Design, synthesis, characterization and analysis of anti-inflammatory properties of novel N-(benzo[d]thiazol-2-yl)-2-[phenyl(2-(piperidin-1-yl) ethylamino] benzamides and N-(benzo[d]thiazol-2-yl)-2-[phenyl (2-morpholino) ethylamino] benzamides derivatives through in vitro and in silico approach

Utami W., Aziz H.A., Nasrudin D., Kusmawan A., Anwar Z., Maulana M., Daryanto M.

Abstract The previous studies explain that bioactive compounds from Ficus religiosa are known as an anti-inflammatory agent. In this research, we investigated the potency of bioactive compounds from Ficus religiosa by using molecular docking between eight bioactive compounds and the COX-2 receptor. The eight ligands were collected from www.pubchem.ncbi.nlm.nih.gov., while the receptor was taken from www.rcsb.org. The result of this study could be a reference for the research in the synthesis of the bioactive compound to minimize failure. The collected data was calculated through Autodock Vina embedded in MGL Tools 1.5.6, and these processes were performed using 100 runs of the Lamarckian Genetic Algorithm (LGA). The lowest energy of complexes was visualized by using Biovia Discovery Studio Visualizer. This result proved that 28-Isofucosterol-COX-2 had smaller binding energy compared to the reference ligand.

Al-Ostoot F.H., Zabiulla, Grisha S., Mohammed Y.H., Vivek H.K., Ara Khanum S.

• We have synthesized caffeic acid (CA) derivatives 7a-j . • Evaluated the synthesized series for anti-inflammatory and analgesic activities. • Also evaluated for ulcerogenic studied. • The results were reconfirmed by docking study. • 7f and 7g are good anti-inflammatory & analgesic agent with least ulceogenic effect. A series of caffeic acid (CA) derivatives 7a-j were synthesized via etherification and coupling action and their chemical structures were elucidated spectroscopically. Motivated by the various biological activities displayed by CA derivatives such as anti-inflammatory, antiviral, anticancer and antioxidant and also based on its extensively consumption in the human diet. In the present work, the newly synthesized compounds 7a-j were evaluated for anti-inflammatory and analgesic action and most of them exerted comparable activity to the reference compound celecoxib. Further, ulcer indexes for the most active compounds were calculated and most of them showed less ulcerogenic effect than the reference drug. Among the title series 7a-j , compounds 7f and 7g with electron withdrawing bromo and chloro group respectively, at the para position of the phenoxy ring was showed good activity compared to all other compounds. Interestingly, the COX-I/COX-II activity ratio of potent compounds 7f and 7g showed an almost equal inhibitory effect on both isoenzymes. Further, molecular docking studies have been performed for the potent compounds which showed statistically significant result.

Sheth K.R., Bernthal N.M., Ho H.S., Bergese S.D., Apfel C.C., Stoicea N., Jahr J.S.

Zheng X., Li C., Cui M., Song Z., Bai X., Liang C., Wang H., Zhang T.

Twenty benzothiazole derivatives bearing a 1,3,4-oxadiazole moiety were synthesized and evaluated for their anti-oxidant and anti-inflammatory activities. Among these compounds, 8h and 8l were appeared to have high radical scavenging efficacies as 0.05 ± 0.02 and 0.07 ± 0.03 mmol/L of IC50 values in ABTS+ bioassay, respectively. In anti-inflammatory tests, compound 8h displayed good activity with 57.35% inhibition after intraperitoneal administration, which was more potent than the reference drug (indomethacin). Molecular modeling studies were performed to investigate the binding mode of the representative compound 8h into COX-2 enzyme. In vitro enzyme study implied that compound 8h exerted its anti-inflammatory activity through COX-2 inhibition.

Kourounakis A.P., Xanthopoulos D., Tzara A.

Morpholine is a heterocycle featured in numerous approved and experimental drugs as well as bioactive molecules. It is often employed in the field of medicinal chemistry for its advantageous physicochemical, biological, and metabolic properties, as well as its facile synthetic routes. The morpholine ring is a versatile and readily accessible synthetic building block, it is easily introduced as an amine reagent or can be built according to a variety of available synthetic methodologies. This versatile scaffold, appropriately substituted, possesses a wide range of biological activities. There are many examples of molecular targets of morpholine bioactive in which the significant contribution of the morpholine moiety has been demonstrated; it is an integral component of the pharmacophore for certain enzyme active‐site inhibitors whereas it bestows selective affinity for a wide range of receptors. A large body of in vivo studies has demonstrated morpholine's potential to not only increase potency but also provide compounds with desirable drug‐like properties and improved pharamacokinetics. In this review we describe the medicinal chemistry/pharmacological activity of morpholine derivatives on various therapeutically related molecular targets, attempting to highlight the importance of the morpholine ring in drug design and development as well as to justify its classification as a privileged structure.

