A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA).

Staphylococcus aureus is a common human pathogen. Methicillin-resistant Staphylococcus aureus (MRSA) infections pose significant and challenging therapeutic difficulties. MRSA often acquires the non-native gene PBP2a, which results in reduced susceptibility to ß-lactam antibiotics, thus conferring resistance. PBP2a has a lower affinity for methicillin, allowing bacteria to maintain peptidoglycan biosynthesis, a core component of the bacterial cell wall. Consequently, even in the presence of methicillin or other antibiotics, bacteria can develop resistance. Due to genes responsible for resistance, S. aureus becomes MRSA. The fundamental premise of this resistance mechanism is well-understood. Given the therapeutic concerns posed by resistant microorganisms, there is a legitimate demand for novel antibiotics. This review primarily focuses on PBP2a scaffolds and the various screening approaches used to identify PBP2a inhibitors. The following classes of compounds and their biological activities are discussed: Penicillin, Cephalosporins, Pyrazole-Benzimidazole-based derivatives, Oxadiazole-containing derivatives, non-ß-lactam allosteric inhibitors, 4-(3H)-Quinazolinones, Pyrrolylated chalcone, Bis-2-Oxoazetidinyl macrocycles (ß-lactam antibiotics with 1,3-Bridges), Macrocycle-embedded ß-lactams as novel inhibitors, Pyridine-Coupled Pyrimidinones, novel Naphthalimide corbelled aminothiazoximes, non-covalent inhibitors, Investigational-ß-lactam antibiotics, Carbapenem, novel Benzoxazole derivatives, Pyrazolylpyridine analogues, and other miscellaneous classes of scaffolds for PBP2a. Additionally, we discuss the penicillin-binding protein, a crucial target in the MRSA cell wall. Various aspects of PBP2a, bacterial cell walls, peptidoglycans, different crystal structures of PBP2a, synthetic routes for PBP2a inhibitors, and future perspectives on MRSA inhibitors are also explored.

Preparation of Terbinafin-Encapsulated Solid Lipid Nanoparticles Containing Antifungal Carbopol® Hydrogel with Improved Efficacy: In Vitro, Ex Vivo and In Vivo Study.

The present research was aimed to develop a terbinafin hydrochloride (TH)-encapsulated solid lipid nanoparticles (SLNs) hydrogel for improved antifungal efficacy. TH-loaded SLNs were obtained from glyceryl monostearate (lipid) and Pluronic® F68 (surfactant) employing high-pressure homogenization. The ratio of drug with respect to lipid was optimized, considering factors such as desired particle size and highest percent encapsulation efficiency. Lyophilized SLNs were then incorporated in the hydrogel prepared from 0.2-1.0% w/v carbopol 934P and further evaluated for rheological parameters. The z-average, zeta potential and polydispersity index were found to be 241.3 nm, -15.2 mV and 0.415, respectively. The SLNs show a higher entrapment efficiency of about 98.36%, with 2.12 to 6.3602% drug loading. SEM images, XRD and the results of the DSC, FTIR show successful preparation of SLNs after freeze drying. The TH-loaded SLNs hydrogel showed sustained drug release (95.47 ± 1.45%) over a period of 24 h. The results reported in this study show a significant effect on the zone of inhibition than the marketed formulation and pure drug in Candida albicans cultures, with better physical stability at cooler temperatures. It helped to enhance skin deposition inthe ex vivostudy and improved, in vitro and in vivo, the antifungal activity.

Mycobacterium enoyl acyl carrier protein reductase (InhA): A key target for antitubercular drug discovery.

Enoyl acyl carrier protein reductase (InhA) is a key enzyme involved in fatty acid synthesis mainly mycolic acid biosynthesis that is a part of NADH dependent acyl carrier protein reductase family. The aim of the present literature is to underline the different scaffolds or enzyme inhibitors that inhibit mycolic acid biosynthesis mainly cell wall synthesis by inhibiting enzyme InhA. Various scaffolds were identified based on the screening technologies like high throughput screening, encoded library technology, fragment-based screening. The compounds studied include indirect inhibitors (Isoniazid, Ethionamide, Prothionamide) and direct inhibitors (Triclosan/Diphenyl ethers, Pyrrolidine Carboxamides, Pyrroles, Acetamides, Thiadiazoles, Triazoles) with better efficacy against drug resistance. Out of the several scaffolds studied, pyrrolidine carboxamides were found to be the best molecules targeting InhA having good bioavailability properties and better MIC. This review provides with a detailed information, analysis, structure activity relationship and useful insight on various scaffolds as InhA inhibitors.

