Compounds 4i Research Articles

Multi-functional tyrosinase inhibitors derived from kojic acid and hydroquinone-like diphenols for treatment of hyperpigmentation: Synthesis and in vitro biological evaluation.

A series of multi-functional tyrosinase inhibitors derived from kojic acid (KA) and hydroquinone-like diphenols were designed and synthesized using click chemistry. The in vitro enzymatic assay revealed that all compounds containing a free enolic structure showed excellent activity against tyrosinase (IC50 = 0.14-3.7 µM), being significantly more potent than KA. The most active compounds were catechol (6c) and α-naphthol (6i) analogs with 138- and 96-fold higher potency than KA. On the other hand, all free phenolic compounds (6a-c and 6g-j) derived from aromatic diols showed outstanding free radical scavenging activities superior to KA. Certainly, the α-naphthol derivative 6i with IC50 = 10.1 µM was the most active anti-oxidant, being as potent as quercetin. The SAR analysis indicated that the enolic head of the conjugate molecules mainly contributes to the anti-tyrosinase activity, and the free phenolic part of the molecules can offer anti-oxidant potency. The anti-melanogenic assay of the most promising derivative, 6i, against melanoma (B16F10) cells demonstrated that the prototype compound 6i can significantly reduce the melanin content, more effectively than KA. By using a conjugation strategy, we have improved the tyrosinase inhibitory and radical scavenging activity in the multi-functional agents such as 6i over the parent compound KA, being potentially useful in the treatment of hyperpigmentation and other skin disorders.

Semi-Preparation and X-ray Single-Crystal Structures of Sophocarpine-Based Isoxazoline Derivatives and Their Pesticidal Effects and Toxicology Study.

Recently, research and development of novel pesticides from natural plant products have received much attention. To accelerate the application of sophocarpine as the agrochemical candidate, a series of novel sophocarpine-based isoxazoline derivatives were prepared by the 1,3-dipolar [2 + 3] cycloaddition reaction of sophocarpine with different chloroximes. Their structures were well characterized by high-resolution mass spectra, infrared spectra, and proton/carbon-13 nuclear magnetic resonance spectra. Eight steric configurations of compounds 5a, 5e', 5f, 5g, 5h, 5i, 5r, and 5u' were further determined by X-ray single-crystallography. Against Aphis citricola Van der Goot, compounds 5n (LD50: 0.032 μg/nymph) and 5o (LD50: 0.024 μg/nymph) exhibited greater than 3.7- and 4.9-fold potent aphicidal activity compared to sophocarpine (LD50: 0.118 μg/nymph). Against Tetranychus cinnabarinus Boisduval, derivative 5g displayed the most promising acaricidal activity with the LC50 value of 0.247 mg/mL, which was 14.2-fold that of sophocarpine. Compounds 5d and 5g also exhibited good control efficacy against T. cinnabarinus. Scanning electron microscopy images indicated that compound 5g can destroy the mite cuticle layer. These results will provide the foundation for the structural modification and use of sophocarpine derivatives as agrochemicals in the future.

Discovery of Janus Kinase and Histone Deacetylase Dual Inhibitors as a New Strategy to Treat Psoriasis.

Psoriasis is a common, chronic, recurrent, and inflammatory skin disease, which causes physical and psychological problems in patients and lacks effective and economic therapeutics. Herein, we designed Janus kinase (JAK) and histone deacetylase (HDAC) dual inhibitors as a new strategy for the treatment of psoriasis. In particular, compound 11i was identified with excellent inhibitory activity toward JAKs (JAK2 IC50 = 0.49 nM) and HDACs (HDAC6 IC50 = 12 nM). Moreover, it exhibited potent activities in inhibiting the proliferation of TNF-α-induced HaCAT cells and the production of nitric oxide. Importantly, compound 11i significantly ameliorated psoriasis-like skin lesions in an imiquimod-induced murine model with low toxicity, which was superior to JAK inhibitor momelotinib, HDAC inhibitor vorinostat, and their combination. This work provided a proof-of-concept for JAK/HDAC dual inhibitors as a promising strategy for the treatment of psoriasis.