Khamees H.A., Mohammed Y.H., S A., Al-Ostoot F.H., Y S., Alghamdi S., Khanum S.A., Madegowda M.

Thiazole derivatives (6a and 6b) have been synthesized and characterised by 1H –13C NMR, as well as LC-MS spectra. The three-dimensional structures have been confirmed by single crystal X-ray diffraction method. 6a and 6b compounds have been crystallized in the Triclinic and the Orthorhombic systems with P-1 and Pbca space groups, respectively. Supramolecular structures revealed the stability of molecules with different intermolecular interactions and different crystal packing environment. Theoretical study by Density functional theory (DFT) with B3LYP functional based on highest basis set 6–311++G(d,p) was employed to calculate the geometry and compared to the experimental data. The electronic structures and intramolecular charge transfers have been investigated by using natural population and natural bond orbital analysis (NBO). Further, DFT studies were performed to assess the frontier molecular orbitals (FMOs), energy gap, softness, hardness, and others chemical reactivity. Hirshfeld surface was investigated to distinguish the different interatomic contacts and understand the crystal packing of molecules with aid of energy frameworks through different intermolecular interaction energies based on the anisotropy of the topology. Nonlinear optical property (NLO) of the synthesized molecules were predicted by (DFT) and examined experimentally by using second harmonic generation (SHG) and revealed the importance of high NLO based on the nature of substituents and conformation. Thiazole derivatives were assessed for anti-inflammation activity by in silico molecular docking studies against COX-1 and COX-2 protein receptors revealed prominent interactions with active site and further molecular dynamics confirms the stability of the protein-ligand model. In vitro assay against cyclooxygenase (COX) enzyme gave IC50 values of 6a and 6b molecules with ortho-difluoro and para-methyl positions on benzoyl group, showed better inhibitor for COX-1 and COX-2, respectively.

Zabiulla, Gulnaz A.R., Mohammed Y.H., Khanum S.A.

The prostaglandins (PG) a group of physiologically active lipid compounds having diverse hormone like effects are important mediators of the body's response to pain and inflammation, and are formed from essential fatty acids found in cell membranes. This reaction is catalyzed by cyclooxygenase, a membrane associated enzyme occurring in two isoforms, COX-1 and COX-2. Nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting the activity of COX. In view of this, a series of novel benzophenones conjugated with oxadiazole sulphur bridge pyrazole moiety 8a-l were designed, synthesized, characterized and subsequently evaluated for anti-inflammatory and analgesic property. The investigation of novel analogues 8a-l for potential anti-inflammatory activity showed high levels of COX-1 and COX-2 inhibitory activity. Among the series, compound 8i with electron withdrawing fluoro group at the para position of the benzoyl ring of benzophenone was characterized by highest IC50 values for both COX-1 and COX-2 inhibition, which is comparable to the standard drug. Further, molecular docking studies have been performed for the potent compound.

ur Rashid H., Xu Y., Ahmad N., Muhammad Y., Wang L.

Chalcones (1, 3-Diphenyl-2-propen-1-one) consist of a three carbon α, β-unsaturated carbonyl system and act as precursors for the biosynthesis of flavonoids in plants. However, laboratory synthesis of various chalcones has also been reported. Both natural and synthetic chalcones are known to exhibit a variety of pharmacological activities such as anti-inflammatory, antitumor, antibacterial, antifungal, antimalarial and antituberculosis. These promising activities, ease of synthesis and simple chemical structure have awarded chalcones considerable attraction. This review focuses on the anti-inflammatory effects of chalcones, caused by their inhibitory action primarily against the activities and expressions of four key inflammatory mediators viz., cyclooxygenase, prostaglandin E2, inducible NO synthase, and nuclear factor κB. Various methodologies for the synthesis of chalcones have been discussed. The potency of recently synthesized chalcones is given in terms of their IC50 values. Structure-Activity Relationships (SARs) of a variety of chalcone derivatives have been discussed. Computational methods were applied to calculate the ideal orientation of a typical chalcone scaffold against three enzymes, namely, cyclooxygenase-1, cyclooxygenase-2 and inducible NO synthase for the formation of stable complexes. The global market of anti-inflammatory drugs and its expected growth (from 2018 to 2026) have been discussed. SAR analysis, docking studies, and future prospects all together provide useful clues for the synthesis of novel chalcones of improved anti-inflammatory activities.

