Compounds 4j Research Articles

Sonochemical replacement of C-3 hydrogen of indole by a pyridine ring: Docking, synthesis and in vitro evaluation of 3-(6-aryl pyridin-2-yl)indoles against SIRT1

As an emerging pharmacological target for cancer, SIRT1 attracted our attention while searching unique approaches or strategies for the identification of new anticancer agents. Accordingly, the 3-(6-aryl pyridin-2-yl)indole framework was pursued for the design of new and possible inhibitors of SIRT1. Initially, the in silico docking of a number of molecules based on this framework was conducted that showed their promising interactions with SIRT1 in addition to probable selectivity towards this protein over SIRT2. The study also suggested VAL412, PHE414, ILE347, ALA262, ILE411, HIS363, GLN345, ASN346, ILE270, ILE316, PHE273 and PHE297 as the common interacting residues. A majority of compounds participated in non-H bonding interactions through their aromatic rings with the hydrophobic active site pocket of hSIRT1. A convenient access to these 3-(6-aryl pyridin-2-yl)indoles (3) was established via the first ultrasound assisted heteroarylation approach involving a CC bond forming reaction between 6-aryl substituted 2-chloropyridine and indoles in the presence of AlCl3. Indeed, the current approach revealed sonochemical replacement of the C-3 hydrogen of indole by the pyridine ring in a regioselective manner. The compounds obtained were assessed for their SIRT1 inhibitory potential in vitro. Correlating the outcome of in silico studies the compound 3c, 3d, 3f and 3g were emerged as the best active molecules (with ≥ 70% inhibition) whereas compound 3a, 3e, 3i, 3j and 3o showed good inhibition (> 55%) of SIRT1 at 10 μM. According to the Structure-Activity-Relationship (SAR) the promising SIRT1 inhibitory activities were noted when a OMe or NO2 group was present at C-6 position of the indole ring. Based on IC50 values the order of activity of compounds was found to be 3g > 3f > 3c > 3d when 3g being the most potent seemed to be better than nicotinamide.

Synthesis of novel 18β-glycyrrhetinic acid sulfonate derivatives displaying significant anti-oomycete activity against Phytophthora capsici

Using 18β-glycyrrhetinic acid (GA) as the lead compound, fourteen GA sulphonate derivatives (3a–n) were prepared by modifying its C-3 OH group, and their structures were well confirmed by 1H NMR, 13C NMR, HRMS and melting points. Moreover, we screened the anti-oomycete activity of these compounds against Phytophthora capsici by using the mycelial growth rate method. Among the fourteen GA sulphonate derivatives evaluated, four compounds 3f, 3j, 3k and 3l exhibited more potent anti-oomycete activity than that of the positive control zoxamide (EC50 = 25.17 mg/L), and had the median effective concentration (EC50) values of 23.04, 16.16, 22.55, and 13.93 mg/L, respectively. Especially compound 3l showed the best anti-oomycete activity against P. capsici with EC50 value of 13.93 mg/L. Overall, the introduction of sulfonyloxy groups at the C-3 position of GA has a significant impact on its anti-oomycete activity, and the corresponding derivative activity varies significantly with different substituents R.

Synthesis, ADME, Molecular Docking and Biological Evaluation of New 2-Aminobenzothiazloes

Background: In recent years, 2-aminobenzothiazoles were reported as antibacterial, antihelmintic, antitumor, antimalarial, antiviral, analgesic and anti-inflammatory agents. Objectives: The study aimed to explore new potential 2-aminobenzothiazoles as antibacterial and anthelmintic agents. Methods: A favorable two-step method was used for the synthesis of new 2-aminobenzothiazole derivatives (4a-4j) by Schiff base. All synthesized compounds were tested for antibacterial activity using an in vitro cup-plate method and antihelmintic activity by recording in vitro earthworm paralysis and death time. Pharmacokinetics in silico studies were performed to predict the drug performance in the body using the Molinspiration kit. The molecular docking was performed to check the catalytic binding site between the dihydrofolate reductase and synthesized compounds (4a-4j). Results: The compound 4d emerged as the most effective vermifuge and vermicide among all tested compounds. The compounds 4c, 4f, 4g, 4i and 4j were examined as highly potent against grampositive bacteria. The compounds 4b, 4h, and 4i showed maximum inhibition against gramnegative bacteria. In support of antibacterial activity, the compounds 4c and 4j showed good binding orientation in the catalytic binding pocket of the DHFR receptor (PDB ID: 4LAE). These synthesized compounds could have evolved to shape orally active compounds shown in pharmacokinetics in silico studies. Conclusions: The research outcomes showed that explored 2-aminobenzothiazoles have good antibacterial and anthelmintic activity.

