Design and synthesis of unique indole-benzosulfonamide oleanolic acid derivatives as potent antibacterial agents against MRSA.

The rapid emergence of antibiotic resistance and the scarcity of novel antibacterial agents have necessitated an urgent pursuit for the discovery and development of novel antibacterial agents against multidrug-resistant bacteria. This study involved the design and synthesis of series of novel indole-benzosulfonamide oleanolic acid (OA) derivatives, in which the indole and benzosulfonamide pharmacophores were introduced into the OA skeleton semisynthetically. These target OA derivatives show antibacterial activity against Staphylococcus strains in vitro and in vivo. Among them, derivative c17 was the most promising antibacterial agent while compared with the positive control of norfloxacin, especially against methicillin-resistant Staphylococcus aureus (MRSA) in vitro. In addition, derivative c17 also showed remarkable efficacy against MRSA-infected murine skin model, leading to a significant reduction of bacterial counts during this in vivo study. Furthermore, some preliminary studies indicated that derivative c17 could effectively inhibit and eradicate the biofilm formation, disrupt the integrity of the bacterial cell membrane. Moreover, derivative c17 showed low hemolytic activity and low toxicity to mammalian cells of NIH 3T3 and HEK 293T. These aforementioned findings strongly support the potential of novel indole-benzosulfonamide OA derivatives as anti-MRSA agents.

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Trial of AWZ1066S, an Anti-Wolbachia Candidate Macrofilaricide.

AWZ1066S has been developed as a potential treatment for the neglected tropical diseases lymphatic filariasis and onchocerciasis. AWZ1066S targets the Wolbachia bacterial endosymbiont present in the causative nematode parasites. This phase 1, first-in-human study aimed to assess the safety and pharmacokinetics of AWZ1066S in healthy human participants. In a randomized double-blind, placebo-controlled, single ascending dose study, healthy adults received a single oral dose of AWZ1066S (or placebo) and were followed up for 10 days. The planned single doses of AWZ1066S ranged from 100 to 1600 mg, and each dose was administered to a cohort of 8 participants (6 AWZ1066S and 2 placebo). In total 30 people participated, 18 (60%) female, median age 30.0 years (minimum 20, maximum 61). The cohorts administered 100, 200, 300, and 400 mg of AWZ1066S progressed unremarkably. After single 700-mg doses all 4 participants developed symptoms of acute gastritis and transient increases in liver enzymes. The severity of these adverse events ranged from mild to severe, with 1 participant needing hospital admission. Pharmacokinetic analysis indicated that AWZ1066S is rapidly absorbed with predictable pharmacokinetics. In conclusion, safety concerns prevented this study from reaching the human exposures needed for AWZ1066S to be clinically effective against lymphatic filariasis and onchocerciasis.

Novel Sophoridine Derivatives as Potential Larvicidal Agents against Aedes albopictus: Synthesis, Biological Evaluation, Acetylcholinesterase Inhibition, and Morphological Study.

Two series of novel sophoridine derivatives were designed, synthesized, and evaluated for their anti-mosquito activity. SOP-2g, SOP-2q, and SOP-2r exhibited potential larvicidal activity against Aedes albopictus larva with LC50 values of 330.98, 430.53, and 411.09 ppm, respectively. Analysis of structure-activity relationships indicated that the oxime ester group was beneficial for improving the larvicidal biological activity, whereas the long-chain aliphatic group and fused-ring group were introduced. Furthermore, the larvicidal mechanism was also investigated based on the inhibition assay of acetylcholinesterase (AChE) and the morphological observation of dead larva treated with derivatives. Results indicated that the AChE inhibitory activity of the preferred three derivatives were 63.16%, 46.67%, and 35.11%, respectively, at 250 ppm concentration. Additionally, morphological evidence demonstrated that SOP-2q and SOP-2r induced changes in the larva's intestinal cavity, caudal gill, and tail, thereby displaying larvicidal action against Ae. albopictus together with AChE inhibition. Therefore, this study implied that sophoridine and its novel derivatives could be used to control the population of mosquito larva, which may also be effective alkaloids to reduce the mosquito population density.

Synthesis and Biological Evaluation of Novel Fusidic Acid Derivatives as Two-in-One Agent with Potent Antibacterial and Anti-Inflammatory Activity.

Fusidic acid (FA), a narrow-spectrum antibiotics, is highly sensitive to various Gram-positive cocci associated with skin infections. It has outstanding antibacterial effects against certain Gram-positive bacteria whilst no cross-resistance with other antibiotics. Two series of FA derivatives were synthesized and their antibacterial activities were tested. A new aromatic side-chain analog, FA-15 exhibited good antibacterial activity with MIC values in the range of 0.781-1.563 µM against three strains of Staphylococcus spp. Furthermore, through the assessment by the kinetic assay, similar characteristics of bacteriostasis by FA and its aromatic derivatives were observed. In addition, anti-inflammatory activities of FA and its aromatic derivatives were evaluated by using a 12-O-tetradecanoylphorbol-13-acetate (TPA) induced mouse ear edema model. The results also indicated that FA and its aromatic derivatives effectively reduced TPA-induced ear edema in a dose-dependent manner. Following, multiform computerized simulation, including homology modeling, molecular docking, molecular dynamic simulation and QSAR was conducted to clarify the mechanism and regularity of activities. Overall, the present work gave vital clues about structural modifications and has profound significance in deeply scouting for bioactive potentials of FA and its derivatives.