Puttaswamy N., Malojiao V.H., Mohammed Y.H., Sherapura A., Prabhakar B.T., Khanum S.A.

Ten new 2(4-hydroxy-3-benzoyl) benzamide-5-phenyl-1,3,4-oxadiazole derivatives (10a-j) were synthesized by coupling 3-benzoyl-4-hydroxybenzoic acid (5) with 2-amino-5-phenyl-1,3,4-oxadiazoles (9a-j). The structures of these compounds were confirmed by IR, 1H, 13C NMR, and mass spectra, and also by elemental analyses. The anti-inflammatory activity of the compounds 10a-j were investigated by screening them against human red blood cells (HRBC) in-vitro. The results reveal that among this series, compound 10j with hydroxy substituent, particularly at the ortho position of the phenyl ring attached to the 5th carbon atom of the oxadiazole ring possess significant membrane stabilizing activity in comparison with the control. Further, in-vivo chick chorioallantoic membrane (CAM) and rat corneal anti-angiogenesis assays were performed to assess the effect of compound 10j on endothelial cell migration. This confirmed that compound 10j inhibits the proliferation of endothelial cells. Anti-inflammatory studies detected the amelioration of carrageen induced rat hind paw edema. Further in-vivo and in-silico approaches revealed the inhibition of inflammatory marker enzyme cyclooxygenase-2 (Cox-2) and myleoperoxidase (MPO). The study reports that the compound 10j effectively act against the inflammatory mediated anti-angiogenic disorders which could be translated into a new drug in future.

Khamees H.A., Jyothi M., Khanum S.A., Madegowda M.

The compound 1-(3,4-dimethoxyphenyl)-3-(4-flurophenyl)-propan-1-one (DFPO) was synthesized by Claisen-Schmidt condensation reaction and the single crystals were obtained by slow evaporation method. Three-dimensional structure was confirmed by single crystal X-ray diffraction method and exhibiting the triclinic crystal system with space group P-1. The crystal structure is stabilized by C H⋯O intermolecular and weak interactions. Computed molecular geometry has been obtained by density functional theory (DFT) and compared with experimental results. The spectra of both FT-IR in the range (4000–400 cm-1) and FT- Raman (3500–50 cm-1) of DFPO were recorded experimentally and computed by (DFT) using B3LYP/6-311G (d,p) as basis sets. Intramolecular charge transfer has been scanned using natural bond orbital (NBO) analysis and revealed the various contribution of bonding and lone pair to the stabilization of molecule. Nonlinear optical activity (NLO) of the title compound has been determined by second harmonic generation (SHG) and computed using DFT method. Hyperpolarizability, HOMO–LUMO energy gap, hardness, softness electronegativity and others Global reactivity descriptors of DFPO has been calculated and revealed complete picture of chemical reactivity of DFPO. Hirshfeld surface analyses were applied to investigate the intermolecular interactions and revealed that more than two-thirds of the inter contacts are associated with O⋯H, C⋯H and H⋯H interactions. Docking studies of DFPO showed inhibition of Vascular endothelial growth Factor human receptor (VEGFR-2) signalling pathway, which indicates DFPO as anti-angiogenesis, that play pivotal role in cancer, so we suggest it for clinical studies to evaluate its potential to treat human cancers.

Chen L., Deng H., Cui H., Fang J., Zuo Z., Deng J., Li Y., Wang X., Zhao L.

Inflammation is a biological response of the immune system that can be triggered by a variety of factors, including pathogens, damaged cells and toxic compounds. These factors may induce acute and/or chronic inflammatory responses in the heart, pancreas, liver, kidney, lung, brain, intestinal tract and reproductive system, potentially leading to tissue damage or disease. Both infectious and non-infectious agents and cell damage activate inflammatory cells and trigger inflammatory signaling pathways, most commonly the NF-κB, MAPK, and JAK-STAT pathways. Here, we review inflammatory responses within organs, focusing on the etiology of inflammation, inflammatory response mechanisms, resolution of inflammation, and organ-specific inflammatory responses.

Tatematsu Y., Hayashi H., Taguchi R., Fujita H., Yamamoto A., Ohkura K.

