Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 19, Issue 3, 2020

The critical link between cancer and inflammation has been known for many years. This complex network was further complexed by revealing the association of the matrix metalloproteinase family members with inflammatory cytokines, which were previously known to be responsible for the development of metastasis. This article summarizes the current studies which evaluate the relationship between cancer and inflammatory microenvironment as well as the roles of MMPs on invasion and metastasis together.

Psoralen or furocoumarin is a linear three ring heterocyclic compound. Psoralens are planar, tricyclic compounds, consisting of a furan ring fused to a coumarin moiety. Psoralen has been known for a wide spectrum of biological activities, spanning from cytotoxic, photosensitizing, insecticidal, antibacterial to antifungal effect. Thus, several structural changes were introduced to explore the role of specific positions with respect to the biological activity. Convenient approaches utilized for the synthesis of psoralen skeleton can be categorized into two parts: (i) the preparation of the tricyclic ring system from resorcinol, (ii) the exocyclic modification of the intact ring system. Furthermore, although psoralens have been used in diverse ways, we mainly focus in this work on their clinical utility for the treatment of psioraisis, vitiligo and skin-related disorder.

Background: Phycocyanin is an algae-derived protein, which binds to pigment for harvesting light. It has been reported in various different species, including that of red algae, dinoflagellates, and cryptophyta. Importantly, phycocyanin has enormous applications, including cosmetic colorant, food additive, biotechnology, diagnostics, fluorescence detection probe, an anticancer agent, anti-inflammatory, immune enhancer, etc. In addition, several different algae were utilized for the isolation of cyano-phycocyanin (C-PC), but most of the purification methods consist of several steps of crude extraction. Aim: To isolate C-PC from a new source of microalgae with better purity level and to evaluate its antimicrobial, algicidal, and antiradical activities. Methods: Biological activity, permeability, pharmacokinetics, and toxicity profile of C-PC were predicted by in silico studies. C-PC was purified and isolated by using ammonium sulphate precipitation, ion-exchange chromatography and gel-filtration chromatography. C-PC was characterized by SDS-PAGE and elution profile (purity ratio) analysis. Antimicrobial and algicial activities of C-PC were evaluated by the microtitre plate based assays. Antiradical activity of C-PC was evaluated by DPPH- and ABTS*+ radical scavenging assays. Conclusion: C-PC was extracted from Oscillatoria minima for the first time, followed by its quantitative as well qualitative evaluation, indicating a new alternative source of this important protein. Furthermore, the antimicrobial, algicidal, and antiradical activities of the isolated C-PC extract have been demonstrated by both in silico as well as in vitro methods.

