Compounds 4j Research Articles

Design and evaluation of novel inhibitors for the treatment of clear cell renal cell carcinoma

The efficacy of conventional chemotherapies in treating clear cell renal cell carcinoma (ccRCC) is often limited due to its high molecular diversity, generally low response rates to standard treatments, and prevalent drug resistance. Recent advancements in the molecular understanding of ccRCC, alongside the discovery of novel therapeutic agents targeting specific proteins, have significantly altered the treatment landscape for ccRCC. Here, we synthesized 27 new compounds that are derivatives of TG-101209 to modulate BUB1B (BUB1 mitotic checkpoint serine/threonine kinase B). BUB1B has been recently identified as a drug target for the development of effective ccRCC treatment based on global transcriptomics profiling of ccRCC tumours and gene co-expression network analysis. We characterized the molecular structures of these 27 compounds by 1H and 13C NMR and Mass spectrometry. We evaluated the effect of these 27 compounds by analysing the modulation of the BUB1B expression. Our primary objective was to design and assess the efficacy of these new compounds in reducing the viability of Caki-1 cells, a ccRCC cell line. We performed the computational docking studies by the Schrödinger Maestro software and demonstrated that three of these compounds (13a, 5i, and 5j) effectively downregulated BUB1B expression and eventually triggered necrosis and apoptosis in the Caki-1 cell line based on the structure–activity relationship (SAR) analysis. The IC50 values for compounds 13a, 5i, and 5j were calculated as 2.047 µM, 10.046 µM, and 6.985 µM, respectively, indicating their potent inhibitory effects on cell viability. Our study suggests that these compounds targeting BUB1B could offer a more effective and promising approach for ccRCC treatment compared to the conventionally used tyrosine kinase inhibitors. Our study underscores the potential of leveraging targeted therapies against specific molecular pathways in ccRCC may open new avenues for the development of effective treatment strategies against ccRCC.

Design, synthesis and biological evaluation of aryl isoxazole incorporated pyrimidin-2-yl)oxazolo[4,5-b]pyridine derivatives as anticancer agents

A new library of Aryl Isoxazole Incorporated Pyrimidin-2-yl)oxazolo[4,5-b]pyridine compounds 11a-j and their structures were characterized by analytical data. Further, the preliminary anticancer activity of the newly prepared compounds 11a-j was examined against four types of human cancer cell lines, breast cancer (MCF-7), lung cancer (A549), colon cancer (Colo-205) and ovarian cancer (A2780) by utilizing the MTT method. Most of the compounds displayed good to moderate activities as compared with the etoposide used as a positive control. Amon, five compounds 11a, 11b, 11h, 11i and 11j exhibited more potent activity than the positive control. Mainly, compound 11h displayed superior anticancer activity.

Copper-Vit B3 MOF preparation, characterization and catalytic evaluation in a one-pot synthesis of benzoxanthenones with docking validation as anti H. pylori.

Copper-Vit B3 MOF was successfully prepared by efficient and eco hydrothermal method. The prepared MOF was characterized as a tetragonal crystal copper-MOF nanoparticles by FTIR, SEM, TEM, EDX and XRD. The prepared nanoparticles were used as an effective, inexpensive and low-toxic catalyst in the one-pot synthesis of some new benzoxanthenone derivatives. As example 4-(9,9-dimethyl-11-oxo-8,10,11,12-tetrahydro-9H-benzo[a]xanthen-12-yl)phenyl benzoate (4h) was synthesized in high yield 92%. The MOF catalyst's role is activating the nucleophilic attack by increasing the carbonyl polarization, and this generally improves the reaction time, which ranges between 20-60 minutes and products' yields ranging between 80-92%. Prepared compounds (4a-4j) undergo molecular docking scanning as Helicobacter pylori type II dehydroquinase inhibitors, and the data obtained showed that there are three promises of the prepared compounds 4d, 4e, 4h and 4j compared with amoxicillin.

Discovery of Highly Selective, Potent, Covalent, and Orally Bioavailable Factor XIIa Inhibitors for the Treatment of Thrombo-Inflammation.