Hepatotoxicity is a known side effect of nonsteroidal anti-inflammatory drugs (NSAIDs). In the present study, the effects of N-phenylanthranilic acid (NPA) scaffold NSAIDs on rat liver mitochondria were examined. Mefenamic acid (MEF, 200 µM) induced mitochondrial swelling, which was inorganic phosphate (Pi)-dependent and suppressed by cyclosporin A (CsA, 2.5 µM), similar to calcium-induced swelling. Mitochondrial swelling was also observed following the addition of 200 µM flufenamic acid (FLU), meclofenamic acid (MCL), and tolfenamic acid (TOL). Less swelling was observed with the addition of 200 µM diclofenac (DIC) or NPA. Diphenylamine (DPA)-induced swelling occurred in a Pi-independent manner and was not sensitive to CsA. The mechanism by which DPA interacted with the mitochondrial inner membrane differed from those of the other NPA scaffold NSAIDs. The addition of 50 µM MEF, MCL, TOL, and FLU had uncoupling effects in mitochondrial inner membrane. These NSAIDs dose-dependently obstructed electron transport in the respiratory chain. NSAIDs are known to have various dynamic structures, and the solvation free energies (dGWs: an index of stereo-hydrophobicity) of the conformers obtained were determined using a molecular orbital analysis. The relationship between the dynamic structures and swelling induced by NPA scaffold NSAIDs was also examined.

Wang P., Cai J., Chen J., Ji M.

A series of new ceritinib analogs by extensive functionalization of the tail piperidine ring with various phosphamides and carbamates have been synthesized. All the ceritinib derivatives were evaluated for their cytotoxic activities against H2228 cell line. From the activity profile obtained, three of the tested compounds (compounds 4, 7 and 9) showed significant cytotoxic effects. Among these derivatives compound 9 was found to possess cytotoxicity that is better than standard drug ceritinib (IC50 = 24 nM). Moreover, compound 9 demonstrated robust tumor growth inhibition in vivo model.

Hu S., Gu Q., Wang Z., Weng Z., Cai Y., Dong X., Hu Y., Liu T., Xie X.

Based on a putative 'Y shape' pharmacophore model of CCR5 inhibitors, a series of novel piperidine-4-carboxamide derivatives were designed and synthesized using a group-reverse strategy. Among synthesized target compounds, 16g (IC₅₀ = 25.73 nM) and 16i (IC₅₀ = 25.53 nM) showed equivalent inhibitory activity against CCR5 to that of the positive control maraviroc (IC₅₀ = 25.43 nM) in calcium mobilization assay. Selected compounds were further tested for their antiviral activity in HIV-1 single cycle assay. Two compounds, 16g and 16i, displayed antiviral activity with IC₅₀ values of 73.01 nM and 94.10 nM, respectively. Additionally, the pharmacokinetic properties and inhibitory potency against hERG of 16g were evaluated, providing a foundation for ongoing optimization.

Herrera-García A., Domínguez-Luis M., Arce-Franco M., López-Fernández J., Feria M., Barreiro O., Sánchez-Madrid F., Díaz-González F.

Diphenylamine-based nonsteroidal antiinflammatory drugs (NSAIDs) are able to cause in vitro the shedding of L-selectin. The aim of this work was to determine the physio-logic relevance of L-selectin shedding in the antiinflammatory effect exerted by NSAIDs in vivo. Chemical compounds structurally related to NSAIDs - including diphenyl-amine, N-phenylanthranilic acid (N-Ph), diphenylacetic acid - as well as the traditional NSAID indomethacin were studied using the zymosan air-pouch mouse model. Animals intramuscularly pretreated with indomethacin or N-Ph, but not with diphenyl-amine or diphenylacetic acid, showed a significant dose-dependent reduction in the number of neutrophils compared with untreated animals (N-Ph, IC50 = 6.7 mg/kg). Except for indomethacin, none of these compounds caused any significant reduction in cyclooxygenase-1 activity in vivo. In flow chamber experiments, N-Ph reduced the capability of human neutrophils to pass across the endothelial barrier by interfering with leukocyte rolling step on HUVEC. N-Ph, but not diphenylacetic acid, induced activation-independent L-selectin shedding in mouse neutrophils. Interestingly, N-Ph exerted an antiinflammatory effect similar to that of the anti-L-selectin blocking antibody Mel-14, although no additive action was observed when both compounds were combined. These data suggest that the L-selectin shedding induced by NSAIDs may be involved in the antiinflammatory action exerted by these compounds in clinical settings.

Nagesh Khadri M.J., Shashikumar U., Tsai P., Manjappa K.B., Ponnusamy V.K., Khanum S.A.