Background: Prevention and treatment of chronic inflammatory diseases require effective and low-toxic medicines. Molecular hybridization is an effective strategy to enhance the biological activity of new compounds. Triterpenoid scaffolds are in the focus of attention owing to their anti-inflammatory, antiviral, antiproliferative, and immunomodulatory activities. Heteroprostanoids have different pleiotropic effects in acute and chronic inflammatory processes. Objective: The study aimed to develop structurally new and low toxic anti-inflammatory agents via hybridization of betulinic acid with azaprostanoic acids. Methods: A series of betulinic acid-azaprostanoid hybrids was synthesized. The synthetic pathway included the transformation of betulin via Jones' oxidation into betulonic acid, reductive amination of the latter and coupling obtained by 3β-amino-3-deoxybetulinic acid with the 7- or 13-azaprostanoic acids and their homo analogues. The hybrids 1-9 were investigated in vivo on histamine-, formalin- and concanavalin A-induced mouse paw edema models and two models of pain - the acetic acid-induced abdominal writhing and the hotplate test. The hybrids were in vitro evaluated for cytotoxic activity on cancer (MCF7, U- 87 MG) and non-cancer humane cell lines. Results: In the immunogenic inflammation model, the substances showed a pronounced anti-inflammatory effect, which was comparable to that of indomethacin. In the models of the exudative inflammation, none of the compounds displayed a statistically significant effect. The hybrids produced weak or moderate analgesic effects. All the agents revealed low cytotoxicity on human immortalized fibroblasts and cancer cell lines compared with 3β- amino-3-deoxybetulinic acid and doxorubicin. Conclusion: The results indicate that the principal anti-inflammatory effect of hybrids is substantially provided with the triterpenoid scaffold and in some cases with the azaprostanoid scaffold, but the latter makes a significant contribution to reducing the toxicity of hybrids. Hybrid 1 is of interest as a potent low toxic agent against immune-mediated inflammation.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) derived local generation of reactive oxygen species (ROS) plays a crucial role in the formation of gastric ulceration. Objective: Therefore, anti-inflammatory analgesics with potent antioxidant activity could be a potential therapeutic strategy for the treatment of pain and inflammatory disorders without gastrointestinal (GI) side effects. Methods: In an effort to develop gastroprotective analgesic and anti-inflammatory agents, a series of 2-methylamino-substituted-1H-benzo[d] imidazol-1-yl) (phenyl) methanone derivatives were synthesized and evaluated in vitro for cyclooxygenase (COX) inhibition as well as anti-oxidant potential by the FRAP assay. The compounds with significant in vitro COX-1/COX-2 inhibitory activity and antioxidant activity were further screened in vivo for their anti-inflammatory and analgesic activities. Moreover, the ulcerogenic potential of test compounds was also studied. To gain insight into the plausible mode of interaction of compounds within the active sites of COX-1 and COX-2, molecular docking simulations were performed. Results: Among the various synthesized molecules, most of the compounds showed good cyclooxygenase inhibitory activity and efficient antioxidant activity in FRAP assay. After preliminary and indicative in vitro assays, three compounds exhibited most significant antiinflammatory and analgesic activity with better gastric tolerability during their in vivo evaluation. Ligand interaction studies indicated highest dock score -43.05 of 1,2- disubstituted benzimidazole derivatives in comparison to the reference ligand -30.70. Overall studies provided us (2-((4-methoxyphenylamino) methyl) -1h-benzo [d] imidazol- 1-yl) (phenyl) methanone as a lead with potent gastro-protective anti-inflammatory and analgesic activities that can be used for future research. Conclusion: From the above results, it can be concluded that designing of multifunctional molecules with COX-1/COX-2 inhibitory and anti-oxidant activities could hold a great promise for further development of GI-safer NSAIDs.

Objectives: Inflammation is our body’s normal defense mechanism, but in some cases, it may be responsible for causing different kinds of disorders. Several antiinflammatory drugs are present for the treatment of these disorders; however, the conventional anti-inflammatory drugs cause side effects when used in the long term and therefore, it is better to use them in a low dose for a shorter duration of time. This study was designed to find out whether there is an augmentation of the therapeutic effectiveness of the antiinflammatory drugs like diclofenac sodium (NSAID), prednisolone (steroid) and atorvastatin (statin) when used in combination with ascorbic acid (antioxidant). Methods: Wistar Rats (n=144) were selected and divided into 24 groups of 6 rats in each. Carrageenan and formalin were used to induce local inflammation and neuropsychiatric effects, respectively. The inhibitions of such responses were measured after administering a drug alone and in combination with ascorbic acid. Results: In case of carrageenan mediated inflammation, the combination of 5 mg/kg diclofenac and 200 mg/kg ascorbic acid gave the highest inhibition of 74.19% compared to other groups of drugs. The combination of 5 mg/kg diclofenac and 200 mg/kg ascorbic acid gave 97.25% inhibition for formalin-mediated inflammation group. In both cases, combination therapy showed statistically significant anti-inflammatory activities compared to monotherapy (p values <0.05). Conclusion: All the data clearly indicate new combinations of drug therapy comprising diclofenac sodium, prednisolone, atorvastatin with ascorbic acid, which may be more effective against both local edema and the neuropsychiatric effect caused due to inflammation.

