Synthesis of 2-aminothiazole sulfonamides as potent biological agents: Synthesis, structural investigations and docking studies.

A simplified synthetic approach involving sulfonylation followed by amino group alkylation produced new 2-aminothiazole derivatives. UV/Vis, infrared, and NMR spectroscopies confirmed their structures. Compounds 36, 22, 34, and 35 showed strong inhibition against Jack bean and Bacillus Pasteurii urease, with IC50 values from 14.06 to 20.21 µM/mL. Compounds 20, 26, 21, 29, 30, 31, and 32 exhibited potent inhibitory effects against α-glucosidase and α-amylase, with IC50 values between 20.34 and 37.20 µM/mL. Compounds 33, 26, and 27 demonstrated potent DPPH scavenging, with IC50 values around 34.4-39.2 µM/mL. FMO analysis showed compounds 21, 22, 24, and 25 having parallel aromatic ring systems due to π cloud interactions, while compounds 32 and 38 had distinct electronic density distributions. Compound 22 had HOMO and LUMO energy gaps of 5.805 eV, with bromo and fluoro substitutions in compounds 21 and 24 slightly increasing the gaps to 6.089 eV and 6.078 eV, respectively. Nitro groups in compounds 25 and 32 reduced the gaps to 0.384 eV and 1.187 eV. All compounds demonstrated high gastrointestinal absorption, non-permeability to the blood-brain barrier, and optimal skin permeation (Log Kp between -5.83 and -6.54 cm/s). Compounds 22, 24, and 38 had promising QED scores of 0.719, 0.707, and 0.860, respectively, with synthetic accessibility scores from 2.057 to 2.517. ADMET predictions indicated minimal toxicity, cardiovascular safety, and significant inhibitory potential for CYP enzymes. Strong in silico binding affinities (binding energies -5.75 to -7.63 kcal/mol) and metabolic stability suggest these derivatives are promising candidates for further drug development.

Insight into the binding mechanisms of fluorinated 2-aminothiazole sulfonamide and human serum albumin: Spectroscopic and in silico approaches.

4-Fluoro-N-(thiazol-2-yl)benzenesulfonamide (3) is a novel fluorinated compound, containing various biological activities. Therefore, absorption spectroscopy, fluorescence quenching, molecular docking, and molecular simulation were employed to investigate the interaction between 3 and human serum albumin (HSA). Firstly, compound 3 meets all criteria for drug-likeness prediction. UV absorption spectra revealed the interaction of 3 with HSA altered the microenvironment of protein, as well as circular dichroism spectroscopic analysis indicated slightly conformational changes and a reduction in α-helical content. The binding parameters of the HSA-3 complex suggested that fluorescence quenching is driven by combined static and dynamic processes. Additionally, the stability of the complex is attributed to conventional hydrogen and hydrophobic bonding interactions. Furthermore, esterase-like activity indicated that the binding of 3 might disrupt HSA's bond networks, leading to structural alterations. Consequently, the strong binding constant (Ka ≈ 1.204 × 106 M-1) aligns with the predicted unbound fraction (0.28) in serum, indicating that thiazole 3 has good bioavailability in plasma and can be effectively transported to target sites, thereby exerting its pharmaceutical effects. However, careful dosage management is essential to prevent potential adverse effects. Overall, these findings highlight the potential of 3 as a therapeutic agent, emphasizing the need for further research to optimize its uses.

Design, synthesis and evaluation of aminothiazole derivatives as potential anti-Alzheimer's candidates.