Thrombo-inflammation is closely associated with a few severe cardiovascular and infectious diseases. Factor XIIa (FXIIa) in the intrinsic coagulation pathway plays a pivotal role in the development of thrombo-inflammation and its inhibition has emerged as a potential therapeutic approach for thrombo-inflammatory disorders. Nonetheless, as of now, few small-molecule FXIIa inhibitors have demonstrated notable effectiveness against thrombo-inflammation, with none progressing into clinical stages. Herein, we present potent, covalent, reversible, and selective small-molecule FXIIa inhibitors such as 4a and 4j obtained through structure-based drug design. Compounds 4a and 4j showed significant anticoagulation and substantial anti-inflammatory effects in vitro, coupled with exceptional plasma stability. Furthermore, in carrageenan-induced thrombosis models, 4a and 4j demonstrated remarkable dual antithrombotic and anti-inflammatory activity when administered orally. Compound 4j exhibited a favorable safety profile without obvious tissue toxicity in mice, suggesting its potential as an oral therapeutic option for thrombo-inflammation.

Discovery of cinnamamide/ester triazole hybrids as potential treatment for Alzheimer’s disease

Developing multitargeted ligands as promising therapeutics for Alzheimer’s disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aβ-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aβ toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood–brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aβ deposition in Aβ1–42-injured mice. Mechanistically, the compound regulated APP processing by promoting the ADAM10-associated nonamyloidogenic signaling and inhibiting the BACE1-mediated amyloidogenic pathway. Moreover, it suppressed intracellular AChE activity and tau phosphorylation. Therefore, compound 4j may be a promising multitargeted active molecule against AD.

Quantum chemical modelling, molecular docking, synthesis and experimental anti-microbial activity of 1,4-diazepan linked piperidine derivative

BackgroundIn this work, we represent synthesis, in silico analysis and biological activity of 1,4 diazepine linked piperidine derivatives (6a–6o). All the derivatives were screened for their anti-microbial activity against gram-positive (Staphylococcus aureus, Bacillus Subtills, Bacillus megaterium) and gram-negative (Escherichia coli, Pseudonymous, Shigella sp.) bacteria. Compounds were synthesized from reaction of tert-butyl 1,4-diazepane-1-carboxylic, butyryl chloride and varied aromatic aldehyde, further characterized by 1H NMR and LCMS spectral techniques.ResultUsing ampicillin as a positive control, the synthetic compounds 6a–6o were tested for their in-silico study and experimental anti-microbial activity against gram-positive (Staphylococcus aureus, Bacillus Subtills, Bacillus megaterium) and gram-negative (Escherichia coli, Pseudonymous, Shigella sp.) bacteria. According to in vitro assay compound 6a, compound 6c, compound 6d, compound 6m and compound 6I showed higher activity against all the tested strains. Molecule 6i, compound 6j, compound 6k, compound 6f has good to moderate antibacterial activity. DFT computations were used to optimize the molecular geometry at the B3LYP/6-31G (d, p) theoretical level. The corresponding energy values of molecular orbitals were visualized using optimized geometries. Moreover, Auto Dock Vina 1.2.0 is used to assess molecular docking against two target proteins, Bacillus subtilis (PDB ID: 6UF6) and Protease Vulgaris (PDB ID: 5HXW). The target molecule 6b displayed the best binding energies for both. Additionally, we calculated the ADME for each molecule (6a–6o).ConclusionAll fifteen synthesized compounds were screened for their in vitro and in silico analysis. In vitro analysis for anti-microbial activity was carried out against gram-positive (Staphylococcus aureus, Bacillus Subtills, Bacillus megaterium) and gram-negative (Escherichia coli, Pseudonymous, Shigella sp.) bacteria and compound 6a, compound 6c, compound 6d, compound 6m and compound 6I exhibits more potent activity towards all tested strains. Molecular docking is performed against target proteins, L-amino acid deaminase from Proteus Vulgaris and LcpA ligase from Bacillus subtilis, representing the Gram-negative bacterium and Gram-positive bacterium, respectively. Compound 6b showed the highest no. of interaction with protein according to molecular docking. With the advent of innovative techniques like ADME, we select their hit compounds early on and anticipate future pharmacokinetic and pharmacodynamic benefits and drawbacks of these promising therapeutic candidates.Graphical abstract

Design, synthesis and pharmacological evaluation of novel thiazole derivatives as c-Met kinase inhibitors and anticancer agents