Design, synthesis and mechanistic study of N-4-Piperazinyl Butyryl Thiazolidinedione derivatives of ciprofloxacin with Anticancer Activity via Topoisomerase I/II inhibition

A new group of thiazolidine-2,4-dione derivatives of ciprofloxacin having butyryl linker 3a-l was synthesized via an alkylation of thiazolidine-2,4-diones with butyryl ciprofloxacin with yield range 48–77% andfully characterized by various spectroscopic and analytical tools. Anti-cancer screening outcomes indicated that 3a and 3i possess antiproliferative activities against human melanoma LOX IMVI cancer cell line with IC50 values of 26.7 ± 1.50 and 25.4 ± 1.43 µM, respectively, using doxorubicin and cisplatin as positive controls with an IC50 of 7.03 ± 0.40 and 5.07 ± 0.29 µM, respectively. Additionally, compound 3j showed promising anticancer activity against human renal cancer A498 cell line with IC50 value of 33.9 ± 1.91 µM while doxorubicin and cisplatin showed IC50 values of 3.59 ± 0.20 and 7.92 ± 0.45, respectively. On the other hand, compound 3i did not show considerable anti-bacterial activity against S. aureus, E. coli and P. aeruginosa, and only moderate activity against K. pneumoniae with only a tenth of the activity of ciprofloxacin, confirming the cytotoxicity observed. Mechanistically, compound 3i inhibited both topoisomerase I and II with IC50 of 4.77 ± 0.26 and 15 ± 0.81 µM. Furthermore, it induced cell cycle arrest at S phase in melanoma LOX IMVI cells. Moreover, 3i provoked substantial levels of early, late apoptosis and necrosis in melanoma LOX IMVI cell line comparable to that induced by doxorubicin. Furthermore, compound 3i increased the expression level of active caspase-3 by 49 folds higher in LOX IMVI cell, increased protein expression level of Bax more than the control by 3 folds and inhibited PARP-1by 33% in LOX IMVI. All results were supported by theoretical docking studies on both tested enzymes confirming potential cytotoxicity for the synthesized hybrids.

In Vitro and In Vivo Biological Evaluation of Novel 1,4-Naphthoquinone Derivatives as Potential Anticancer Agents.

A novel library of naphthoquinone derivatives (3-5 aa) was synthesized and evaluated for their anticancer properties. Specifically, compounds 5 i, 5 l, 5 o, 5 q, 5 r, 5 s, 5 t, and 5 v demonstrated superior cytotoxic activity against the cancer cell lines that were studied. All the studied compounds exhibited a higher selectivity index (SI) and a favourable safety profile than the standard drug doxorubicin. Notably, compound 5 v displayed a greater cytotoxic effect on MCF-7 cells (IC50=1.2 μM, and 0.9 μM at 24 h and 48 h, respectively) compared to the standard drug doxorubicin (IC50=2.4 μM, and 2.1 μM at 24 h and 48 h, respectively). To further investigate the mechanism of cytotoxic effect, additional anticancer studies were conducted with 5 v in MCF-7 cells. The studies are including morphological changes, AO/EB (acridine orange/ethidium bromide) double staining, apoptosis analysis, cell colony assay, SDS-PAGE and Western blotting, cell cycle analysis, and detecting reactive oxygen species (ROS) assay. The findings showed that 5 v triggered cytotoxic effects in MCF-7 cells through the initiation of cell cycle arrest at the G1/S phase and necrosis. In vivo ecotoxicity studies indicated that 5 v had lower toxicity towards zebrafish larvae (LC50=50.15 μM) and had an insignificant impact on cardiac functions. In vivo xenotransplantation of MCF-7 cells in zebrafish larvae demonstrated a significant reduction in tumour volume in the xenograft. Approximately 95 % of the zebrafish larvae with 5 v xenografts survived after 10 days of the treatment. Finally, a computational modelling study was conducted on four protein receptors, namely ER, EFGR, BRCA1, and VEFGR2. The findings highlight the importance of the aminonaphthoquinone moiety, amide linkage, and propyl thio moiety in enhancing the anticancer properties. 5 v exhibited superior drug-likeness features and docking scores (-9.1, -7.1, -8.9, and -10.9 kcal/mol) compared to doxorubicin (-7.2, -6.1, -6.9, and -7.3 kcal/mol) against ER, EFGR, BRCA1, and VEGFR2 receptors, respectively. Therefore, the notable antitumor effects of naphthoquinone derivatives (3-5 aa) suggest that these molecular frameworks may play a role in the development of promising anticancer agents for cancer treatment.

