Potentiating-antibiotic activity and absorption, distribution, metabolism, excretion and toxicity properties (ADMET) analysis of synthetic thiadiazines against multi-drug resistant (MDR) strains.

BACKGROUND: Thiadiazines are heterocyclic compounds that contain two nitrogen atoms and one sulfur atom in their structure. These synthetic molecules have several relevant pharmacological activities, such as antifungal, antibacterial, and antiparasitic. OBJECTIVES: The present study aimed to evaluate the possible in vitro and in silico interactions of compounds derived from thiadiazines. METHODS: The compounds were initially synthesized, purified, and confirmed through HPLC methodology. Multi-drug resistant bacterial strains of Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to evaluate the direct and modifying antibiotic activity of thiadiazine derivatives. ADMET assays (absorption, distribution, metabolism, excretion, and toxicity) were conducted, which evaluated the influence of the compounds against thousands of macromolecules considered as bioactive targets. RESULTS: There were modifications in the chemical synthesis in carbon 4 or 3 in one of the aromatic rings of the structure where different ions were added, ensuring a variability of products. It was possible to observe results that indicate the possibility of these compounds acting through the cyclooxygenase 2 mechanism, which, in addition to being involved in inflammatory responses, also acts by helping sodium reabsorption. The amine group present in thiadiazine analogs confers hydrophilic characteristics to the substances, but this primary characteristic has been altered due to alterations and insertions of other ligands. The characteristics of the analogs generally allow easy intestinal absorption, reduce possible hepatic toxic effects, and enable possible neurological and anti-inflammatory action. The antibacterial activity tests showed a slight direct action, mainly of the IJ23 analog. Some compounds were able to modify the action of the antibiotics gentamicin and norfloxacin against multi-drug resistant strains, indicating a possible synergistic action. CONCLUSIONS: Among all the results obtained in the study, the relevance of thiadiazine analogs as possible coadjuvant drugs in the antibacterial, anti-inflammatory, and neurological action with low toxicity is clear. Need for further studies to verify these effects in living organisms is not ruled out.

Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators.

The synthesis and biological evaluation on AMPA and kainate receptors of new examples of 3,4-dihydro-2H-1,2,4-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxides is described. The introduction of a cyclopropyl chain instead of an ethyl chain at the 4-position of the thiadiazine ring was found to dramatically improve the potentiator activity on AMPA receptors, with compound 32 (BPAM395) expressing in vitro activity on AMPARs (EC2x = 0.24 µM) close to that of the reference 4-cyclopropyl-substituted benzothiadiazine dioxide 10 (BPAM344). Interestingly, the 4-allyl-substituted thienothiadiazine dioxide 27 (BPAM307) emerged as the most promising compound on kainate receptors being a more effective potentiator than the 4-cyclopropyl-substituted thienothiadiazine dioxide 32 and supporting the view that the 4-allyl substitution of the thiadiazine ring could be more favorable than the 4-cyclopropyl substitution to induce marked activity on kainate receptors versus AMPA receptors. The thieno-analogue 36 (BPAM279) of the clinically tested S18986 (11) was selected for in vivo evaluation in mice as a cognitive enhancer due to a safer profile than 32 after massive per os drug administration. Compound 36 was found to increase the cognition performance in mice at low doses (1 mg/kg) per os suggesting that the compound was well absorbed after oral administration and able to reach the central nervous system. Finally, compound 32 was selected for co-crystallization with the GluA2-LBD (L504Y,N775S) and glutamate to examine the binding mode of thienothiadiazine dioxides within the allosteric binding site of the AMPA receptor. At the allosteric site, this compound established similar interactions as the previously reported BTD-type AMPA receptor modulators.

Synthesis and biological evaluation of novel 5-substituted/unsubstituted triazolothiadiazines as tubulin depolymerizing and vascular disrupting agents with promising antitumor activity.