In search of novel anticancer agents, the design and synthesis of novel sixteen thiazole derivatives (7a-p) have been reported along with their characterization using 1H NMR, 13C NMR, FT-IR, MS, and HPLC. All the synthesized compounds were evaluated against c-Met kinase, followed by anticancer evaluation of the most promising compounds using the MTT assay. The results of these studies identified compound 7a with an IC50 value of 0.4 nM against c-Met kinase along with good anticancer activity against HT29 (IC50 = 7.79 µM, SI of 6.33) and MDA-MB-231 (IC50 = 5.78 µM, SI of 8.65) cancer cell lines. In order to study the in-depth binding interactions of all the synthesized compounds at the active site of c-Met kinase using molecular docking, the typical U-shaped bent conformation of the identified compounds was predicted for all synthesized compounds. Compounds 7a and 7j were found with the best binding energy of −7.98 and −8.26 kcal/mol, respectively. The present work has led to the start-point in the design and discovery of thiazole derivatives as novel c-Met kinase inhibitors and potential anticancer agents.

Organo Mediated Sustainable Synthesis and In‐Silico Studies of Novel Benzisoxazole‐Chromene Acyl Hydrazones as AChE Inhibitors

AbstractA new class of benzisoxazole‐Chromene (BC) analogues containing acyl hydrazones BCA (5a‐5m) were obtained by the condensation of different benzo hydrazides with BCs in good yield. All the synthesized BCA analogues were evaluated for their in‐silico activity against Acetylcholine Esterase (AChE). According to docking experiments, the co‐crystallized ligand was outperformed by derivatives 5e (4‐benzisoxazole‐chromene‐3‐(4hydroxyphenyl) acrylohydrazide), 5m (7‐chloro,4‐hydroxy) and 5l (8‐methyl, m‐nitro) showed superior binding modes and binding free energies whereas compound 5j (8‐methyl, 4‐hydroxy) showed appropriate binding energy. These moieties containing acyl hydrazone has shown 4‐fold increase in the binding interactions and orientation. According to ADMET and toxicity studies, derivatives 5e, 5m, 5j, and 5l had the potential to be drugs and have proven to be safe when evaluated using seven toxicity models. Further on checking selectivity with the other cholinesterase enzyme, 5l came out to be selective towards AChE whereas 5e & 5j were acting on another target as well. Finally, DFT analysis validated the binding of the derivatives towards AChE and moreover Molecular Dynamic investigation revealed that 5l is the most capable candidate to interact with the target receptor by comparing its molecular orbital energies, molecular electrostatic potential maps, and ligand movement against the co‐crystallized Ligand.

Design, synthesis, and anti-oomycete activity of 3-acyloxymaltol/ethyl maltol derivatives

Twenty 3-acyloxymaltol/ethyl maltol derivatives (7a-j and 8a-j) were synthesized and evaluated in vitro for their anti-oomycete activity against Phytophthora capsici, respectively. Among all of twenty derivatives, more than half of the compounds 7f, 7h, 8a-h and 8j had anti-oomycete activity higher than the positive control zoxamide (EC50 = 22.23 mg/L), and the EC50 values of 18.66, 20.32, 12.80, 16.18, 10.59, 14.98, 16.80, 10.36, 15.32, 12.64, and 13.59 mg/L, respectively. Especially, compounds 8c and 8f exhibited the best anti-oomycete activity against P. capsici with EC50 values of 10.59 and 10.36 mg/L, respectively. Overall, hydroxyl group of maltol/ethyl maltol is important active modification site.

Design, Synthesis, and Cytotoxic Assessment of New Haloperidol Analogues as Potential Anticancer Compounds Targeting Sigma Receptors.

Sigma receptors (SRs), including SR1 and SR2 subtypes, have attracted increasing interest in recent years due to their involvement in a wide range of activities, including the modulation of opioid analgesia, neuroprotection, and potential anticancer activity. In this context, haloperidol (HAL), a commonly used antipsychotic drug, also possesses SR activity and cytotoxic effects. Herein, we describe the identification of novel SR ligands, obtained by a chemical hybridization approach. There wereendowed with pan-affinity for both SR subtypes and evaluated their potential anticancer activity against SH-SY5Y and HUH-7 cancer cell lines. Through a chemical hybridization approach, we identified novel compounds (4d, 4e, 4g, and 4j) with dual affinity for SR1 and SR2 receptors. These compounds were subjected to cytotoxicity testing using a resazurin assay. The results revealed potent cytotoxic effects against both cancer cell lines, with IC50 values comparable to HAL. Interestingly, the cytotoxic potency of the novel compounds resembled that of the SR1 antagonist HAL rather than the SR2 agonist siramesine (SRM), indicating the potential role of SR1 antagonism in their mechanism of action. The further exploration of their structure-activity relationships and their evaluation in additional cancer cell lines will elucidate their therapeutic potential and may pave the way for the development of novel anticancer agents that target SRs.