One-pot synthesis of fused isoxazolo[4′,5′:4,5]thiopyrano[2,3-d]pyrimidines as potent EGFR targeting anti-lung cancer agents

The requirement for scaffolds has prompted synthetic chemists to devise simple and effective methods for optimal synthesis, which are critical in the medical industry. Under comparatively optimized conditions, a click followed by a CC bond coupling reaction between iodoalkyne (4) and substituted nitrile oxide was utilized to explore the synthesis of fused isoxazoles containing thiopyrano[2,3-d]pyrimidine under microwave irradiation. The synthesized compounds were tested for their anticancer activity against EGFR wild-type human non-small cell lung cancer cells (NCI-H460 and A549). The compounds 6i and 6l have shown more potent activity against both cancer cell lines as compared to standard drugs doxorubicin and erlotinib. And also compounds 6e, 6j, and 6k have shown more potent activity as compared to Doxorubicin and moderate activity compared to erlotinib. Later, in vitro EGFR results of more potent compounds revealed that compounds 6l and 6k have shown potent EGFR activity compared to standard erlotinib. To evaluate the molecular interactions of more potent compounds with the human epidermal growth factor receptor. It was observed that all the potent compounds exhibited greater binding energies in comparison to the standard drug erlotinib.

Discovery of novel third generation P-glycoprotein inhibitors bearing an azo moiety with MDR-reversing effect

P-glycoprotein (P-gp)-caused multidrug resistance (MDR) is a crucial factor in the cancer chemotherapy failure. Herein, a total of twenty two azo-containing WK-X-34 (WK34, a third generation P-gp inhibitor) derivatives were synthesized as novel P-gp inhibitors. Biological evaluation revealed that compound 7i effectively reversed P-gp-mediated MDR in K562/A02 cells, with a higher reversal fold (RF) value than WK34 (142.79 vs. 64.41). Further investigation indicated that 7i dose-dependently inhibited P-gp function, without affecting its expression. CETSA results illustrated that 7i could obviously improve P-gp stability, suggesting its high affinity with P-gp. Molecular docking analysis revealed that 7i fit well into P-gp's binding pocket, thus displaying potent reversal effect on P-gp-mediated tumor MDR Optical properties evaluation confirmed that azo-containing 7i can undergo reversible changes in the cis and trans configurations under the irradiation of 365 nm and 520 nm wavelength of light. Notably, the configuration change of azo might affect the MDR-reversal potency, and cis-7i has a lower RF value than trans-7i (122.70 vs. 142.79), suggesting that development of photoswitchable P-gp inhibitors might be a novel strategy to reduce the systemic toxicity caused by indiscriminate inhibition of P-gp by traditional inhibitors. Collectively, 7i, as a novel P-gp inhibitor, warranted further investigation.

Non-food renewable and bioactive products for pesticides: Synthesis, anti-oomycete and anti-fungal activities of 9R-acyloxyquinine derivatives bearing an 1,3,4-oxadiazole moiety

Quinine is the main alkaloids in the bark of Cinchona and its homologous plants of Rubiaceae. To discover biorational natural product-based pesticides, a series of 9R-acyloxyquinine derivatives containing 1,3,4-oxadiazole moieties were prepared by ingeniously introducing an active ester group and a 1,3,4-oxadiazole five membered heterocyclic ring at its C-9 position, and their structures were well characterized by 1H NMR, 13C NMR, HRMS, and m.p. The stereochemical configuration of target compound 6 t was unambiguously subjected to single-crystal X-ray diffraction. Furthermore, bioactivities of these compounds as anti-oomycete and anti-fungal agents against two serious agricultural diseases, Phytophthora capsici and Fusarium graminearum we assessed. Among all tested compounds, 1) Compounds 6c and 6d displayed promising anti-oomycete against P. capsici, with EC50 values of 38.42 and 35.49 mg/L, respectively. 2) Compound 6i exhibited promising anti-fungal against F. graminearum, with an EC50 value of 29.92 mg/L. Moreover, some interesting results of structure-activity relationships were also observed. The results of this study pave the way for further design, structural modification, and development of quinine derivatives as plant anti-oomycetes and anti-fungal agents in crop protection.