Synthesis, in silico and in vitro studies of novel quinazolinone derivatives as potential SARS-CoV-2 3CLpro inhibitors

A series of new quinazolinone derivatives (5a-l) were designed as 3CL protease inhibitors for SARS-CoV-2 infection. The designed derivatives were efficiently synthesized by S-alkylation/arylation of an intermediate, 6-fluoro-3-(4-fluorophenyl)-2-mercaptoquinazolin-4(3H)-one and their successful synthesis was established by analytical methods, viz. IR, 1H NMR, &13C NMR spectroscopy. The in silico inhibitory potential against 3CLpro of SARS-CoV-2 were studied by means of docking and dynamics simulations, and compared with the co-crystallized ligand (VR4) of SARS-CoV-2 3CLpro. The compounds interacted strongly within the active catalytic dyad (Cys-His) site, thereby anticipated to obstruct the function of 3CLpro of SARS-CoV-2. Compounds 5b, 5c, 5i, 5j and 5l showed efficient binding with protease 3CLpro with XP Gscore of −7.4, −8.3, −7.8, −7.5 and −8.2 respectively. Furthermore, molecular dynamic simulation study of these compounds (5b, 5c, 5i, 5j and 5 l) showed stable interaction over 50 ns production run. Swiss ADME and pkCSM web tools showed favorable physicochemical and pharmacokinetic properties and fulfilled the criteria for drug-likeness of these selected studied compounds. The toxicity determination of these selected compounds predicted that some compounds were hepatotoxic, but were not AMES toxic. Compounds 5b, 5c, 5i, 5j and 5 l revealed their inhibitory potential against the SARS-CoV-2 3CLpro, and their IC50 values were attained at 1.58, 1.25, 1.97, 0.44 and 2.56 µM, respectively. In addition, these compounds were found to have devoid of any significant cytotoxicity even at a higher concentration of 20 µM against VeroE6 cells. These quinazolinone derivatives showed potent binding and inhibitory potential against SARS-CoV-2 3CLpro and may emerge as compounds that might act as prospective inhibitors.

Novel coumarin benzamides as potent and reversible monoamine oxidase-B inhibitors: Design, synthesis, and neuroprotective effects

A series of new 6-amidocoumarin derivatives, 3a–j, was synthesized and evaluated for their inhibitory activity against monoamine oxidase (MAO) and cholinesterase. All compounds, except 3 g, showed higher inhibitory activity towards MAO-B than MAO-A. Compound 3i most potently inhibited MAO-B with an IC50 value of 0.095 μM, followed by 3j (0.150 μM), 3b (0.190 μM), and 3c (0.204 μM). Compound 3i demonstrated the highest selectivity index (>421.05) for MAO-B. The remarkable MAO-B inhibitory activity of compounds 3i, 3j, 3b, and 3c highlighted the substantial role of the substituents at the 3,4-position of the terminal phenyl group in achieving optimal MAO-B inhibition, especially 3-Cl (3i) > 3-CF3 (3b). In the kinetic study, the Ki value of 3i for MAO-B was 0.046 ± 0.010 μM with a competitive reversible mode. Moreover, compounds 3i and 3j were nontoxic to normal (MDCK), cancer (HL-60), and neuroblastoma (SH-SY5Y) cells and showed protective effects against damage induced by reactive oxygen species in SH-SY5Y neuroblastoma cells. Moreover, molecular docking and molecular dynamics simulations highlighted the tight interactions of 3i with Tyr398 at the binding site of MAO-B. These findings suggest that 3i is a potent, reversible, and selective MAO-B inhibitor that could potentially treat neurological disorders.