A novel series of 5-substituted/unsubstituted [1,2,4]triazolo[3,4-b][1,3,4] thiadiazine compounds has been achieved successfully through chemoselective reduction of the C = N bond, based on our prior work. Initial biological evaluation illustrated that the most active derivative 7j exhibited significant cell growth inhibitory activity toward MCF-7, A549, HCT116, and A2780 with the IC50 values of 0.75, 0.94, 2.90, and 4.15 µM, respectively. Most importantly, all the representative analogs did not demonstrate obvious cytotoxic activity against the non-tumoural cell line HEK-293 (IC50 > 100 µM). The mechanism study revealed that 7j caused the G2 /M phase arrest, induced cell apoptosis in HeLa cells in a concentration-dependent manner, and also showed potent tubulin polymerization inhibitory effect. Meanwhile, 7j exerted significant antivascular activity in the wound-healing and tube formation assays. These observations indicate that 5-unsubstituted 6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine scaffold might be considered as a potential lead for antitubulin inhibitors to develop highly efficient anticancer agents with potent selectivity over normal human cells.

New insights in the development of positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides: Introduction of (mono/difluoro)methyl groups at the 2-position of the thiadiazine ring.

Positive allosteric modulators of the AMPA receptors (AMPAR PAMs) have been proposed as new drugs for the management of various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder, depression, and schizophrenia. The present study explored new AMPAR PAMs belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides (BTDs) characterized by the presence of a short alkyl substituent at the 2-position of the heterocycle and by the presence or absence of a methyl group at the 3-position. The introduction of a monofluoromethyl or a difluoromethyl side chain at the 2-position instead of the methyl group was examined. 7-Chloro-4-cyclopropyl-2-fluoromethyl-3,4-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (15e) emerged as the most promising compound associating high in vitro potency on AMPA receptors, a favorable safety profile in vivo and a marked efficacy as a cognitive enhancer after oral administration in mice. Stability studies in aqueous medium suggested that 15e could be considered, at least in part, as a precursor of the corresponding 2-hydroxymethyl-substituted analogue and the known AMPAR modulator 7-chloro-4-cyclopropyl-3,4-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (3) devoid of an alkyl group at the 2-position.

One pot domino synthesis of new 3,5-disubstituted-tetrahydro-2H-1,3,5-thiadiazine-2-thiones (THTTs) as anti-inflammatory and antinociceptive candidates: A proof from in-vivo to in-vitro and in-silico mechanistic studies.

A series of alkyl/aryl/aralkylamines or amino acids appended tetrahydro-2H-1,3,5-thiadiazine-2-thiones (4a-i, 5a-g, 6 and 7) were synthesized via one pot domino synthesis. The synthesis involved reacting alkyl/aryl/aralkylamines or amino acids with carbon disulfide employing basic aqueous medium and further cyclization with formaldehyde and alkyl/aryl/aralkylamines or amino acids. In addition, the carboxy-functionalized 1,3,5-thiadiazine-2-thione 6 was further subjected to esterification. All the structures were confirmed through spectral techniques i.e IR, 1H NMR, 13C NMR, and MS analysis. Furthermore, the newly synthesized compounds were biologically assessed via in vitro COX-2 and 5-LOX assays, in vivo anti-nociceptive and anti-inflammatory activities. Among the screened compounds, 6, 5f, and 7 exhibited highest inhibitory potency against COX-2 with IC50 values of 11.96, 13.54, and 13.93 µM, respectively. Moreover, compounds 6 and 7 exhibited excellent inhibitory potential against 5-LOX with IC50 values of 14.01 and 14.13 µM. The in-vivo anti-inflammatory bioassay studies showed that compounds 6, 7 and 5f dramatically reduced the paw edema size at 1 h and 3 h time intervals. In the anti-nociceptive activity, compound 6 showed pain protection comparative to Tramadol in all tested time intervals. In addition, studies of molecular docking revealed the compounds binding modes in the allosteric site of COX-2 and active site of 5-LOX, where these compounds exhibited higher binding scores and good binding interactions.