Aim: The objective of the present study was to design, synthesize and evaluate diverse Schiff bases and thiazolidin-4-one derivatives of aminothiazole as key pharmacophores possessing acetylcholinesterase inhibitory activity. Materials & methods: Two series of compounds (13 each) were synthesized and evaluated for their acetylcholinesterase inhibition and antioxidant activity. Molecular docking of all compounds was performed to provide an insight into their binding interactions. Results: Compounds 2j (IC50 = 0.03 µM) and 3e (IC50 = 1.58 µM) were found to be the best acetylcholinesterase inhibitors among compounds of their respective series. Molecular docking analysis supported the results of in vitro activity by displaying good docking scores with the binding pocket of human acetylcholinesterase (Protein Data Bank ID: 4EY7). Conclusion: Compound 2j emerged as a potential lead compound with excellent acetylcholinesterase inhibition, antioxidant and chelation activity.

Synthesis and antibacterial activities of phosphonate derivatives containing aminothiazoloxime fragment / 药学学报

Based on the principle of molecular hybridization, fifteen compounds were designed and synthesized through the combination of aminothiazoloxime and phosphonate fragment. The results showed that these compounds had better inhibitory effects on the tested bacteria. In particular, the activities of compounds Ⅲf and Ⅲi against S. aureus, E. coli, methicillin-resistant S. aureus (MRSA) and fluoroquinolone-resistant E. coli (FREC) were the most significant, the minimal inhibitory concentration (MIC) of Ⅲf was 1, 8, 4, 16 μg·mL-1 respectively, and the MIC of Ⅲi was 4, 4, 16, 8 μg·mL-1 respectively, which were slightly lower than that of the control drug oxacillin, and their anti-E. coli, MRSA and FREC activities were superior to that of the control drug oxacillin. Their activities to S. aureus were close to that of oxacillin, and to E. coli, MRSA and FREC were superior to that of oxacillin, which is worthy of further study.

2-Aminothiazole-Flavonoid Hybrid Derivatives Binding to Tau Protein and Responsible for Antitumor Activity in Glioblastoma.

Tau protein has been described for several decades as a promoter of tubulin assembly into microtubules. Dysregulation or alterations in Tau expression have been related to various brain cancers, including the highly aggressive and lethal brain tumor glioblastoma multiform (GBM). In this respect, Tau holds significant promise as a target for the development of novel therapies. Here, we examined the structure-activity relationship of a new series of seventeen 2-aminothiazole-fused to flavonoid hybrid compounds (TZF) on Tau binding, Tau fibrillation, and cellular effects on Tau-expressing cancer cells. By spectrofluorometric approach, we found that two compounds, 2 and 9, demonstrated high affinity for Tau and exhibited a strong propensity to inhibit Tau fibrillation. Then, the biological activity of these compounds was evaluated on several Tau-expressing cells derived from glioblastoma. The two lead compounds displayed a high anti-metabolic activity on cells related to an increased fission of the mitochondria network. Moreover, we showed that both compounds induced microtubule bundling within newly formed neurite-like protrusions, as well as with defection of cell migration. Taken together, our results provide a strong experimental basis to develop new potent molecules targeting Tau-expressing cancer cells, such as GBM.

Design, synthesis, and antimicrobial evaluation of 2-aminothiazole derivatives bearing the 4-aminoquinazoline moiety against plant pathogenic bacteria and fungi.

BACKGROUND: To find more effective agricultural antibiotics, a class of new 2-aminothiazole derivatives containing the 4-aminoquinazoline moiety were synthesized and evaluated for their antimicrobial properties against phytopathogenic bacteria and fungi of agricultural importance. RESULTS: All the target compounds were fully characterized by 1 H NMR, 13 C NMR, and high-resolution mass spectrometry. The bioassay results showed that compound F29 with a 2-pyridinyl substituent exhibited an outstanding antibacterial effect against Xanthomonas oryzae pv. oryzicola (Xoc) in vitro, having an half-maximal effective concentration (EC50 ) value as low as 2.0 µg/mL (over 30-fold more effective than the commercialized agrobactericide bismerthiazol, with an EC50 value of 64.3 µg/mL). In addition, compound F8 with a 2-fluorophenyl group demonstrated a good inhibitory activity toward the bacterium Xanthomonas axonopodis pv. citri (Xac), around twofold more active than bismerthiazol in terms of their EC50 values (22.8 versus 71.5 µg/mL). Interestingly, this compound also demonstrated a notable fungicidal effect against Phytophthora parasitica var. nicotianae, with an EC50 value largely comparable with that of the commercialized fungicide carbendazim. Finally, mechanistic studies revealed that compound F29 exerted its antibacterial effects by increasing the permeability of bacterial membranes, reducing the release of extracellular polysaccharides, and triggering morphological changes of bacterial cells. CONCLUSION: Compound F29 has promising potential as a lead compound for developing more efficient bactericides to fight against Xoc. © 2023 Society of Chemical Industry.