Design, synthesis, and biological investigation of selective human carbonic anhydrase II, IX, and XII inhibitors using 7-aryl/heteroaryl triazolopyrimidines bearing a sulfanilamide scaffold

A novel library of human carbonic anhydrase (hCA) inhibitors based on the 2-sulfanilamido[1,2,4]triazolo[1,5-a]pyrimidine skeleton modified at its 7-position was prepared by an efficient convergent procedure. These derivatives were evaluated in vitro for their inhibition properties against a representative panel of hCA isoforms (hCA I, II, IV, IX, and XII). The target tumour-associated isoforms hCA IX and XII were potently inhibited with K Is in the low nanomolar range of 5–96 nM and 4–72 nM, respectively. Compounds 1d, 1j, 1v, and 1x were the most potent hCA IX inhibitors with K Is of 5.1, 8.6, 4.7, and 5.1 nM, respectively. Along with derivatives 1d and 1j, compounds 1r and 1ab potently inhibited hCA XII isoform with K Is in a single-digit nanomolar range of 8.8, 5.4, 4.3, and 9.0 nM, respectively. Compounds 1e, 1m, and 1p exhibited the best selectivity against hCA IX and hCA XII isoforms over off-target hCA II, with selectivity indexes ranging from 5 to 14.

Design, synthesis, biological evaluation and molecular docking study of new pyrazolo[1,5-a]pyrimidines as PIM kinase inhibitors and apoptosis inducers

This study involved designing and synthesizing new derivatives of pyrazolo[1,5-a]pyrimidine 5a-l, which were prepared via reaction of 4-Arylazo-1H-pyrazole-3,5-diamines 3a,b with arylidenemalononitriles (4a-f) in refluxing methanol. The structure of the synthesized derivatives were confirmed using different spectroscopic techniques. Virtual screening was achieved for the newly designed derivatives using docking simulation between the target pyrazolo[1,5-a]pyrimidine 5j and the active binding site of the PIM-1 enzyme. The cytotoxicity of novel derivatives of pyrazolo[1,5-a]pyrimidine framework was screened on the cancer cell lines: colon (HCT-116), hepatocellular (Hep-G2), and breast (MCF-7). Comparing with doxorubicin, compounds 2,5-diamino-7-(4-ethoxyphenyl)-3-(p-tolyldiazenyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile; 5h, 2,5-diamino-7-(4-hydroxy-3-methoxyphenyl)-3-(p-tolyldiazenyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile; 5j, and 2,5-diamino-7-(furan-2-yl)-3-(p-tolyldiazenyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile; 5l exhibited noteworthy anticancer properties, with half maximal inhibitory concentration (IC50 range) = 1.26–3.22 μM. In addition, the most potent compound, 5j demonstrated a lower level of toxicity towards normal cells (WI-38 cell line), suggesting an increased level of safety. Compounds 5h, 5j, and 5l were evaluated for their activity against three different PIM kinases (PIM-1, PIM-2, and PIM-3 enzymes) in an effort to elucidate their inhibitory potential on PIM kinases. Additionally, the apoptotic potency of 5j was assessed on MCF-7 cells. Results revealed that compound 5j was potent against both PIM-1 and PIM-2 having IC50 0.158 and 0.297 μM, respectively, comparing to staurosporine's IC50 0.294 and 0.477 μM against both enzymes, respectively, while its inhibitory activity against PIM-3 enzyme was moderate. In addition, compound 5j promoted apoptosis via elevating the levels of Bax, p53, and caspase-3 and dropping down Bcl-2 level. G1 phase arrest of cell cycle was also observed. Furthermore, docking analyses of 5j in the PIM-1 binding site was conducted.