1,3,5-Thiadiazinane thione derivatives as significant urease inhibitors.

We report the promising urease inhibitory activity of four sets of tetrahydro thiadiazine thiones (THTT) namely 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine thiones: THTT 5-8 (set A) having alkyl/aryl substituents at N-3 and N-5 positions; THTT 9-12 (set B) and THTT 13-14 (set C) with 3-carboxylic acid derivatives and tetrahydro-2H-1,3,5-thiadiazine-6-thione esters 15-16 (set D). Gratifyingly, all four sets of THTT were recognized as promising inhibitors of urease enzyme. Among 12 tested compounds; THTT 6, 8, 10, 14 and 15 from each set respectively, demonstrated significant urease inhibitory activity with IC50 values between 11.2-29.8µM which is mostly found higher than that for thiourea, a standard urease inhibitor with IC50 value of 22.4µM. Furthermore, compound 7 showed almost the same level of inhibition (IC50 = 22.5µM) as of standard. In addition, molecular docking study supported the phenomenon that thiadiazinane ring itself is an active pharmacophore that binds through CH2 groups and S atom via carbon-hydrogen/π-sulfur interactions respectively to the active site of the urease enzyme. The optimistic results from this study suggest the use of thiadiazinane skeleton as a guided template for the advancement of new urease inhibitors in drug discovery.

1-Phenyl ethyl substituted tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives as promising antimicrobial agents.

Seven derivatives of 1-phenyl ethyl group containing 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine-thiones (THTT) were prepared and examined for their antibacterial and antifungal properties by using Microplate Alamar Blue Assay (MABA) and agar tube dilution protocol respectively. In vitro antifungal potential was investigated against five human pathogens and compared with the standard drugs amphotericin B and miconazole. In vitro antibacterial activity was investigated against four pathogens and compared with the ofloxacin. All compounds exhibited very promising antifungal activities against all tested pathogens. Structure activity relationship showed the importance of the presence of 1-phenyl ethyl substituent at N-3 of THTT nucleus for antifungal effects. However, these compounds showed significant antibacterial activity only against S. aureus. The compound 6c of the series was found most active compound that displayed promising antifungal potential against all tested pathogens [Growth Inhibition (GI) = 100%], and also showed promising antibacterial potential against S. aureus (GI% = 83.49) which is very much closer to the standard ofloxacin (GI% = 88.05). The study may be useful in the development of improved antimicrobial agents.

Discovery of ( ±)-3-(1H-pyrazol-1-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazine derivatives with promising in vitro anticoronavirus and antitumoral activity.

A new series of ( ±)-(3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-yl)(phenyl)methanones were efficiently synthesized starting from 4-amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol 1, acetyl acetone 2, various aromatic and heterocyclic aldehydes 3 and phenacyl bromides 4. All the newly synthesized compounds were tested for their antiviral and antitumoral activity. It was shown that subtle structural variations on the phenyl moiety allowed to tune biological properties toward antiviral or antitumoral activity. Mode-of-action studies revealed that the antitumoral activity was due to inhibition of tubulin polymerization.

TAK-653, an AMPA receptor potentiator with minimal agonistic activity, produces an antidepressant-like effect with a favorable safety profile in rats.