Synthesis and evaluation of multitarget new 2-aminothiazole derivatives as potential anti-Alzheimer's agents.

In this study, two diverse series of 2-aminothiazole-based multitarget compounds, one propenamide and the other propanamide derivatives, were designed and synthesized. Subsequently, their anticholinesterease and antioxidant (ORAC) activities were tested. Among them, compound 3e was the most potent acetylcholinesterase (AChE) inhibitor (AChE IC50 = 0.5 µM, butyrylcholinesterase [BChE] IC50 = 14.7 µM) and compound 9e was the most potent BChE inhibitor (AChE IC50 = 3.13 µM, BChE IC50 = 0.9 µM). Kinetic experiments showed that both compounds were mixed-type inhibitors. According to the anticholinesterease activity results, five compounds (3e, 4e, 5e, 9d, and 9e) were selected for further activity studies, all of which are dual cholinesterase inhibitors. Then, selected compounds were investigated in terms of their metal chelation activity. Moreover, their neuroprotective effects against H2 O2 -induced damage in the PC12 cell line were evaluated at 10 µM and the results showed that the neuroprotective effect of 3e was 53% compared with the reference ferulic acid (77%). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) results of selected compounds revealed that the compounds were noncytotoxic. Additionally, 3e was more effective in reducing lipopolysaccharides-induced interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α), and nitric oxide (NO) production in the human monocyte derived from patient with acute monocytic leukemia cell line compared with other selected compounds. Finally, a molecular docking study was also performed.

Design, Synthesis, and Biological Evaluation of 2-Aminothiazole Derivatives as Novel Checkpoint Kinase 1 (CHK1) Inhibitors.

A series of 2-aminothiazole derivatives were designed, synthesized on the basis of bioisosterism strategy and evaluated for their CHK1 inhibitory activity. Most of them exhibited potent CHK1 inhibition, and excellent antiproliferative activity against MV-4-11 and Z-138 cell lines. Systematic structure-activity relationship (SAR) efforts led to the discovery of a promising compound 8 n, which showed potent CHK1 inhibitory activity with IC50 value of 4.25±0.10 nM, excellent antiproliferative activity against MV-4-11 and Z-138 cells with IC50 value of 42.10±5.77 nM and 24.16±6.67 nM, respectively, as well as moderate oral exposure (AUC(0-t) =1076.25 h ⋅ ng/mL) in mice. Additionally, treatment of MV-4-11 cells with compound 8 n for 2 h led to robust inhibition of CHK1 autophosphorylation on serine 296. Furthermore, kinase selectivity assay revealed that 8 n displayed acceptable selectivity toward 15 kinases. These results demonstrated that compound 8 n may be a promising potential anticancer agent for further development.

Tetrazole-based inhibitors of the bacterial enzyme N-succinyl-l,l-2,6-diaminopimelic acid desuccinylase as potential antibiotics.

Based on a hit from a high-throughput screen, a series of phenyltetrazole amides was synthesized and assayed for inhibitory potency against DapE from Haemophilus influenzae (HiDapE). The inhibitory potency was modest but confirmed, with the most potent analog containing an aminothiazole moiety displaying an IC50 = 50.2 ± 5.0 µM. Docking reveals a potential binding mode wherein the amide carbonyl bridges both zinc atoms in the active site, and the tetrazole forms key hydrogen bonds with Arg330.