Mycobacterial Membrane Protein Large 3 (MmpL3) Inhibitors: A Promising Approach to Combat Tuberculosis.

Tuberculosis is a prominent aliment throughout the world and a leading cause of mortality among infectious diseases. Drug development for multi-drug resistance and reducing the current therapy time is the top priority. Mycobacterial membrane protein large 3 (MmpL3) is a promising target with high potential, however, it has not been explored to its greatest potential. It is a membrane transporter that translocates trehalose-monomycolate which is a precursor for the synthesis of mycolic acid that is essential for the synthesis of the bacterial cell wall and is pathogenic in nature. In this review, we have discussed the current development of MmpL3 inhibitors, different scaffolds, their derivatives, and their synthetic schemes and provide insight into the challenges in developing these inhibitors.

Development of novel indole-linked pyrazoles as anticonvulsant agents: A molecular hybridization approach.

A series of 3-{2-[1-acetyl-5-(substitutedphenyl)-4,5-dihydropyrazol-3-yl]hydrazinylidene}-1,3-dihydro-2H-indol-2-ones 24-43 was synthesized using an appropriate synthetic route and evaluated experimentally by the maximal electroshock test. These compounds were evaluated for antidepressant and antianxiety activities. The most active compound, 3-{2-[1-acetyl-5-(4-chlorophenyl)-4,5-dihydropyrazol-3-yl]hydrazinylidene}-1,3-dihydro-2H-indol-2-one 25, exhibited an ED50 of 13.19 mmol/kg, a TD50 of 43.49 mmol/kg, and a high protective index of 3.29, compared with the standard drug diazepam. To get insights into the intermolecular interactions, molecular docking studies were performed at the active site of the GABAA receptor and the MAO-A enzyme. Molecular docking studies are also in agreement with the pharmacological evaluation with potent compounds, exhibiting docking scores of -1.5180 and 0.7458 for the GABAA receptor and MAO-A, respectively. The 3D-QSAR analysis was carried out by Vlife MDS engine 4.3.1, and a statistically reliable model with good predictive power (r2 = 0.7523, q2 = 0.3773) was achieved. The 3D-QSAR plots gave insights into the structure-activity relationship of these compounds, which may aid in the design of potent benzopyrrole derivatives as anticonvulsant agents. So, our research can make a great impact on those medicinal chemists who work on the development of anticonvulsant agents.

Design and Development of Novel 2-(Morpholinyl)-N-substituted Phenylquinazolin-4-amines as Selective COX-II Inhibitor.

BACKGROUND: A novel series of 2-(Morpholin-4-yl)-N-phenylquinazolin-4- amine derivatives were synthesized and confirmed with spectral and elemental techniques. METHODS: The compounds were tested for analgesic and anti-inflammatory activity by various pain models in rodents whereas the selectivity towards COX-2 receptor is determined by in vitro assay. RESULTS: Screening results of compounds exhibited comparable biological activity with that of standard compound Indomethacin used for study. Compound 5d was found to be significantly potent with respect to its anti-inflammatory and analgesic activity with substantial COX-II selectivity. CONCLUSION: In silico analysis by molecular docking and 3D-QSAR studies justifies activity profile of compound 5d, suggesting that it may have potential for further evaluation and development as lead molecule for therapy in pain management.

Development of self-assembled nanocarriers to enhance antitumor efficacy of docetaxel trihydrate in MDA-MB-231 cell line.