Synthesis of new pyrazolidines by [3+2] cycloaddition: Anticancer, antioxidant activities, and molecular docking studies

A series of novel pyrazolidine derivatives 2a-j from N-acyl hydrazones 1a-j were designed and synthesized by N-triflylphosphoramide (NTPA) catalyzed [3 + 2] cycloaddition. The structural elucidation of synthesized compounds was carried out using a variety of spectroscopic methods, including IR, 1H and 13C NMR, MS, and elemental analysis. Cytotoxic activity of the pyrazolidine derivatives 2a-j was evaluated against human lung cancer (A549), pancreatic cancer (PANC 1), prostate cancer (DU-145), breast cancer (MCF-7), and in human dermal fibroblast (HDF) by MTS assay. The compounds 2f (IC50= 12.5 μM) and 2g (IC50= 21.8 μM) showed higher antiproliferative activity than all other compounds against the A549 human lung cancer line and PANC1 pancreatic cancer line, respectively. The antioxidant potential of the new pyrazolidines 2a-j was evaluated by the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity assay. Compounds 2a, 2d, and 2j were found to exhibit significant antioxidant activity compared to standards. Through molecular docking studies, the antiproliferative properties of the novel pyrazolidine compounds 2a–j were studied, and the interactions between the ligand and the protein were determined for the most active compounds, 2f and 2g.

Synthesis, Antifungal Ergosterol Inhibition, Antibiofilm Activities, and Molecular Docking on β-Tubulin and Sterol 14-Alpha Demethylase along with DFT-Based Quantum Mechanical Calculation of Pyrazole Containing Fused Pyridine-Pyrimidine Derivatives.

Multidrug-resistant fungal infections have become much more common in recent years, especially in immune-compromised patients. Therefore, researchers and pharmaceutical professionals have focused on the development of novel antifungal agents that can tackle the problem of resistance. In continuation to this, a novel series of pyrazole-bearing pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione derivatives (4a-4o) have been developed. These compounds have been screened against Candida albicans, Aspergillus niger, and Aspergillus clavatus. The synthesized compounds were characterized by well-known spectroscopic techniques, i.e., IR, 1H NMR, 13C NMR, and mass spectrometry. In vitro antifungal results revealed that compound 4n showed activity against C. albicans having MIC value of 200 μg/mL. To know the plausible mode of action, the active derivatives were screened for anti-biofilm and ergosterol biosynthesis inhibition activities. The compounds 4h, 4j, 4k, and 4n showed greater ergosterol biosynthesis inhibition than the control DMSO. To comprehend how molecules interact with the receptor, studies of molecular docking of 4k and 4n have been performed on the homology-modeled protein of β-tubulin. The molecular docking revealed that the active compounds 4h, 4j, 4k, 4l, and 4n interacting with the active site amino acid of sterol 14-alpha demethylase (PDB ID: 5v5z) indicate one of the possible modes of action of ergosterol inhibition activity. The synthesized compounds 4c, 4e, 4h, 4i, 4j, 4k, 4l, and 4n inhibited biofilm formation and possessed the potential for anti-biofilm activity. DFT-based quantum mechanical calculations were carried out to optimize, predict, and compare the vibration modes of the molecule 4a.

Ultrasound assisted synthesis of 4-(1H-indol-3-yl)thieno[2,3-d]pyrimidine derivatives via AcOH mediated C[sbnd]C bond forming reaction

A sonochemical approach for the synthesis of 4-(1H-indol-3-yl)thieno[2,3-d]pyrimidine derivatives has been accomplished via the heteroarylation of 4-chloro thieno[2,3-d]pyrimidines with a range of indoles. The reaction was performed using AcOH as a promoter as well as solvent to give the corresponding products in good to acceptable yields. This metal free method proceeded via the CC bond forming reaction and offers advantages such as simple conditions, shorter duration and the use of eco-friendly energy. In addition to its drawbacks, the usefulness of the methodology is presented and exemplified by the medicinal value of the compounds synthesized. The compound 3i and 3j showed good inhibition of TNF-α in vitro and were identified as the initial hit molecules.

Design, synthesis and biological evaluation of novel ketone derivatives containing benzimidazole and 1,3,4-triazole as CA inhibitors

In this study, we synthesized a series of new benzimidazole-triazole (6a-6k) derivatives and characterized them by 1H NMR, 13C NMR, and HRMS. These compounds were evaluated for their inhibitory activity against hCA-I and hCA-II. All the compounds exhibited good hCA-I and hCA-II inhibitory activities with IC50 values in the range of 1.158 µM to 3.48 µM. Among all these compounds, compound 6j, with an IC50 value of 1.288 µM and 1.6197 µM, is the most active against hCA-I and hCA-II, respectively. Compounds 6a-6k were also evaluated for their cytotoxic effects on the L929 mouse fibroblast (normal) cell line. Enzyme inhibition kinetics showed all compounds 6a-6k to inhibit the enzyme by non-competitive. The most active compound 6j was subjected to molecular docking, which revealed their binding interactions with the enzyme's active site, confirming the experimental findings.