Chitosan-based composite films to remove cationic and anionic dyes simultaneously from aqueous solutions: Modeling and optimization using RSM.

Regarding the existence of cationic and anionic dyes in the water environment developing new and effective techniques to remove them simultaneously is essential. Herein, a chitosan/poly-2-aminothiazole composite film reinforced with multi-walled carbon nanotube-Mg Al-layered double hydroxide (CPML) was created, characterized, and used as an effective adsorbent for methylene blue (MB) and methyl orange (MO) dyes removal from the aquatic medium. The SEM, TGA, FTIR, XRD, and BET methods were used to characterize the synthesized CPML. Response surface methodology (RSM) was utilized to evaluate dye removal based on the initial concentration, dosage, and pH factors. The highest adsorption capacities were measured at 471.12 and 230.87 mg g-1 for MB and MO, respectively. The study of different isotherm and kinetic models revealed that the adsorption of the dyes onto CPML nanocomposite (NC) was correlated with the Langmuir and pseudo-second-order kinetic model, which indicated a monolayer adsorption manner on the homogeneous surface of NCs. The reusability experiment clarified that the CPML NC could be applied multiple times. Experimental results show that the CPML NC has sufficient potential for treating cationic and anionic dye-contaminated water.

2-Aminothiazole-Oxadiazole Bearing N-Arylated Butanamides: Convergent Synthesis, Tyrosinase Inhibition, Kinetics, Structure-Activity Relationship, and Binding Conformations.

A multi-step synthesis of novel bi-heterocyclic N-arylated butanamides was consummated through a convergent strategy and the structures of these medicinal scaffolds, 7a-h, were corroborated using spectral techniques. The in vitro analysis of these hybrid molecules revealed their potent tyrosinase inhibition as compared to the standard used. The kinetics mechanism was investigated through Lineweaver-Burk plots which exposed that, 7f, inhibited tyrosinase enzyme non-competitively by forming the enzyme-inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 0.025 µM. Their binding conformations were ascertained by in silico computational studies whereby these molecules disclosed good binding energy values (kcal/mol). So, it was anticipated from the current research that these bi-heterocyclic butanamides might be probed as imperative therapeutic agents for melanogenesis.

Identification of a 3-(5-methyl-2-thiazolylamino)phthalide as a new minor groove agent.

A new 3-(5-methyl-2-thiazolylamino)phthalide molecule, 3-((5-methylthiazol-2-yl)amino)isobenzofuran-1(3H)-one, was synthesized and characterized experimentally by FT-IR, NMR, UV-Vis, and single-crystal X-ray analysis and theoretically by quantum chemical calculations. The single-crystal X-ray studies revealed that the compound crystallizes in the monoclinic space group P-21/c with unit-cell parameters a = 8.0550(6) Å, b = 6.1386(3) Å, c = 23.3228(18) Å, ß = 97.724(6)° and Z = 4. Optimized geometries and the vibrational frequencies were studied at the density functional theory (DFT) level by using the hybrid functional B3LYP with a 6-311 G (d,p) basis set. The title compound was evaluated for its anti-quorum sensing (anti-QS) activity on Chromobacterium violaceum 12472 and additionally for its antibacterial activity against Staphylococcus aureus 29213, Staphylococcus epidermidis 12228, Pseudomonas aeruginosa 27853, Escherichia coli 25922, and Proteus mirabilis 14153. The lowest MIC value was 0.24 µg/mL for S. aureus 29213 and the highest MIC value was 30.75 µg/mL for E. coli 25922. While anti-bacterial activity was observed in those other than the S. epidermidis and P. Mirabilis, anti-QS activity wasn't detected. Investigations on dsDNA binding affinity indicate that the title compound binds to dsDNA via the groove binding mode. Molecular docking calculations and molecular dynamics simulations results showed also that the title compound prefers binding to the minor groove of dsDNA and remains stable in the minor groove throughout the molecular dynamics simulation.Communicated by Ramaswamy H. Sarma.