Synthesis of new N-(5,6-methylenedioxybenzothiazole-2-yl)-2-[(substituted)thio/piperazine]acetamide/propanamide derivatives and evaluation of their AChE, BChE, and BACE-1 inhibitory activities.

In this study, the synthesis of N-(5,6-methylenedioxybenzothiazole-2-yl)-2-[(substituted)thio/piperazine]acetamide/propanamide derivatives (3a-3k) and to investigate their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β-secretase 1 (BACE-1) inhibition activity were aimed. Mass, 1H NMR, and 13C NMR spectra were utilized to determine the structure of the synthesized compounds. Compounds 3b, 3c, 3f, and 3j showed AChE inhibitory activity which compound 3c (IC50 = 0.030 ± 0.001 µM) showed AChE inhibitory activity as high as the reference drug donepezil (IC50 = 0.0201 ± 0.0010 µM). Conversely, none of the compounds showed BChE activity. Compounds 3c and 3j showed the highest BACE-1 inhibitory activity and IC50 value was found as 0.119 ± 0.004 µM for compound 3j whereas IC50 value was 0.110 ± 0.005 µM for donepezil, which is one of the reference substance. Molecular docking studies have been carried out using the data retrieved from the server of the Protein Data Bank (PDBID: 4EY7 and 2ZJM). Using in silico approach behavior active compounds (3c and 3j) and their binding modes clarified.

Newly synthesized based Schiff of phenylferrocene: Molecular and crystal structures, Density Functional Theory calculations, Hirshfeld surface analyses, and improved molecular docking data

In three steps, ferrocene-derived Schiff bases were synthesized, beginning with an arylation reaction, followed by a reduction reaction. The last step describes a condensation reaction between 4-ferrocenylaniline 2a and various aromatic aldehydes in ethanol under reflux. Several techniques were used to determine the structures of the prepared compounds, including 1HNMR , 13CNMR , FTIR, UV/Vis and single crystal X-ray diffraction for compounds 3a, 3f, and 3j. Hirshfeld surface analysis measurements were also performed to measure the interaction energies between molecules. Moreover, the geometric structure of the selected compound (3a, 3f, and 3j) was optimized using a computational analysis involving density functional theory (DFT) calculations based on B3LYP/6–31 G (d, p). Strong binding affinities were observed via both hydrophobic and H-bond interactions with pertinent molecules when molecular docking investigations were conducted on the target crystal structure, the FabX (7e1q). The maximum binding energy is found in the 3d, at -7.99 kcal/mol. Therefore, it is feasible that this structure will work well as a potential lead structure for the synthesis and design of stronger inhibitors that can be used in conjunction with anti-corrosive drugs to treat gastric cancer.

Insight on Some Newly Synthesized Trisubstituted Imidazolinones as VEGFR-2 Inhibitors.

Two series of ten new 1,2,4-trisubstituted imidazolin-5-ones were synthesized and screened against MCF-7 breast cancer and A549 lung cancer cell lines to test their potential in vitro anticancer activity. The results revealed preferential activity of the tested compounds toward MCF-7 cell lines compared to A549 cell lines. The most promising ten compounds (3a, 3c, 3f, 3g, 3h, 3i, 3j, 6a, 6f, and 6i) were subjected to VEGFR-2 enzyme inhibitory activity testing to further explore their mechanism of action. The tested compounds showed remarkable enzyme inhibition in micromolar concentrations ranging from 0.07 to 0.36 μM, compared with Sorafenib and Sunitinib with IC50 values of 0.06 and 0.12 μM, respectively. The most promising candidate, 3j, was further evaluated for its cell cycle phases, apoptotic induction ability, as well as its antiproliferative activity and inhibitory potential for endothelial cell migration, analyzed by a cell scratch assay. Furthermore, in silico studies were also performed to identify and detect the stability of the binding poses.