The N-methyl-d-aspartate receptor antagonist, ketamine, exhibits rapid and sustained antidepressant activity in patients with treatment-resistant depression (TRD), but its use is associated with psychotomimetic side effects. Evidence has suggested that the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors followed by activation of the mechanistic target of rapamycin (mTOR) signaling pathway and production of brain derived neurotrophic factor (BDNF) protein may underlie the antidepressant efficacy of ketamine. In this study, we characterized the antidepressant-like effects of TAK-653, a novel AMPA receptor potentiator with virtually no agonistic activity. In rat primary cortical neurons, TAK-653 significantly increased phosphorylated and activated forms of mTOR and p70S6 kinase and their upstream regulators Akt and extracellular signal-regulated kinase (ERK). TAK-653 also significantly increased BDNF protein levels in rat primary cortical neurons. Ketamine at 30 mg/kg, i.p. produced antidepressant-like effects in the reduction of submissive behavior model (RSBM) in rats. Ketamine's antidepressant-like effect was blocked by pretreatment with the AMPA receptor antagonist NBQX at 10 mg/kg, i.p., indicating the essential role of AMPA receptor activation in the antidepressant-like effect of ketamine. Consistent with this finding, a sub-chronic administration of TAK-653 for 6 days produced significant antidepressant-like effect in the rat RSBM. Unlike ketamine, however, TAK-653 did not induce a hyperlocomotor response in rats, which is a behavioral index associated with psychotomimetic side effects in humans. TAK-653 may be a promising drug for the treatment of major depressive disorders including TRD with the potential for an improved safety profile compared with ketamine.

Synthesis and Evaluation of Novel 1,2,6-Thiadiazinone Kinase Inhibitors as Potent Inhibitors of Solid Tumors.

A focused series of substituted 4H-1,2,6-thiadiazin-4-ones was designed and synthesized to probe the anti-cancer properties of this scaffold. Insights from previous kinase inhibitor programs were used to carefully select several different substitution patterns. Compounds were tested on bladder, prostate, pancreatic, breast, chordoma, and lung cancer cell lines with an additional skin fibroblast cell line as a toxicity control. This resulted in the identification of several low single digit micro molar compounds with promising therapeutic windows, particularly for bladder and prostate cancer. A number of key structural features of the 4H-1,2,6-thiadiazin-4-one scaffold are discussed that show promising scope for future improvement.

Preparation and Size Control of Efficient and Safe Nanopesticides by Anodic Aluminum Oxide Templates-Assisted Method.

Efficient and safe nanopesticides play an important role in pest control due to enhancing target efficiency and reducing undesirable side effects, which has become a hot spot in pesticide formulation research. However, the preparation methods of nanopesticides are facing critical challenges including low productivity, uneven particle size and batch differences. Here, we successfully developed a novel, versatile and tunable strategy for preparing buprofezin nanoparticles with tunable size via anodic aluminum oxide (AAO) template-assisted method, which exhibited better reproducibility and homogeneity comparing with the traditional method. The storage stability of nanoparticles at different temperatures was evaluated, and the release properties were also determined to evaluate the performance of nanoparticles. Moreover, the present method is further demonstrated to be easily applicable for insoluble drugs and be extended for the study of the physicochemical properties of drug particles with different sizes.

Taurultams incorporating arylsulfonamide: First in vitro inhibition studies of α-, ß- and γ-class Carbonic Anhydrases from Vibrio cholerae and Burkholderia pseudomallei.

A new series of taurultambenzenesulfonamides 1-17 were prepared and considered for their inhibitory activity in vitro against the Carbonic Anhydrases from Vibrio cholerae (VchCA-α, VchCA-ß and VchCA-γ) and Burkholderia pseudomallei (BpsCA-ß and BpsCA-γ). Among the compounds tested, derivatives 4, 5, 7, 10, 12, and 16 resulted in highly effective VchCAα inhibitors (KI values spanning within the 6.1-9.6 nM range) and endowed with excellent Selectivity Indexes (SIs; KI VchCA-α/KI hCA II) all comprised between 0.04 and 0.09. Potent in vitro inhibitors for the BpsCA-γ were also identified (KIs of 18.9-19.5 nM). The results here reported may represent the blueprint for the future development of a new generation of CA-based antibiotics integrated with free of resistance mechanisms of action adopted from known drugs.

Synthesis and evaluation of multi-target-directed ligands with BACE-1 inhibitory and Nrf2 agonist activities as potential agents against Alzheimer's disease.