AbstractNitrogen, oxygen, and sulfur‐containing heterocyclic compounds are broadly established as key scaffolds with potential chemical and biological properties. Benzimidazole, indole, benzoxazole, benzothiazole, pyrazole, and thiophene analogs are significant heterocyclic motifs that bear almost all pharmacological activities. Anti‐inflammatory activity is one of the most commonly associated biological activities with these heterocycles and thus has attracted the interest of researchers to synthesize and study them in‐depth. The present review highlights mainly the various synthetic methodologies utilized to prepare these diverse heterocycles and their associated pharmacological properties limited to anti‐inflammatory activities. Further, this review will provide a comprehensive idea of the methodologies used to prepare biologically active nitrogen, oxygen, and sulfur‐bearing heterocycles and possibly invoke new thoughts in the search for rational designs for developing more promising anti‐inflammatory agents.

Vincy C.D., Sankar G.B., Bemina R.S., Kumar S.M., Dhas S.S., Kumar A.A., T J.B.

The FT-IR, FT-Raman, and UV–Vis spectra of bis(benzimidazolium) maleate (BM) were analysed. Quantum computations with the DFT methodology were used for finding the stable conformer and structural optimization deploying the Gaussian '09 software. An X-ray diffraction study on a single crystal revealed that the grown crystal is an orthorhombic system with a space group. To examine the numerous intra- and intermolecular interactions in a molecular system, natural bond orbital (NBO) analysis is performed. After completing normal coordinate analysis to identify the vibrational modes, PED assignments were established. According to vibrational analysis, the stretching wavenumber of hydrogen bond donor NH and hydrogen bond acceptor CO2 is red-shifted due to interaction. DOS spectral analysis is used to investigate the molecular orbital contributions. The HOMO–LUMO analysis is used to determine the studied compound’s conductivity, reactivity, and stability. The COO− groups are vulnerable to electrophilic attack, whereas the NH group in the benzimidazolium ring is probably nucleophilic, according to the MEP plot, Fukui function, and natural population analysis. The Kirby-Bauer disc diffusion technique was used to determine the antifungal activity of the BM against Candida albicans and Aspergillus niger fungal pathogens. Molecular docking studies were used to elucidate the interaction between ligands and proteins. According to ADME parameter analysis and the Lipinski rule for the BM molecule, the chemical possesses good drug-like qualities and could eventually be developed into an antifungal medication.

Wang L., Li C., Li X., Xia Z., Yang J., Xu B., Zhang H.

AbstractCellulose has a wide range of uses. It could be modified to create cellulose‐based hydrophobic materials and cellulose‐based conductive and stable flexible films, but it did not have antibacterial properties and was susceptible to bacterial erosion. In order to improve the utilization of cellulose materials and broaden the application of cellulose materials, cellulose could be given certain antibacterial properties by combining it with antimicrobial agents. This study focused on creating an organic antimicrobial agent, Benzothiocyanine (TCMTB), from CH2ClBr, and then developing a TCMTB‐CMC composite antimicrobial film by combining TCMTB with CMC. The successful synthesis of TCMTB was confirmed through NMR hydrogen spectroscopy testing. By varying the proportions of TCMTB in CMC, three types of composite antimicrobial cellulose film were produced. The study also assessed the impact of TCMTB on the mechanical strength of CMC film and tested the antimicrobial effectiveness of the composite film using the plate counting method. Results showed that the composite film had high inhibition rates, with 96.2% against Escherichia coli and 98.6% against Staphylococcus aureus. To establish a theoretical foundation for its use in seed encapsulation, leather preservation, and other applications.

Kashyap P., Verma S., Gupta P., Narang R., Lal S., Devgun M.

Antimicrobial resistance (AMR) is a worldwide concern among infectious diseases due to increased mortality, morbidity and treatment cost. According to WHO 2019 report, among the 32 antibiotics in the clinical trials, only six were classified as innovative and containing novel moiety. The remaining antibiotics from this list contain previously known moiety (WHO AMR 2019). Therefore, the development of novel antibiotics to control resistance problems is crucial. Benzothiazole derivatives are of great interest due to their wide range of biological activities and medicinal applications. Reported data indicated that benzothiazole derivatives displayed antibacterial activity by inhibiting the dihydroorotase, DNA gyrase, uridine diphosphate-n-acetyl enol pyruvyl glucosamine reductase (MurB), peptide deformylase, aldose reductase, casdihydrofolate reductase, enoyl acyl carrier protein reductase, dialkylglycine decarboxylase, dehydrosqualene synthase, dihydropteroate synthase and tyrosine kinase. The present review analyzed the synthesis, structure-activity relationship (SAR) and mechanism of action studies of benzothiazole derivatives as antibacterial agents reported by various research groups in the last five years (2018–2022). Different patents on the antimicrobial activity of benzothiazole derivatives have also been summarized. The finding of the present review will be beneficial for the researchers in the development of novel antibacterial molecules based on benzothiazole moiety.