals were included. Quality of retrieved papers was assessed using standard tools. The characteristics of screened papers were described and findings of included studies were contextualized to either a mechanistic or a clinical framework.
Results: Seventy-eight papers were included in the review; the majority (56) were relative to the non-antibiotic properties of beta-lactam molecules. The non-antibiotic effects reviewed were divided accordingly to the amount of information available for each one. Twelve papers outlined the epileptogenic effects induced by beta-lactam molecules administration; these included both clinical and basic research as well as probable mechanistic explanations. Eighteen papers described a potential neuroprotective effect, mostly in basic in vitro and in vivo experiments. Analgesic properties where identified in twelve papers and basic research was described alongside with both experimental and serendipic clinical findings. Seven papers described a down-regulation effect exerted by beta-lactam molecules administration in different addiction animal models. Finally other effects such as penile erection, dopamine release facilitation and anti-neoplasic effects where described from seven papers.
Conclusion: The findings of this review show that beta-lactam molecules may induce several effects, which may be clinically relevant in a lot of different diseases. This paper is, to our knowledge, the first comprehensive review of the non-antibiotic effects shown by beta-lactam molecules and may help increase the interest in this field, which may result in a direct translation of this effects to a clinical context.

Cardioprotection by Conditioning Mimetic Drugs by Elpidio Santillo, Monica Migale, Demetrio Postacchini, Fabrizio Balestrini, Raffaele Antonelli Incalzi (15-30).
Background: At present, ischemic heart disease (IHD) is one of the main causes of morbidity and mortality world-wide. An important insight into both IHD pathophysiology and cardioprotection was achieved in 1986 when Murry et al. described for the first time the ischemic preconditioning (IP). IP can be defined as an innate phenomenon by which brief episodes of ischemia confer protection to a tissue from a subsequent more protracted ischemic insult. Suggested mechanisms explaining IP comprise the action of circulating substances (e.g. adenosine, bradykinin, nitric oxide). These mediators are released after a prolonged ischemic stress, causing activation of molecular pathways that induce favorable posttranslational changes of proteins and adaptive modifications in genetic expression.
Purpose: Briefly review evidences from clinical studies on drugs that exert their effects by mimicking IP, discussing their therapeutic properties and the potential clinical employment in order to obtain cardioprotection.
Methods: Literature regarding IP mimicking pharmacological agents was searched in Medline and Google Scholar. Authors reviewed relevant researches in English language including both clinical studies and reviews of clinical studies published from 1986 to 2016.
Results: Several pharmacological agents reproducing IP protective actions have been evaluated in many clinical trials. Examined molecules include adenosine, nicorandil and atrial natriuretic peptide. Interestingly IP mimicking effects of drugs have been also analyzed perioperatively in the context of ischaemia-reperfusion heart injury. Moreover evidences suggest that also some anaesthetic drugs (especially volatile agents) are able to provide myocardial protection by inducing IP.
Conclusion: Drugs capable of mimicking IP exhibit a high therapeutic potential because of their properties of eliciting an effective cardioprotective signaling. Future studies should clarify the optimal doses and timing of administration of IP mimetic agents in order to favor the advent of new cardioprotective strategies beyond available reperfusive therapies.

Background: Non-steroidal anti-inflammatory drugs (NSAIDS) are clinically used as anti-inflammatory, analgesic and antipyretic agents but they have the drawbacks such as gastric irritation and gastric ulceration. Recently, quinoline derivatives have shown significant anti-inflammatory and less ulcerogenic activity. The present study deals with the synthesis and pharmacological assessment of a series of novel quinoline derivatives bearing azetidinones scaffolds as anti-inflammatory and analgesic agents.
Methods: A series of newer 3-chloro-1-(substituted)-4-(tetrazolo [1,5-a]quinolin-4- yl)azetidin-2-one derivatives (6a-l) was synthesized starting with acetanilide (1). Initially, acetanilide (1) was allowed to react with Vilsmeier-Haack reagent (DMF + POCl3) to form 2- chloro-3-formyl quinoline (2). The 2-chloro-3-formyl quinoline (2) was further treated with p-toluenesulphonic acid and sodium azide which yielded Tetrazolo [1,5-1] quinoline-4- carbaldehyde (3). The reaction of formyl group with various substituted amines (4a-l) formed corresponding Schiff base intermediates (5a-l), which were further allowed to react with chloroacetyl chloride to produce 3-chloro-1-(substituted)-4-(tetrazolo [1,5-a]quinolin-4-yl) azetidin-2-one derivatives (6a-l). The structure of the final analogues (6a-l) has been confirmed on the basis of elemental analysis, IR, 1H NMR, 13C NMR and mass spectra. All the synthesized compounds were evaluated for their anti-inflammatory and analgesic activities by using carrageenan induced rat paw model and Eddy's hot plate method respectively.
Results: All the values of elemental analysis, IR, 1H NMR, 13C NMR and mass spectra were found to be prominent. The anti-inflammatory activity test revealed that 3-chloro-1-(4-methoxyphenyl)- 4-(tetrazolo[1,5-a] quinolin-4-yl)azetidin-2-one (6b), 3-chloro-1-(2-methoxyphenyl)- 4-(tetrazolo[1,5-a]quinolin-4-yl)azetidin-2-one (6a) exhibited significant anti-inflammatory and analgesic activity as compared to control group.
Conclusion: The results of the current study indicate that substitution at quinoline derivatives bearing azetidinones scaffolds showed potent analgesic and anti-inflammatory activities.