Larvicidal Activity of Two Rutaceae Plant Essential Oils and Their Constituents Against Aedes albopictus (Diptera: Culicidae) in Multiple Formulations.

Aedes albopictus (Skuse) is a vector of several arboviruses, such as dengue, chikungunya, West Nile, and Zika viruses. At present, the use of synthetic insecticides is the main vector control strategy. However, the widespread and long-term use of insecticides has aroused several problems, including insecticide resistance, environmental pollution, and non-target species effects, thereby encouraging researchers to search for new alternatives derived from natural products. In recent decades, essential oils (EOs) as natural alternatives to control mosquitoes have received increasing attention. In the initial larvicidal activity screen, two Rutaceae plants (Citrus aurantium and Citrus paradisi) EOs were selected and evaluated for killing Ae. albopictus larvae. The LC50 values of C. aurantium and C. paradisi EOs against Ae. albopictus were 91.7 and 100.9 ppm, respectively. The main components of C. aurantium EO include diethyl o-phthalate (37.32%), limonene (10.04%), and methyl dihydrojasmonate (6.48%). The main components of C. paradisi EO include limonene (60.51%), diethyl o-phthalate (11.75%), linalool (7.90%), and styralyl acetate (6.28%). Among these main components of the two EOs, limonene showed potent larvicidal activity, with the LC50 value of 39.7 ppm. The nanoemulsions of limonene were prepared and characterized. The duration of larvicidal activity was greater in the limonene nanoemulsions than when limonene was applied in solvent. This study demonstrates that EOs of plants in family Rutaceae are a potential resource to develop new larvicides, and nanoemulsification is an effective method for improving the physicochemical properties and efficacy of natural products as larvicides.

Ligand and structure-based approaches for the exploration of structure-activity relationships of fusidic acid derivatives as antibacterial agents.

Introduction: Fusidic acid (FA) has been widely applied in the clinical prevention and treatment of bacterial infections. Nonetheless, its clinical application has been limited due to its narrow antimicrobial spectrum and some side effects. Purpose: Therefore, it is necessary to explore the structure-activity relationships of FA derivatives as antibacterial agents to develop novel ones possessing a broad antimicrobial spectrum. Methods and result: First, a pharmacophore model was established on the nineteen FA derivatives with remarkable antibacterial activities reported in previous studies. The common structural characteristics of the pharmacophore emerging from the FA derivatives were determined as those of six hydrophobic centers, two atom centers of the hydrogen bond acceptor, and a negative electron center around the C-21 field. Then, seven FA derivatives have been designed according to the reported structure-activity relationships and the pharmacophore characteristics. The designed FA derivatives were mapped on the pharmacophore model, and the Qfit values of all FA derivatives were over 50 and FA-8 possessed the highest value of 82.66. The molecular docking studies of the partial target compounds were conducted with the elongation factor G (EF-G) of S. aureus. Furthermore, the designed FA derivatives have been prepared and their antibacterial activities were evaluated by the inhibition zone test and the minimum inhibitory concentration (MIC) test. The derivative FA-7 with a chlorine group as the substituent group at C-25 of FA displayed the best antibacterial property with an MIC of 3.125 µM. Subsequently, 3D-QSAR was carried on all the derivatives by using the CoMSIA mode of SYBYL-X 2.0. Conclusion: Hence, a computer-aided drug design model was developed for FA, which can be further used to optimize FA derivatives as highly potent antibacterial agents.

Enantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205.

Synthetic endoperoxide antimalarials, such as 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes, are promising successors for current front-line antimalarials, semisynthetic artemisinin derivatives. However, limited solubility of second-generation analogues in biological-relevant media represents a barrier in clinical development. We present methodology for the synthesis of nonlinear analogues of second-generation tetraoxane antimalarials E209 and N205 to investigate reduced molecular symmetry on in vitro antimalarial activity and physicochemical properties. While maintaining good antimalarial activity and metabolic stability, head-to-head comparison of linear and nonlinear counterparts showed up to 10-fold improvement in FaSSIF solubility for three of the four analogues studied. Pharmacokinetic studies in rats comparing a selected nonlinear analogue 14a and its parent N205 showed improvement on oral absorption and exposure in vivo with more than double the AUC and a significant increase in oral bioavailability (76% versus 41%). These findings provide support for further in vivo efficacy studies in preclinical animal species.

Chemical Composition, Antimicrobial and Insecticidal Activities of Essential Oils of Discarded Perfume Lemon and Leaves (Citrus Limon (L.) Burm. F.) as Possible Sources of Functional Botanical Agents.