Cumulative evidence suggests that ß-amyloid and oxidative stress are closely related with each other and play key roles in the process of Alzheimer's disease (AD). Multitarget regulation of both pathways might represent a promising therapeutic strategy. Here, a series of selenium-containing compounds based on ebselen and verubecestat were designed and synthesized. Biological evaluation showed that 13f exhibited good BACE-1 inhibitory activity (IC50 = 1.06 µΜ) and potent GPx-like activity (ν0 = 183.0 µM min-1). Aß production experiment indicated that 13f could reduce the secretion of Aß1-40 in HEK APPswe 293T cells. Moreover, 13f exerted a cytoprotective effect against the H2O2 or 6-OHDA caused cell damage via alleviation of intracellular ROS, mitochondrial dysfunction, Ca2+ overload and cell apoptosis. The mechanism studies indicated that 13f exhibited cytoprotective effect by activating the Keap1-Nrf2-ARE pathway and stimulating downstream anti-oxidant protein including HO-1, NQO1, TrxR1, GCLC, and GCLM. In addition, 13f significantly reduced the production of NO and IL-6 induced by LPS in BV2 cells, which confirmed its anti-inflammatory activity as a Nrf2 activator. The BBB permeation assay predicted that 13f was able to cross the BBB. In summary, 13f might be a promising multi-target-directed ligand for the treatment of AD.

Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites.

The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can also act prophylactically. We report a phenotypic quantitative high-throughput screen (qHTS), based on concentration-response curves, which was designed to identify compounds active against Plasmodium liver and asexual blood stage parasites. Our qHTS screened over 450,000 compounds, tested across a range of 5 to 11 concentrations, for activity against Plasmodium falciparum asexual blood stages. Active compounds were then filtered for unique structures and drug-like properties and subsequently screened in a P. berghei liver stage assay to identify novel dual-active antiplasmodial chemotypes. Hits from thiadiazine and pyrimidine azepine chemotypes were subsequently prioritized for resistance selection studies, yielding distinct mutations in P. falciparum cytochrome b, a validated antimalarial drug target. The thiadiazine chemotype was subjected to an initial medicinal chemistry campaign, yielding a metabolically stable analog with sub-micromolar potency. Our qHTS methodology and resulting dataset provides a large-scale resource to investigate Plasmodium liver and asexual blood stage parasite biology and inform further research to develop novel chemotypes as causal prophylactic antimalarials.

The different modes of chiral [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines: crystal packing, conformation investigation and cellular activity.

The crystal structures of four new chiral [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines are described, namely, ethyl 5'-benzoyl-5'H,7'H-spiro[cyclohexane-1,6'-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3'-carboxylate, C19H22N4O3S, ethyl 5'-(4-methoxybenzoyl)-5'H,7'H-spiro[cyclohexane-1,6'-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3'-carboxylate, C20H24N4O4S, ethyl 6,6-dimethyl-5-(4-methylbenzoyl)-6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine-3-carboxylate, C17H20N4O3S, and ethyl 5-benzoyl-6-(4-methoxyphenyl)-6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine-3-carboxylate, C21H20N4O4S. The crystallographic data and cell activities of these four compounds and of the structures of three previously reported similar compounds, namely, ethyl 5'-(4-methylbenzoyl)-5'H,7'H-spiro[cyclopentane-1,6'-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3'-carboxylate, C19H22N4O3S, ethyl 5'-(4-methoxybenzoyl)-5'H,7'H-spiro[cyclopentane-1,6'-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3'-carboxylate, C19H22N4O4S, and ethyl 6-methyl-5-(4-methylbenzoyl)-6-phenyl-6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine-3-carboxylate, C22H22N4O3S, are contrasted and compared. For both crystallization and an MTT assay, racemic mixtures of the corresponding [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines were used. The main manner of molecular packing in these compounds is the organization of either enantiomeric pairs or dimers. In both cases, the formation of two three-centre hydrogen bonds can be detected resulting from intramolecular N-H...O and intermolecular N-H...O or N-H...N interactions. Molecules of different enantiomeric forms can also form chains through N-H...O hydrogen bonds or form layers between which only weak hydrophobic contacts exist. Unlike other [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines, ethyl 5'-benzoyl-5'H,7'H-spiro[cyclohexane-1,6'-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3'-carboxylate contains molecules of only the (R)-enantiomer; moreover, the N-H group does not participate in any significant intermolecular interactions. Molecular mechanics methods (force field OPLS3e) and the DFT B3LYP/6-31G+(d,p) method show that the compound forming enantiomeric pairs via weak N-H...N hydrogen bonds is subject to greater distortion of the geometry under the influence of the intermolecular interactions in the crystal. For intramolecular N-H...O and S...O interactions, an analysis of the noncovalent interactions (NCIs) was carried out. The cellular activities of the compounds were tested by evaluating their antiproliferative effect against two normal human cell lines and two cancer cell lines in terms of half-maximum inhibitory concentration (IC50). Some derivatives have been found to be very effective in inhibiting the growth of Hela cells at nanomolar and submicromolar concentrations with minimal cytotoxicity in relation to normal cells.