Novel hybrid benzoisothiazole-1,2,3-triazole-4-carboxamides with sub-micromolar toxicity towards human breast carcinoma cells and high affinity to DNA

A pharmacophore hybridization strategy to combine biologically active scaffolds was implemented for design and synthesis of benzoisothiazole-1,2,3-triazole-4-carboxamide conjugates via piperazine linker. In vitro screening led to identification of the compounds 5h and 5j, with para-chlorine- or fluorine- substitution on the phenyl ring, and isopropyl or cyclopropyl substituents in position 5 of 1,2,3-triazole cycle as potent anticancer agents. These compounds demonstrated toxicity towards human breast adenocarcinoma cells of the MCF-7 line in sub-micromolar concentrations with IC50 = 0.76 ± 0.04 μM and 0.90 ± 0.02 μM, respectively, while showing no toxicity in normal cells (IC50 > 100 μM). Colony formation and proliferation of carcinoma MCF-7 cells were effectively inhibited by the derivatives 5h and 5j. These derivatives caused DNA fragmentation of the MCF-7 cells. We suggest that the DNA-damaging action of the compounds 5h and 5j may be related to their high capability of intercalating into DNA molecule that is comparable to such ability of known anticancer agent – the doxorubicin. High affinity of the compounds 5h and 5j for the DNA was confirmed using computational molecular docking in silico.

Studies on Methylpyrazole-Substituted Benzimidazoles to Target Helicobacter pylori Infection through HpIMPDH Inhibition.

The prevalence of Helicobacter pylori infection has been increasing rapidly due to the genetic heterogeneity and antibacterial resistance shown by the bacteria, affecting over 50% of the world population and over 80% of the Indian population, in particular. In this regard, novel drug targets are currently being explored, one of which is the crucial metabolic enzyme inosine-5'-monophosphate dehydrogenase (IMPDH) involved in the de novo nucleotide biosynthesis pathway, in order to combat the infection and devise efficient therapeutic strategies. The present study reports the development of methylpyrazole-substituted benzimidazoles as small molecule inhibitors of H. pylori IMPDH with a nanomolar range of enzyme inhibition. A set of 19 small molecules have been designed, synthesized, and further evaluated for their inhibitory potential against H. pylori IMPDH using in silico, in vitro, biochemical, and biophysical techniques. Compound 7j was found to inhibit H. pylori IMPDH with an IC50 value of 0.095 ± 0.023 μM, which is close to 1.5-fold increase in the inhibitory activity, in comparison to the previously reported benzimidazole-based hit C91. Moreover, kinetic characterization has provided significant insights into the uncompetitive inhibition shown by these small molecules on H. pylori IMPDH, thus providing details about the enzyme inhibition mechanism. In conclusion, methylpyrazole-based small molecules indicate a promising path to develop cheap and bioavailable drugs to efficiently treat H. pylori infection in the coming years, in comparison to the currently available therapy.

Investigating the antibacterial potential of novel N-Boc isatin Schiff bases: Combining synthesis with in-vitro and in-silico studies

The abstract explores into the antibacterial efficacy of newly synthesized N-Boc isatin Schiff bases against a range of pathogenic bacteria, including multidrug-resistant strains. The characterization of the synthesized compounds was achieved through various spectroscopic methods including 1H NMR, 13C NMR, and HRMS techniques, providing detailed structural insights. The in vitro antibacterial assessments were conducted via the agar diffusion method, revealing that compounds 3a, 3d, 3g, and 3j exhibited potent activity against both gram-positive (B. subtilis, MRSA) and gram-negative (E. coli) bacterial strains, providing objective data on their effectiveness. Furthermore, compound 3j, which featured bromine substitution at C5 of N-allyl isatin, displayed significant inhibition zones of 27 mm and 20 mm against E. coli and VRE, respectively, surpassing the activity of ciprofloxacin used as a standard drug molecule, thereby providing specific results. The molecular docking studies against E. coli Peptide Deformylase complex further confirmed the antibacterial potential of the synthesized compounds, adding a scientific basis for their efficacy. Additionally, in silico ADME predictions indicated favourable oral bioavailability, highlighting the promise of N-Boc substituted isatin Schiff bases as potential candidates for the development of novel antibacterial agents, thus contributing to the objective evaluation of their pharmacokinetic properties. Consequently, our studies demonstrated that these compounds not only possess significant antibacterial activity but also show promising pharmacokinetic properties, positioning them as strong candidates for the development of new antibacterial agents.