New thiourea and benzamide derivatives of 2-aminothiazole as multi-target agents against Alzheimer's disease: Design, synthesis, and biological evaluation.

In this study, two series of compounds were designed and synthesized, bearing thiourea and benzamide derivatives at position 2 of 4-subtituted-2-aminothiazole, respectively. Then, the inhibition potency of all final compounds for cholinesterase enzymes were evaluated. Among the thiourea derivatives, 3c (IC50 = 0.33 µM) was identified as the most potent and selective butyrylcholinesterase inhibitor. Additionally, benzamide derivative 10e (AChE IC50 = 1.47 and BChE IC50 = 11.40 µM) was found as a dual cholinesterase inhibitor. The type of inhibition for both compounds was determined by kinetic studies and the results showed that the compounds were mixed type inhibitors. Moreover, all title compounds were investigated in terms of their antioxidant (DPHH, ORAC) and metal chelator activities. In addition, the neuroprotective effects of selected compounds (3c, 3e, 6c, 6e and 10e) against H2O2-induced damage in the PC12 cell line were tested. The experimental findings demonstrated that thiourea-derived 6e (40.4 %) and benzamide-derived 10e (37.8 %) have a neuroprotective effect of about half as ferulic acid at 10 µM. Subsequently, the cytotoxicity of selected compounds was examined by the MTT assay, and the compounds were found not to have cytotoxic effect on the PC12 cell line in 24 h. Additionally, compounds 6e and 10e were also found to be more effective in inhibiting the release of IL-1ß, IL-6, TNF-α and NO compared to other selected compounds in this study.

Riluzole and novel naphthalenyl substituted aminothiazole derivatives prevent acute neural excitotoxic injury in a rat model of temporal lobe epilepsy.

Epileptogenic seizures, or status epilepticus (SE), leads to excitotoxic injury in hippocampal and limbic neurons in the kainic acid (KA) animal model of temporal lobe epilepsy (TLE). Here, we have further characterized neural activity regulated methylaminoisobutryic acid (MeAIB)/glutamine transport activity in mature rat hippocampal neurons in vitro that is inhibited by riluzole (IC50 = 1 µM), an anti-convulsant benzothiazole agent. We screened a library of riluzole derivatives and identified SKA-41 followed by a second screen and synthesized several novel chlorinated aminothiazoles (SKA-377, SKA-378, SKA-379) that are also potent MeAIB transport inhibitors in vitro, and brain penetrant following systemic administration. When administered before KA, SKA-378 did not prevent seizures but still protected the hippocampus and several other limbic areas against SE-induced neurodegeneration at 3d. When SKA-377 - 379, (30 mg/kg) were administered after KA-induced SE, acute neural injury in the CA3, CA1 and CA4/hilus was also largely attenuated. Riluzole (10 mg/kg) blocks acute neural injury. Kinetic analysis of SKA-378 and riluzoles' blockade of Ca2+-regulated MeAIB transport in neurons in vitro indicates that inhibition occurs via a non-competitive, indirect mechanism. Sodium channel NaV1.6 antagonism blocks neural activity regulated MeAIB/Gln transport in vitro (IC50 = 60 nM) and SKA-378 is the most potent inhibitor of NaV1.6 (IC50 = 28 µM) compared to NaV1.2 (IC50 = 118 µM) in heterologous cells. However, pharmacokinetic analysis suggests that sodium channel blockade may not be the predominant mechanism of neuroprotection here. Riluzole and our novel aminothiazoles are agents that attenuate acute neural hippocampal injury following KA-induced SE and may help to understand mechanisms involved in the progression of epileptic disease.

Design, synthesis, and biological evaluation of ocotillol derivatives fused with 2-aminothiazole via A-ring as modulators of P-glycoprotein-mediated multidrug resistance.