Phytotoxicity of chitosan-based agronanofungicides in the vegetative growth of oil palm seedling.

Although fungicides could be the best solution in combating fungal infections in crops, however, the phytotoxic level of fungicides to the crops should be tested first to ensure that it is safe for the crops. Moreover, nanocarrier systems of fungicides could play a significant role in the advancement of crop protection. For this reason, chitosan was chosen in the present study as a nanocarrier for fungicides of hexaconazole and/or dazomet in the development of a new generation of agronanofungicides with a high antifungal potent agent and no phytotoxic effect. Hence, the encapsulation of fungicides into the non-toxic biopolymer, chitosan was aims to reduce the phytotoxic level of fungicides. In the present study, the in vivo phytotoxicity of chitosan-fungicides nanoparticles on the physiological and vegetative growth of oil palm seedlings was evaluated in comparison to its pure fungicides as well as the conventional fungicides. The results revealed the formation of chitosan-fungicides nanoparticles could reduce the phytotoxic effect on oil palm seedlings compared to their counterparts, pure fungicides. The chitosan-fungicides nanoparticles were seen to greatly reduce the phytotoxic effect compared to the conventional fungicides with the same active ingredient.

Antimicrobial evaluation of thiadiazino and thiazolo quinoxaline hybrids as potential DNA gyrase inhibitors; design, synthesis, characterization and morphological studies.

A series of thiadiazino[5,6-b]quinoxaline and thiazolo[4,5-b]quinoxaline derivatives was designed and synthetized from the reaction of 2,3-dichloro-6-(morpholinosulfonyl)quinoxaline (2) with thiosemicarbazide or thiocarbohydrazide and thiourea derivatives to give nineteen quinoxaline derivatives 3-16. All the synthesized compounds were evaluated for in vitro antimicrobial potential against various bacteria and fungi strains that showed considerable antimicrobial activity against tested microorganisms. The most potent compounds 2, 7, 9, 10, 12 and 13c were exhibited bactericidal activity, in addition to fungistatic activity by dead live assay. Moreover, these compounds showed a significant result against all multi-drug resistance (MDRB) used especially compound 13c that displayed the best results with MICs of MDRB (1.95, 3.9, 2.6, 3.9 µg/mL) for stains used in this study, compared with Norfloxacin (1.25, 0.78, 1.57, 3.13 µg/mL). Also, cytotoxicity on normal cell (Vero cells ATCC CCL-81) by MTT assay was performed with lower toxicity results. Additionally, morphological studies, immunostimulatory potency and DNA gyrase inhibition assay of most active compounds was done. A molecular docking study has also been carried out to support the effective binding of the most promising compounds at the active site of the target enzyme S. aureus DNA gyrase (2XCT).