Design, Synthesis, and Molecular Docking Studies of 1,3,4-Oxadiazole Scaffolds as Potential Antimicrobial Agents

In search of suitable antimicrobial compounds, we report here the synthesis, characterization, and biological activities of 2-((5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl)thio)-N-arylacetamide (5a-5p). The molecules were characterized by infrared, mass, hydrogen-1 nuclear magnetic resonance (1H NMR), 13C NMR, and elemental analysis. The in vitro antimicrobial activity was investigated against pathogenic Gram-positive and Gram-negative bacterial and fungal strains. The results were explained with a molecular docking study against microbial DNA gyrase. It was found that the compounds 5h, 5i, 5j, 5k, 5l, 5n, and 5p showed significant activities against tested organisms as compared to standard drugs (fluconazole and ciprofloxacin).

A facile synthesis and characterization of some novel benzimidazole derivatives

We successfully synthesized a series of novel benzimidazole derivatives with high yields in our current research study. The synthesis procedure involved condensing Ethyl 3-[[3-amino-4-(treiethylamino) benzoyl] (pyridine-5-yl) amino]-propanoate with various aromatic carboxylic acids, using EDC.HCl and a small amount of DMAP as catalysts. The resulting compounds underwent cyclization through coupling in the presence of acetic acid under reflux conditions. Notably, both the coupling and cyclization reactions were efficiently achieved, with the former occurring at room temperature and the latter at reflux temperature. Our synthesis method is both environmentally friendly and cost-effective. To characterize the synthesized compounds, we employed modern spectroscopic techniques such as FT-IR, 1H NMR, 13C NMR, and mass spectrometry. The compound 4i shown the most potent in vitro anticancer activity. The compound 4e and 4f were also found to have good in vitro anticancer activity compared to other synthesized compounds. The result of in vitro anticancer activity says that the combination of pyridine, benzimidazole and thiophene ring best apposite for the development of novel anticancer agent. The other derivatives have also shown good activity such as compounds 4b, 4c, 4 h and 4j with electron withdrawing group on phenyl ring.

Synthesis of novel spirochromane incorporating Schiff's bases, potential antiproliferative activity, and dual EGFR/HER2 inhibition: Cell cycle analysis and in silico study

Spirochromanes incorporating Schiff's bases and semicarbazones 4a-e and 5a-j were synthesizedand analyzed for their potential antiproliferative activity using four human cancer cell lines (MCF-7, HCT-116, PC3, and A549). Compounds 5a, 5b and 5g possessed the highest antiproliferative activity among the tested compounds,with an IC50 range of 1.154–9.09 μM. Compound 5j selectively inhibited the PC3 cell proliferation (IC50 = 5.47 μM). Spirochromanes 5a, 5b and 5g exhibited high inhibitory activity against EGFR (IC50 = 0.116, 0.132, and 0.077 μM, respectively) and HER2 (IC50 = 0.055, 0.210 and 0.085 μM, respectively) compared with the references, erlotinib (IC50 = 0.090 and 0.038 μM, respectively) and gefitinib (IC50 = 0.052 and 0.072 μM, respectively). Cell cycle analysis and apoptosis results showed that compounds 5a, 5b and 5g arrested growth inthe S phase, and the programmed cell death induced by these compounds was an apoptotic mechanism rather than a necrotic pathway. Molecular docking studies of spirochromanes 5a, 5b and 5g to EGFR and HER2 binding sites were performed to explore the orientation mode and interaction.

Design, Synthesis, and Biological Evaluation of Novel Derivatives of the Marine Natural Product Laurene.