Self-assembled nanocarriers (SANs) as a novel colloidal controlled delivery for docetaxel trihydrate (DTX) were engineered by high-pressure homogenization method to overcome the several clinical problems. Drug-excipient compatibility was studied using DSC and FTIR spectroscopy. The fabricated SANs was characterized by particle size, zeta potential, and SEM. QbD based central composite design of experiment was employed for formula optimization. The cell viability of DTX-hydroalcoholic solution (DTX-HA) and DTX-loaded SANs has been determined in MDA-MB-231 cell line by MTT assay. The stability study of selected SANs formulations were carried out at various storage conditions as per ICH guidelines. The summary of results obtained shows high drug content with higher entrapment efficiency (91.23 ±â€¯3.41% w/w) of DTX-loaded SANs. It shows diffusion controlled release of DTX over the period of 12 h which is higher than DTX-HA solution, releases the DTX within 4 h. The MTT assay expressed lower cellular viability and improved cell inhibition leads to increase cytotoxicity of formulations towards cells. The stability study reveals stability of DTX-loaded SANs formulations at various storage conditions over a period of three months. The strong experimental evidence confirms the SANs as an effective approach to formulate the controlled delivery system of antineoplastics with improved stability.

Nanostructured Cubosomes in a Thermoresponsive Depot System: An Alternative Approach for the Controlled Delivery of Docetaxel.

The aim of the present study was to develop and evaluate a thermoresponsive depot system comprising of docetaxel-loaded cubosomes. The cubosomes were dispersed within a thermoreversible gelling system for controlled drug delivery. The cubosome dispersion was prepared by dilution method, followed by homogenization using glyceryl monooleate, ethanol and Pluronic® F127 in distilled water. The cubosome dispersion was then incorporated into a gelling system prepared with Pluronic® F127 and Pluronic® F68 in various ratios to formulate a thermoresponsive depot system. The thermoresponsive depot formulations undergo a thermoreversible gelation process i.e., they exists as free flowing liquids at room temperature, and transforms into gels at higher temperatures e.g., body temperature, to form a stable depot in aqueous environment. The mean particle size of the cubosomes in the dispersion prepared with Pluronic® F127, with and without the drug was found to be 170 and 280 nm, respectively. The prepared thermoresponsive depot system was evaluated by assessing various parameters like time for gelation, injectability, gel erosion, and in-vitro drug release. The drug-release studies of the cubosome dispersion before incorporation into the gelling system revealed that a majority (∼97%) of the drug was released within 12 h. This formulation also showed a short lag time (∼3 min). However, when incorporated into a thermoresponsive depot system, the formulation exhibited an initial burst release of ∼21%, and released only ∼39% drug over a period of 12 h, thus indicating its potential as a controlled drug delivery system.

Comparison of UV spectrophotometry and high performance liquid chromatography methods for the determination of repaglinide in tablets.

BACKGROUND: Repaglinide is a miglitinide class of antidiabetic drug used for the treatment of type 2 diabetes mellitus. A fast and reliable method for the determination of repaglinide was highly desirable to support formulation screening and quality control. OBJECTIVE: UV spectrophotometric and reversed-phase high performance liquid chromatography (RP-HPLC) methods were developed for determination of repaglinide in the tablet dosage form. MATERIALS AND METHODS: The UV spectrum recorded between 200 400 nm using methanol as solvent and the wavelength 241 nm was selected for the determination of repaglinide. RP-HPLC analysis was carried out using Agilent TC-C18 (2) column and mobile phase composed of methanol and water (80:20 v/v, pH adjusted to 3.5 with orthophosphoric acid) at a flow rate of 1.0 ml/min. Parameters such as linearity, precision, accuracy, recovery, specificity and ruggedness are studied as reported in the International Conference on Harmonization (ICH) guidelines. RESULTS: The developed methods illustrated excellent linearity (r(2) > 0.999) in the concentration range of 5-30 µg/ml and 5-50 µg/ml for UV spectrophotometric and HPLC methods, respectively. Precision (%R.S.D < 1.50) and mean recoveries were found in the range of 99.63-100.45% for UV spectrophotometric method and 99.71-100.25% for HPLC method which shows accuracy of the methods. CONCLUSION: The developed methods were found to be reliable, simple, fast, accurate and successfully used for the quality control of repaglinide as a bulk drug and in pharmaceutical formulations.

Isolation of phytosterols and antihyperlipidemic activity of Lagenaria siceraria.