Overexpression of P-glycoprotein (P-gp) plays a key role in the development of multidrug resistance (MDR), the major reason for the failure of chemotherapy in clinics. Ocotillol and its derivatives had been reported with good P-gp-mediated tumor MDR reversal activity in vitro. Herein, a series of ocotillol derivatives fused with 2-aminothiazole (2-AT) via A-ring were designed and synthesized to further improve the tumor MDR reversal potency. These compounds were evaluated for their MDR reversal activity against the KBV cells by MTT assay. Among them, the most promising derivative against P-gp-mediated MDR was compound 12 with 2-AT and glycine in the A-ring. Rhodamine123 (Rh123) accumulation assay, Western blot assay, and P-gp-Glo™ assay showed that compound 12 efficiently inhibited the efflux function of P-gp by stimulating P-gp ATPase rather than downregulating its expression. Moreover, compound 12 sensitized KBV cells to paclitaxel arrested cells in the G2/M phase and induced cell apoptosis. Importantly, compound 12 significantly inhibited the growth of KBV cell-derived xenograft tumors in nude mice by increasing the sensitivity of paclitaxel in vivo. Finally, the structure-activity relationships (SARs) of ocotillol derivatives were further investigated. In summary, compound 12 has the potential to overcome MDR in cancer caused by P-gp.

2-Amino-4-ferrocenyl-thia-zole.

The title compound, [Fe(C5H5)(C8H7N2S)], was synthesized by the direct reaction of acetyl-ferrocene, thio-urea and resublimed iodine. The structure shows one mol-ecule in the asymmetric unit. The amino-thia-zole ring makes an angle of 14.53 (13)° with the ferrocenyl ring to which it is attached. In the crystal, pairs of complex mol-ecules inter-act via inter-molecular N-H⋯N hydrogen bonds, forming a cyclic dimer which then inter-acts with other dimers through C-H⋯π inter-actions.

Discovery of Novel Quinazoline-2-Aminothiazole Hybrids Containing a 4-Piperidinylamide Linker as Potential Fungicides against the Phytopathogenic Fungus Rhizoctonia solani.

A total of 29 novel quinazoline-2-aminothiazole hybrids containing a 4-piperidinylamide linker were designed, synthesized, and evaluated for their anti-microbial properties against phytopathogenic fungi and bacteria of agricultural importance. The anti-fungal assays indicated that some of the target compounds exhibited excellent inhibitory effects in vitro against Rhizoctonia solani. For example, 11 compounds within this series (including 4a, 4g, 4h, 4j, 4o, 4s, 4t, 4u, 4v, 4y, and 4b') were found to possess EC50 values (effective concentration for 50% activity) ranging from 0.42 to 2.05 µg/mL against this pathogen. In particular, compound 4y with a 2-chloro-6-fluorophenyl substituent displayed a potent anti-R. solani efficacy with EC50 = 0.42 µg/mL, nearly threefold more effective than the commercialized fungicide Chlorothalonil (EC50 = 1.20 µg/mL) and also slightly superior to the other fungicide Carbendazim (EC50 = 0.53 µg/mL). Moreover, compound 4y could efficiently inhibit the growth of R. solani in vivo on the potted rice plants, displaying an impressive protection efficacy of 82.3% at 200 µg/mL, better than those of the fungicides Carbendazim (69.8%) and Chlorothalonil (48.9%). Finally, the mechanistic studies showed that compound 4y exerted its anti-fungal effects by altering the mycelial morphology, increasing the cell membrane permeability, and destroying the cell membrane integrity. On the other hand, some compounds demonstrated good anti-bacterial effects in vitro against Xanthomonas oryzae pv. oryzae (Xoo). Overall, the presented results implied that 4-piperidinylamide-bridged quinazoline-2-aminothiazole hybrids held the promise of acting as lead compounds for developing more efficient fungicides to control R. solani.