Background: Effective screening of colorectal cancer (CRC) in early stage could reduce the advancement of CRC and therefore mortality. Effective screening is based on either stool dependent tests or colon dependent examination. Aims: The aim of the study was a comparative evaluation of chromocolonoscopy and Colon Cancer-Specific Antigen-2 test for early detection of colorectal cancer in Egyptian patients. Methods: This case control study was carried out on 55 patients classified into 3 groups: Group I consisted of twenty patients with precancerous lesions detected by colonoscopy, Group II consisted of twenty patients diagnosed with colorectal cancer and Group III consisted of fifteen individuals (who underwent colonoscopy for other indications) as a control group. All the subjects were subjected to measure occult blood in the stool, measurement of Colon Cancer-Specific Antigen-2 level in serum and tissue and chromo colonoscopy using Indigo Carmine stain. Results: In group II, there was a statistically significant increase in CCSA2 in serum as compared to the other 2 groups. Cutoff >11.3 CCSA2 in serum showed 65% sensitivity, 85% specificity, 81.2% PPV, 70.8% NPV and 70.3% accuracy in the differentiation of group II with cancer colon from group I with premalignant colonic lesions. A cutoff > 9.1 CCSA2 in serum showed 95% sensitivity, 46.67% specificity, 70.4% PPV, 87.5% NPV and 73.5% accuracy in differentiating group II with cancer colon from normal controls (group III). Conclusion: CCSA-2 level in serum was significantly higher in cancer colon. Chromoendoscopy has a role in the detection of polyps, both neoplastic and non-neoplastic.

Background: Caryocar brasiliense, popularly known as pequi, is widely distributed in the Amazon rainforest and Brazilian savannah. The fruit obtained from pequi is used in cooking and has folk use as an anti-inflammatory and for the treatment of respiratory disease. Until now, these two properties had not been scientifically demonstrated for Pequi oil in a carrageenan model. Objective: Our group determined the composition and safe use of Pequi oil from the Savannah of Campo Grande, and the anti-inflammatory and anti-nociceptive activities of this pequi oil were investigated in vivo models. Materials and Methods: Doses of 300, 700, and 1000 mg/kg of Pequi oil were administered orally (p.o.) to Swiss male mice, and three parameters of inflammation (mechanical hyperalgesia, cold, hyperalgesia, and oedema) were analyzed in a carrageenan model to induce an inflammatory paw state. Results and Discussion: The effects of Pequi oil were also carrageenan in pleurisy model, formalin, and acetic acid induced nociception. Oral administration of 1,000 mg/kg orally Pequi oil (p.o.) inhibited (*P<0.05), the migration of total leukocytes, but not alter plasma extravasation, in the pleurisy model when compared to control groups. The paw edema was inhibited with doses of 700 (P <0.05) and 1,000 mg (P<0.001) of pequi oil after 1, 2, and 4 hours after carrageenan. Pequi oil (1,000 mg/kg) also blocked the mechanical hyperalgesy and reduced cold allodynia induced by carrageenan in paw (P <0.05). Pequi oil treatment (1,000 mg/kg) almost blocked (P < 0.001) all parameters of nociception observed in formalin and acid acetic test. Conclusion: This is the first time that the analgesic and anti-inflammatory effects of Pequi oil have been shown.

Background: Polyalthia longifolia is a popular medicinal plant and has been widely used as a traditional remedy for centuries in curing of various ailments. The purpose of this study was conducted to determine the in situ antimicrobial synergistic effects between Polyalthia longifolia leaf ethyl acetate fraction (PLEAF) and ampicillin against MRSA local isolate by using modern microscopy technique. Methods: Hence, the evaluation of the synergistic activity of PLEAF and ampicillin against MRSA local isolate was conducted with scanning electron microscopy (SEM). Results: The combinational effect of PLEAF fraction and ampicillin exhibited significant antibacterial activity against MRSA. Bacterial cells observations showed invagination, impaired cell division, extensive wrinkles, cell shrinkage, the appearance of a rougher cell with fibrous matrix and clustered cells which confirmed the synergistic effect of PLEAF and ampicillin against MRSA local isolate by SEM. Conclusion: Conclusively, the in situ SEM observation proved the synergistic antimicrobial activity between PLEAF fraction and ampicillin to destroy the MRSA resistance bacteria which is an important aspect of PLEAF fraction to be used in the future combinational therapy.

The anti-IgE Omalizumab may be helpful to treat clopidogrel hypersensitivity without stopping thienopyridine administration in patients requirining continuous antiplatellet therapy after coronary stent placement.