Discovery of acetophenone/piperazin-2-one hybrids as selective anti-TNBC cancer agents by causing DNA damage

Twenty-five acetophenone/piperazin-2-one (APPA) hybrids were designed and synthesized based on key pharmacophores found in anti-breast cancer drugs Neratinib, Palbociclib, and Olaparib. Compound 1j exhibited good in vitro antiproliferative activity (IC50 = 6.50 μM) and high selectivity (SI = 9.2 vs HER2-positive breast cancer cells SKBr3; SI = 7.3 vs normal breast cells MCF-10A) against triple negative breast cancer (TNBC) cells MDA-MB-468. In addition, 1j could selectively cause DNA damage, inducing the accumulation of γH2AX and P53 in MDA-MB-468 cells. It also reduced the phosphorylation level of P38 and the expression of HSP70, which further prevented the repair of DNA damage and caused cells S/G2-arrest leading to MDA-MB-468 cells death.

Synthesis, crystal structure, Hirshfeld, DFT, molecular docking, dynamics studies, and anti-cancer activity of 1-substituted-2-(4-(diethylamino)-2-hydroxyphenyl)- 1H-benzo[d]imidazole-5-ethyl carboxylates

In our present work, a novel series of 1-substituted-2–2-(4-(diethylamino)-2-hydroxyphenyl)- 1H-benzo[d]imidazole-5-ethyl carboxylates were synthesized by an efficient “one-pot” nitro reductive cyclization method using sodium dithionite is reported as potential anticancer agents. IR, 1H & 13C NMR and Mass spectral data confirmed the synthesized compounds' structure. Compound 6a and 6j were confirmed by their single crystal XRD studies. The Hirshfeld surfaces computational method was applied to visualize and analyse the intermolecular interactions within the crystal structure. All the synthesized compounds were assessed for in vitro anticancer activity towards human lung adenocarcinoma A549 cells and breast cancer MCF-7 cell lines. Compound 6j showed a promising activity with an IC50 value 42.7 μg/mL and 89.63 μg/mL against A549 and MCF-7 cell lines respectively. The potent compounds were assessed for cytotoxicity study on human embryonic kidney HEK 293 cell line and found to be non-toxic. Also, apoptosis study indicated compound 6j induced early apoptosis in the A549 lung adenocarcinoma and MCF-7 breast cancer cells. Molecular docking and dynamic simulation studies were carried out on human estrogen receptor protein (PDB: 3ERT).

Design and discovery of urease and Helicobacter pylori inhibitors based on benzofuran/benzothiophene-sulfonate and sulfamate scaffolds for the treatment of ureolytic bacterial infections

A series of sulfonate and sulfamate derivatives bearing benzofuran or benzothiophene scaffold exhibited potent inhibitory effect on urease enzyme. Most of the derivatives exhibited significantly higher potency than thiourea, the standard inhibitor. Compound 1s was identified as the most potent urease inhibitor with an IC50 value of 0.42 ± 0.08 μM, which is 53-fold more potent than thiourea, positive control (IC50 = 22.3 ± 0.031 μM). The docking results further revealed the binding interactions towards the urease active site. Phenotypic screening revealed that compounds 1c, 1d, 1e, 1f, 1j, 1n, and 1t exhibit high potency against H. pylori with MIC values ranging from 0.00625 to 0.05 mM and IC50 values ranging from 0.0031 to 0.0095 mM, much more potent than the positive control, acetohydroxamic acid (MIC and IC50 values were 12.5 and 7.38 mM, respectively). Additional studies were performed to investigate the toxicity of these compounds against the gastric epithelial cell line (AGS) and their selectivity profile against E. coli, and five Lactobacillus species representative of the gut microflora. Permeability characteristics of the most promising derivatives were investigated in Caco-2 cell line. The results indicate that the compounds could be targeted in the GIT only without systemic side effects.

Development of natural perfume as potential fungicide candidates: construction and biological evaluation of vanillin analogs bearing the 1,3,4-oxadiazole/1,3-thiazolidin-4-one fragments

Two series of vanillin derivatives containing 1,3,4-oxadiazole and 1,3-thiazolidin-4-one scaffolds were prepared and evaluated for their antifungal activity. The results revealed that compounds 6j (29.73 μg/ml) and 7a (38.15 μg/ml) displayed excellent inhibitory activity against the spore of Fusarium solani. The inhibitory activity of compound 7d (10.53 μg/ml) against the spore of Alternaria solani was more than 42-fold that of vanillin. Compound 7a (37.54 μg/ml) showed better antifungal activity against the spore of B. cinerea than positive controls. The cytotoxicity assay confirmed that compounds 6k, 7a, and 7d showed good selectivity and less toxicity to normal mammalian cells.