Background: The present study reports the synthesis and biological evaluation of thiazolidinone derivatives bearing benzenesulfonamide investigated for cyclooxygenase-2 (COX-2) inhibitory activity and in vivo anti-inflammatory activity.
Methods: The synthesis of 4-(4-oxo-2-substituted-1,3-thiazolidin-3-yl) benzenesulfonamide derivatives were carried out by conventional synthesis, involves the one-pot condensation reaction of sulfanilamide. The synthesized compounds were evaluated against COX-1 and human recombinant COX-2 by using colorimetric enzyme assay kit and in-vivo study was carried out by carageenan induced rat paw edema method.
Results: Five derivatives 3a, 3b, 3f, 3g, and 3j showed pronounced COX-2 percentage inhibition (55.76, 61.75, 46.54, 43.32, and 49.77% respectively). Structure activity relationship suggested that the compound with a 4-hydroxy group on phenyl ring leads to more selective inhibition of COX-2 than celecoxib, which is supported by molecular docking study. In silico ADME properties showed that compound 3a, 3b, 3f, 3g, and 3j complies Lipinski's rule of five and show no violation. Molecular docking study divulged the binding interactions of thiazolidinone derivatives into the active site of COX-2 and thereby helps to design the potent inhibitors.
Conclusion: The overall studies inferred that compound 3b rendered it as a good leadcandidate for the further development of more potent anti-inflammatory agent.

Background: Furanone and pyrrolone heterocyclic ring system represent important and interesting classes of bioactive compounds. Medicinal chemists use these heterocycyclic moieties as scaffolds in drug design and discovery.
Methods: A series of 3-arylidene-5-(naphthalene-2-yl)-furan-2(3H)-ones (2a-j) were synthesized by incorporating pharmacophore of COX-2 inhibitor rofecoxib and naphthyl ring of naproxen as potential non steroidal anti-inflammatory agents. These furanone derivatives were subsequently reacted with dry ammonia gas and benzylamine to furnish corresponding 3-arylidene-5-(naphthlen-2-yl)-1H-pyrrol-2(3H)-ones (3a-e) and 3-arylidene-1-benzyl-5- (naphthalene-2-yl)-1H-pyrrol-2(3H)-ones (4a-e), respectively. The newly prepared heterocyclics were screened for their expected in-vivo biological activities including anti-inflammatory, analgesic and ulcerogenic actions in rodents. The COX-2 inhibitory behavior of synthesized compounds was also assessed via automated docking studies.
Results: The chemical structure of the synthesized compounds was characterized by using modern spectroscopic techniques. Result of in-vivo pharmacological studies demonstrated that almost all N-Benzyl-pyrrol-2(3H)-ones (4a-e) showed better anti-inflammatory and analgesic activities in comparison with the other two series of furan-2(3H)-ones and pyrrol- 2(3H)-ones. The moldock score value of the tested compounds was found in the range of -116.66 to -170.328 and was better than the standard drug.
Conclusion: Among all the synthesized compounds, only nine compounds (2d, 2g, 2h, 3d, 4a, 4b, 4c, 4d and 4e) exhibited potent anti-inflammatory and analgesic activities with significantly reduced gastrointestinal toxicity in various animal models in comparison to standard drug, diclofenac. Therefore, it is recommended to explore the potential of the synthesized compounds as lead candidates for the development of new therapeutic agents.