Lagenaria siceraria (Molina) Standl in the Cucurbitaceae family is a large, pubescent, climbing, or trailing herb cultivated throughout India and the tropical regions of the world. Phytochemical investigation of the methanol extract obtained from the fruits of the plant L. siceraria showed a positive Liebermann-Burchard test for sterols. The white sterol crystals or phytosterols from the methanol extract were isolated for the first time and identified as a mixture of four sterols, including fucosterol (1), racemosol (2), stigmasterol (3), and stigmasta-7,22-dien-3ß,4ß-diol (4). These compounds were identified by spectroscopic evidence including FTIR, (1)H-NMR, MS, and GC. The white sterol crystals, which are the mixture of four sterols, were evaluated for antihyperlipidemic activity in Wistar rats. The blood samples were collected from the retro-orbital plexus and serum was separated and analyzed for lipid profiles. These sterol crystals (30 mg/kg) showed significant reductions in lipid profiles which included cholesterol, triglycerides, LDL and VLDL. In addition, a significant increase in HDL cholesterol observed, which is a good cholesterol that protects hearts from coronary artery diseases. These sterol crystals or phytosterols can be used as an antihyperlipidemic agent to treat the hyperlipidemic.

Synthesis and anti-inflammatory activity of alkyl/arylidene-2-aminobenzothiazoles and 1-benzothiazol-2-yl-3-chloro-4-substituted-azetidin-2-ones.

Ten new derivatives of 1-benzothiazol-2-yl-3-chloro-4-substituted-azetidin-2-ones (3a-j) were synthesized using various Schiff bases (alkyl/arylidene-2-aminobenzothiazoles; 2a-j), which in turn were prepared starting from 2-aminobenzothiazole (1). All the synthesised compounds were characterised by elemental analyses and spectral (IR, 1H-NMR, 13C-NMR and EI-MS) data. The title compounds 2a-j and 3a-j were screened in vivo using carrageenan-induced rat paw edema model. All the test compounds showed anti-inflammatory activity when tested in vivo. In general, compounds 3a-j were found to be more potent compared to compounds 2a-j. Among the compounds tested, compound 2g in the alkyl/arylidene-2-aminobenzothiazoles series and compound 3 g in the 1-benzothiazol-2-yl-3-chloro-4-substituted-azetidin-2-ones series were found to be the most potent. All the test compounds were also evaluated to check the gastric ulcer incidence. In gastric ulceration studies, all the test compounds were generally found to be safe at the 100 mg/kg dose level. Furthermore the most potent compounds 2 g and 3 g from each series were screened in vitro for inhibition of both COX-2 and COX-1 catalysed prostaglandin biosynthesis (radiochemical assay). Like most of the commercially available non-steroidal anti-inflammatory drugs (NSAIDs), in the in vitro study, compounds 2 g and 3 g showed anti-inflammatory activity by blocking the metabolism of arachidonic acid to prostaglandin via the cyclooxygenase pathways. In general, in the vitro assay, test compounds 2 g and 3 g were found to be more active after 15 min pre-incubation with the enzyme. Compound 3 g was found to be more COX-2 selective, while compound 2 g was found to be equally COX-2 and COX-1 selective.

Synthesis and anticonvulsant activity of 3-(6-substituted-benzothiazol-2-yl)-6-phenyl-[1, 3]-xazinane-2-thiones.

A new series of 3-(6-substituted-benzothiazol-2-yl)-6-phenyl-[1, 3]-oxazinane-2-thiones (4a-j) has been synthesised using an appropriate synthetic route (Scheme 1) and characterised by elemental analyses and spectral (IR, (1)HNMR, (13)C NMR, and EI MS) data. The anticonvulsant activity of all the title compounds (4a-j) was evaluated against Maximal Electroshock (MES) induced seizures and furthermore the most potent compounds were evaluated against subcutaneous pentylenetetrazole (sc PTZ) induced seizures model in mice. The neurotoxicity was assessed using the rotorod procedure. All the test compounds were administered intraperitoneally at various dose levels ranging from 30-200 mg/kg body wt and the median effective dose (ED(50)), median toxic dose (TD(50)), and protection index (PI) values were determined (Table 2). Among the compounds tested, the 3-(6-dimethylaminobenzothiazol-2-yl)-6-phenyl-[1, 3]-oxazinane-2-thiones (4j) was found to be the most potent (ED(50): 9.85 and 14.8 in MES model and 12 and 17 in scPTZ model at t = 0.5 h and 4 h, respectively, and TD(50) 42.8 and 44 at t = 0.5 h and 4 h, respectively, which has been found to be significant at p < 0.01 with respect to reference standard phenytoin) with protection index (PI) 4.85.