Chitosan-Based Agronanofungicides as a Sustainable Alternative in the Basal Stem Rot Disease Management.

The rise of environmental and health concerns due to the excessive use of the conventional fungicide urges the search for sustainable alternatives of agronanofungicides where the latter is aimed to enhance plant uptake and minimize the volatilization, leaching, and runoff of fungicides. With this in mind, fungicides of hexaconazole and/or dazomet were encapsulated into chitosan nanoparticles for the formulation of chitosan-based agronanofungicides. In the present study, chitosan nanoparticles (2 nm), chitosan-hexaconazole nanoparticles (18 and 168 nm), chitosan-dazomet nanoparticles (7 and 32 nm), and chitosan-hexaconazole-dazomet nanoparticles (5 and 58 nm) were synthesized and used as potent antifungal agents in combating the basal stem rot (BSR) disease caused by Ganoderma boninense in which they were evaluated via an artificial inoculation of oil palm seedlings with the rubber woodblock, which was fully colonized with the fungal Ganoderma boninense mycelium. The results revealed that chitosan nanoparticles could act as dual modes of action, which are themselves as a biocide or as a nanocarrier for the existing fungicides. In addition, the particle size of the chitosan-based agronanofungicides plays a crucial role in suppressing and controlling the disease. The synergistic effect of the double-fungicide system of 5 nm chitosan-hexaconazole-dazomet nanoparticles can be observed as the system showed the highest disease reduction with 74.5%, compared to the untreated infected seedlings.

Synthesis and docking study of benzimidazole-triazolothiadiazine hybrids as aromatase inhibitors.

Aromatase is involved in the biosynthesis of estrogen and thus is a critical target for breast cancer. In this study, to identify new aromatase enzyme inhibitors, seven 3-[4-(5-methyl-1H-benzo[d]imidazol-2-yl)phenyl]-6-(substituted phenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives were synthesized. First, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to determine the inhibitory activity of the synthesized compounds on the MCF-7 cell line. The aromatase inhibitory activity was determined for the active compounds 5b, 5c, 5e, and 5g on the MCF-7 cell line. Compound 5g showed significant aromatase inhibitory activity (IC50 = 0.037 ± 0.001 µM). Interestingly, this compound, which bears a difluoro substituent at positions 2 and 4 of the phenyl ring, displayed the most potent aromatase inhibitory activity without significant cytotoxicity to a normal healthy cell line (NIH3T3). Furthermore, the interactions between the best active compounds and the active site of the enzyme were analyzed through a docking study. The results of this study determined that benzimidazole-triazolothiadiazine derivatives are promising compounds that should be further developed as a novel class of aromatase inhibitors.

Effects of Dazomet Fumigation on Soil Phosphorus and the Composition of phoD-Harboring Microbial Communities.

The soil phosphorus (P) cycle and P transformation are largely driven by the soil bacterial microbial community. However, little is known about the effects of dazomet (DZ) soil fumigation on soil P and soil microbial communities associated with P transformation. This research investigated P released from three farm soils as a result of DZ fumigation and changes in enzyme activity, gene abundance, and the encoding alkaline phosphatase PhoD microbial community. After DZ fumigation, we observed a briefly significant increase in the available P and the active P fractionation. The soil ALP activity, 16s rRNA abundance, and the phoD gene decreased significantly after DZ fumigation. The abundance and diversity of phoD-harboring microbes also decreased shortly after fumigation, increased significantly 14-28 days later, and then decreased again toward the end of the experimental period of 86 days. The shared OTUs between treatments became fewer with increasing time after fumigation. The changes in available P and the active P fractionation after DZ fumigation were significantly correlated with the abundance of the dominant phoD-harboring microbes. DZ fumigation promoted P mineralization in these farm soils and changed the composition of phoD-harboring microbial communities, which will benefit crops able to absorb and use P.