Two essential oils were isolated from discarded perfume lemon and leaves (Citrus limon (L.) Burm. F.) by hydro-distillation with good yield (0.044% for perfume lemon and 0.338% for leaves). Their biological activities were evaluated against five selected bacterial strains and Aedes albopictus (Ae. albopictus, Diptera: Culicidae). Chemical composition indicated that both essential oils were rich in essential phytochemicals including hydrocarbons, monoterpenes and sesquiterpene. These constituents revealed some variability among the oils displaying interesting chemotypes (R)-(+)-limonene (12.29-49.63%), citronellal (5.37-78.70%) and citronellol (2.98-7.18%). The biological assessments proved that the two essential oils had similar effect against bacterial (inhibition zones diameter ranging from 7.27 ± 0.06 to 10.37 ± 0.15 mm; MICs and MBCs ranging from 1.6 to 6.4 mg/mL); against Ae. albopictus larvae (LC50 ranging from 384.81 to 395.09 ppm) and adult mosquito (LD50 ranging from 133.059 to 218.962 µg/cm2); the activity of the two chemotypes ((R)-(+)-limonene and citronellal): larvae (LC50 ranging from 267.08 to 295.28 ppm), which were all presented in dose-dependent manners. Through this work, we have showcased that recycling and reusing of agriculture by-products, such as discarded perfume lemon and leaves can produce eco-friendly alternatives in bacterial disinfectants and mosquito control product.

Synthesis and biological evaluation of pentacyclic triterpenoid derivatives as potential novel antibacterial agents.

A series of ursolic acid (UA), oleanolic acid (OA) and 18ß-glycyrrhetinic acid (GA) derivatives were synthesized by introducing a range of substituted aromatic side-chains at the C-2 position after the hydroxyl group at C-3 position was oxidized. Their antibacterial activities were evaluated in vitro against a panel of four Staphylococcus spp. The results revealed that the introduction of aromatic side-chains at the C-2 position of GA led to the discovery of potent triterpenoid derivatives for inhibition of both drug sensitive and resistant S. aureus, while the other two series derivatives of UA and OA showed no significant antibacterial activity even at high concentrations. In particular, GA derivative 33 showed good potency against all four Staphylococcus spp. (MIC = 1.25-5 µmol/L) with acceptable pharmacokinetics properties and low cytotoxicity in vitro. Molecular docking was also performed using S. aureus DNA gyrase to rationalize the observed antibacterial activity. This series of GA derivatives has strong potential for the development of a new type of triterpenoid antibacterial agent.

Therapeutic Potential of Nitazoxanide: An Appropriate Choice for Repurposing versus SARS-CoV-2?

The rapidly growing COVID-19 pandemic is the most serious global health crisis since the "Spanish flu" of 1918. There is currently no proven effective drug treatment or prophylaxis for this coronavirus infection. While developing safe and effective vaccines is one of the key focuses, a number of existing antiviral drugs are being evaluated for their potency and efficiency against SARS-CoV-2 in vitro and in the clinic. Here, we review the significant potential of nitazoxanide (NTZ) as an antiviral agent that can be repurposed as a treatment for COVID-19. Originally, NTZ was developed as an antiparasitic agent especially against Cryptosporidium spp.; it was later shown to possess potent activity against a broad range of both RNA and DNA viruses, including influenza A, hepatitis B and C, and coronaviruses. Recent in vitro assessment of NTZ has confirmed its promising activity against SARS-CoV-2 with an EC50 of 2.12 µM. Here we examine its drug properties, antiviral activity against different viruses, clinical trials outcomes, and mechanisms of antiviral action from the literature in order to highlight the therapeutic potential for the treatment of COVID-19. Furthermore, in preliminary PK/PD analyses using clinical data reported in the literature, comparison of simulated TIZ (active metabolite of NTZ) exposures at two doses with the in vitro potency of NTZ against SARS-CoV-2 gives further support for drug repurposing with potential in combination chemotherapy approaches. The review concludes with details of second generation thiazolides under development that could lead to improved antiviral therapies for future indications.

Design, synthesis and α-glucosidase inhibition study of novel embelin derivatives.

Embelin is a naturally occurring para-benzoquinone isolated from Embelia ribes (Burm. f.) of the Myrsinaceae family. It was first discovered to have potent inhibitory activity (IC50 = 4.2 µM) against α-glucosidase in this study. Then, four series of novel embelin derivatives were designed, prepared and evaluated in α-glucosidase inhibition assays. The results show that most of the embelin derivatives synthesised are effective α-glucosidase inhibitors, with IC50 values at the micromolar level, especially 10d, 12d, and 15d, the IC50 values of which are 1.8, 3.3, and 3.6 µM, respectively. Structure-activity relationship (SAR) studies suggest that hydroxyl groups in the 2/5-position of para-benzoquinone are very important, and long-chain substituents in the 3-position are highly preferred. Moreover, the inhibition mechanism and kinetics studies reveal that all of 10d, 12d, 15d, and embelin are reversible and mixed-type inhibitors. Furthermore, docking experiments were carried out to study the interactions between 10d and 15d with α-glucosidase.