Plant pathogenic fungi and viruses are seriously threatening agricultural production. There is an urgent need to develop novel fungicides and antiviral agents with low toxicity and high efficiency. In this study, we designed and synthesized 32 thiazole-, hydrazone-, and amide-containing derivatives of laurene and systematically evaluated their antiviral activities and fungicidal activities. Structure-simplified compounds 5a-5c, 5i, 5k, 5l, 11a, 11j, and 12c displayed higher antiviral activities than that of ningnanmycin. Compound 11a with a simple chemical structure, convenient synthetic route, and excellent antiviral activity emerged as a secondary lead compound. The docking results show that compounds 5i, 5k, and 11a have strong interactions with the tobacco mosaic virus coat protein (TMV CP). These compounds also exhibited significant fungicidal activities. Compounds 5g, 5k, 11j, and 11l displayed 9.15-17.45 μg/mL EC50 values against Pyricularia grisea, and compounds 5h (EC50: 8.01 μg/mL) and 11i (EC50: 15.23 μg/mL) exhibited a similar level of EC50 values with chlorothalonil (EC50: 7.33 μg/mL) against Physalospora piricola. Preliminary fungicidal mechanism research indicated that compound 5h has a certain destructive effect on the hyphae of P. piricola. This work lays a foundation for the application of laurene derivatives in plant protection.

Design, Synthesis, and Biological Activity Determination of Novel Phenylpyrazole Protoporphyrinogen Oxidase Inhibitor Herbicides Containing Five-Membered Heterocycles.

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitor herbicides have attracted widespread attention in recent years as ideal herbicides due to their high efficiency, low toxicity, and low pollution. In this article, 30 phenylpyrazole derivatives containing five-membered heterocycles were designed and synthesized according to the principle of bioelectronic isoarrangement and active substructure splicing. A series of structural characterizations were performed on the synthesized compounds. The herbicide activity in greenhouse was evaluated to determine their growth inhibition effect on weeds, their IC50 value through in vitro PPO enzyme activity measurement was calculated, and target compounds 2i and 3j that have herbicide effects comparable to pyraflufen-ethyl were selected. Crop safety experiments have shown that when the spraying concentration is 300 g of ai/ha, gramineous crops such as wheat, corn, and rice are more tolerant to compound 2i, with wheat exhibiting high tolerance, which is equivalent to the crop safety of pyraflufen-ethyl. Compound 2i can be used as a candidate herbicide for wheat, corn, and paddy fields, and the results are consistent with the cumulative concentration experiment. Molecular docking results showed that compound 2i interacted with the amino acid residue ARG-98 by forming two hydrogen bonds and interacted with the amino acid residue PHE-392 by forming two π-π stacking interactions, indicating that compound 2i has more excellent herbicidal activity than pyraflufen-ethyl and is expected to become a potential lead compound of phenylpyrazole PPO inhibitor herbicides.

Anti-Proliferative, Anti-EGFR and In Silico Studies of a Series of New Imidazole Tethered 1,2,4-Oxadiazoles

Herein, we prepared some new imidazole-1,2,4-oxadiazole hybrids (6a–6o) and investigated their antiproliferative potential on three human cancer cell lines (HepG2, A549 and MCF-7) using Erlotinib as standard drug. In common, most of the compounds showed better potential on MCF-7 in comparison to HepG2 and A549. Out of all, compound 6o had greater activity on MCF-7, while, it, had most promising activity on HEPG2 and A549. Compounds 6f, 6j and 6l also exhibited significant activity on MCF-7. As well, in vitro anti-EGFR evaluation of most active compounds 6f, 6j, 6l, and 6o revealed that compound 6o displayed most promising activity as compared to Erlotinib. Molecular docking studies revealed the possible binding interactions of derivatives 6f, 6j, 6l, and 6o with EGFR (PDB ID-4HJO). Finally, compounds 6f, 6j, 6l, and 6o are possessing ‘druglikeness’ with CLogP values ranging from 1.86 to 3.13.