Synthesis of (tricyanofuran-3-ylmethylene)hydrazinyl thiazole-containing chromophore: A study of its photophysical properties, solvatochromism, and TD-DFT computations.

The chromophore 2-2-(3-cyano-5,5-dimethyl-4-((2-[thiazol-2-yl]hydrazono)methyl)-furan-2(5H)-ylidene)malononitrile (TzHTCF) was prepared by diazo-coupling of diazotized 2-aminothiazole with 3-cyano-2-(dicyanomethylene)-4,5,5-trimethylfuran (TCF). The TzHTCF absorption solvatochromism, in different polarity solvents, demonstrated a ΔEmax = +4.74 in which the positive sign implied the occurrence of a red shift and the TzHTCF lowest excited state was more polar than its ground state. In addition, the TzHTCF fluorescence spectrum produced a λem in the 416-670 nm range and was more dependent on the solvent polarity than the absorption λmax , despite both exhibiting a red shift of 24 and 254 nm, respectively. To discover the Stokes shift ( ∆ ν ¯ ) behaviour of the TzHTCF derivative, Lippert-Mataga and linear solvation-energy relationship (LSER) formulations were utilized in which the LSER approach displayed better results than the Lippert-Mataga method (R2 = 0.9931). Furthermore, the LSER showed that the absorption and fluorescence solvatochromic behaviours were dependent on the solvent's hydrogen-bond donor (α) and acceptor (ß), along with the solvent's polarizability (π*). Moreover, DFT calculations showed that TzHTCF has a planar configuration and its simulated absorption and emission spectra in dimethyl sulphoxide revealed that λmax primarily originated from the HOMO→LUMO and HOMO-1→LUMO transitions, respectively.

Design, synthesis and biological evaluation of chromone derivatives as novel protein kinase CK2 inhibitors.

Protein kinase CK2 is a potential target for the discovery of anticancer drugs. Flavonoids are reported to be effective CK2 inhibitors. Herein, based on structural trimming of flavonoids, a series of chromone-2-aminothiazole derivatives (1a-d, 2a-g, 4a-j, 5a-k) were designed and synthesized by hybridizing the chromone skeleton with 2-aminothiazole scaffold. Among these compounds, compound 5i was the most effective CK2 inhibitor (IC50 = 0.08 µM) and possessed potent anti-proliferative activity against HL-60 tumor cells (IC50 = 0.25 µM). Cellular thermal shift assay (CESTA) confirmed that 5i directly bound to the CK2, and the possible binding mode of 5i toward CK2 was also simulated. Further studies showed that 5i induced the apoptosis of HL-60 cells and arrested the cell cycle. Finally, western-blot analysis showed that 5i could inhibit the downstream of CK2, including α-catenin/Akt pathway and PARP/Survivin pathway.

Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole.

Antimicrobial drug resistance is currently one of the most critical health issues. Pathogens resistant to last-resort antibiotics are increasing, and very few effective antibacterial agents have been introduced in recent years. The promising drug candidates are often discontinued in the primary stages of the drug discovery pipeline due to their unspecific reactivity (PAINS), toxicity, insufficient stability, or low water solubility. In this work, we investigated a series of substituted N-oxazolyl- and N-thiazolylcarboxamides of various pyridinecarboxylic acids. Final compounds were tested against several microbial species. In general, oxazole-containing compounds showed high activity against mycobacteria, especially Mycobacterium tuberculosis (best MICH37Ra = 3.13 µg/mL), including the multidrug-resistant strains. Promising activities against various bacterial and fungal strains were also observed. None of the compounds was significantly cytotoxic against the HepG2 cell line. Experimental measurement of lipophilicity parameter log k'w and water solubility (log S) confirmed significantly (typically two orders in logarithmic scale) increased hydrophilicity/water solubility of oxazole derivatives in comparison with their thiazole isosteres. Mycobacterial ß-ketoacyl-acyl carrier protein synthase III (FabH) was suggested as a probable target by molecular docking and molecular dynamics simulations.