Synthesis and mechanism of action of new purine derivatives against triple negative breast cancer

Triple negative breast cancer (TNBC) is considered to be the most difficult subtype of breast cancer to treat because of its extremely prone to metastasis and the lack of targeted therapy drugs. New purine derivatives were synthesized and evaluated in a series of kinases and cell lines. The most active compounds 3g and 3j were selected based on their antiproliferative activities, then their pharmaceutical activity and mechanism in MDA-MB-231 cells were analyzed. The results in vitro indicated that compounds 3g and 3j can induce MDA-MB-231 cells apoptosis, and inhibit its migration and angiogenesis through influencing protein expression such as Bcl-2, Bax, Bcl-xl, P38, MMP2, MMP9, AKT and EGFR. In vivo results indicate that compounds 3g and 3j can inhibit tumor growth and metastasis and reduce the expression of Ki67 and CD31 protein in TNBC xenograft models. These findings not only broaden our understanding of the anti-TNBC effects and mechanisms of compounds 3g and 3j, but also provide new ideas and reference directions for the treatment of TNBC.

Synthesis, Antifungal, and Antibacterial Activities of Novel Benzoylurea Derivatives Containing a Pyrimidine Moiety.

To explore more efficient and less toxic antibacterial and antifungal pesticides, we utilized 2,6-difluorobenzamide as a starting material and ultimately synthesized 23 novel benzoylurea derivatives containing a pyrimidine moiety. Their structures were characterized and confirmed by 1H NMR, 13C NMR, 19F NMR, and HRMS. The bioassay results demonstrated that some of the title compounds exhibited moderate to good in vitro antifungal activities against Botrytis cinerea in cucumber, Botrytis cinerea in tobacco, Botrytis cinerea in blueberry, Phomopsis sp., and Rhizoctonia solani. Notably, compounds 4j and 4l displayed EC50 values of 6.72 and 5.21 μg/mL against Rhizoctonia solani, respectively, which were comparable to that of hymexazol (6.11 μg/mL). Meanwhile, at 200 and 100 concentrations, the target compounds 4a-4w exhibited lower in vitro antibacterial activities against Xanthomonas oryzae pv. oryzicola and Xanthomonas citri subsp. citri, respectively, compared to those of thiodiazole copper. Furthermore, the molecular docking simulation demonstrated that compound 4l formed hydrogen bonds with SER-17 and SER-39 of succinate dehydrogenase (SDH), providing a possible explanation for the mechanism of action between the target compounds and SDH. This study represents the first report on the antifungal and antibacterial activities of novel benzoylurea derivatives containing a pyrimidine moiety.

Microwave Facilitated Discovery of Substituted 1,2,4-triazaspiro[4.5] dec-2-en-3-amines: Biological and Computational Investigations

Background: Tuberculosis is an effectual infectious disease caused by the spread of tu-bercular bacteria within the lungs via droplets of coughs and sneezes. In 2021, 1.6 million people died due totuberculosis, which is the 13th leading killer disease and 2nd leading after COVID-19 infectious disease. Objective: Many drugs are available as antitubercular drug, but still, requires more efficacious drug molecules with lower toxicity, side effects and small-sized molecules. To fulfill said prospective, computational study such as molecular docking and ADMET studies guides towards an ideal drug molecule with small -sized, unique spiro structures. Methods: Conventional and microwave-initiated Reaction of cyclohexanone, hydrazine carbothio-amide, and 2-amino-4-methoxy-6-methyl-1,3,5-triazine affords compound 1, which is subjected to the Schiff base reaction with diverse aldehydes. All structures are defined using IR, 1H NMR, 13C NMR, and mass spectroscopy. The entire series is exposed to in vitro antibacterial and antitubercu-lar and in silico molecular docking and ADMET studies. Results: Compounds 2c and 2b have been established to be potential antibacterial agents, whereas compounds 2d, 2e, 2j, 2k and 2l are extremely effective against tubercular strains. Furthermore, molecular docking of related molecules is performed, and compounds 2d, 2e, 2j, 2k, and 2l have higher affinities toward antitubercular proteins. ADMET parameters such as water solubility, SA score, PCaco2 value, and TPSA values are satisfactory. Conclusion: The microwave method has been proven to be a greener method as compared to the con-ventional heating method. Comparative results of in vitro analysis are obtained with referenced anti-bacterial drugs and antitubercular drugs. In silico observations supports their in vitro assessments. Appraisal obtained from the ADMET study leads to the formation of ideal drug molecules.