Rationale design and synthesis of new roflumilast analogues as preferential selective and potent PDE-4B inhibitors

In this study, we designed and synthesized novel analogues of roflumilast that exhibit selective inhibition of PDE-4B. To accomplish this target; synthesis of novel series (4a-u, 5a-i, and 6) was done, aiming at obtaining new PDE-4B inhibitors hits based on the proposed pharmacophore, 1-(cyclopropylmethoxy)-2-(difluoromethoxy) benzene moiety. Enzyme assay was used to measure the IC50 values for the PDE-4B inhibition of all the synthesized compounds along with roflumilast as a reference drug. The results demonstrated that most of the examined candidates exhibited considerable inhibitory activity against the PDE-4B enzyme. The four compounds (4i, 4k, 4p, and 4q) exhibited the highest potency (IC50 = 7.25, 7.15, 5.50, 7.19 nM, respectively) with no significant inhibition difference from roflumilast (no statistical difference at p < 0.05). Interestingly, compound 4p with 3-OH and 4-OCH3 substituents was found to be the most potent against PDE-4B enzyme (IC50 = 5.50 nM), compared to that of roflumilast (IC50 = 2.36 nM). Moreover, the most potent derivatives 4i, 4k, 4p, and 4q were further tested for PDE-4D inhibitory activity to investigate their PDE-4D/PDE-4B selectivity ratio. Compound 4k showed the highest selectivity towards PDE-4B isozyme more than the reference drug roflumilast (PDE-4D/4B IC50 ratio for compound 4k and roflumilast = 3.22 and 3.02, respectively). Additionally, compound 4p was chosen to test its selectivity for PDE-4B over PDE-8A, PDE-11A, and PDE-1B compared to thereference drug roflumilast. Compound 4p showed approximately 6-fold selectivity for PDE-4B over PDE-8A, about 5-fold selectivity for PDE-4B over PDE-11A, and 11-fold selectivity of PDE-4B over PDE-1B. Compound 4p showed a higher selectivity towards PDE-4B than PDE-1B, more than the reference compound roflumilast. Furthermore, the most potent compounds (4i, 4k, 4p, 4q) were subjected to further investigation, and their effects on the cAMP level and percentage of inhibition of tumor necrosis factor-alpha (TNF-α) were studied and compared with reference drug roflumilast. Compound 4q showed the highest increase in the level of intracellular cAMP (6.55 ± 0.37 pmol/mL) and compound 4i showed the highest % of TNF-α inhibition (77.22 %). On the other side, a molecular docking study against PDE-4B clarified that all the examined candidates achieved nearly similar binding modes with similar orientations to that of the native roflumilast ligand and showed higher docking scores than roflumilast.

New quinoxaline-oxadiazole hybrids as tubulin inhibitors: Synthesis, cytotoxicity, and molecular dynamics simulations

This study describes the synthesis and biological evaluation of a series of novel quinoxaline-oxadiazole hybrid compounds. These compounds were designed to enhance anticancer activity through the incorporation of specific pharmacophoric groups. Structural characterization using NMR and HRMS spectroscopy confirmed the successful synthesis of the hybrids. Cytotoxicity assays revealed that several compounds exhibited significant activity against various cancer cell lines. Compounds 8a and 8f demonstrated potent activity against A549 cells, while 8a, 8b, and 8c were effective against HaCaT cells. Additionally, compounds 8i and 8a showed activity against HepG2 cells. Molecular docking and dynamics simulations suggested that compounds 8c and 8d bind strongly to the tubulin protein, a target for anticancer drugs. These compounds exhibited binding affinities comparable to known anticancer compounds. The results of this study highlight the potential of quinoxaline-oxadiazole hybrids, especially those with halogen substitutions, as promising candidates for the development of novel anticancer therapeutics.

Phytotoxic and Cytogenetic Assessment of Glycerol Triazole Derivatives in Model Plants and Weeds.

Weed invasion represents a challenge for farmers, who typically manage it with herbicides. However, this approach raises concerns about environmental and human health, as well as increasing resistance in these plants with continued use. Therefore, exploring alternative methods, such as heterocyclic compounds, triazoles, is essential due to their biological and environmental relevance. This study aimed to evaluate the effects of twelve 1,2,3-triazoles on the germination and early development of Lactuca sativa, Bidens pilosa, and Lolium multiflorum, as well as their impact on cell division in the cells of L. sativa. Triazole derivatives 4a, 4b, 4c, 4g, 4h, 4i, 4k, and 4l exhibited phytotoxicity, showing varying levels of inhibition in germination, germination speed index, and root growth. Chlorinated compounds were the most detrimental to lettuce development. B. pilosa was notably affected by compounds 4h, 4i, 4k, and 4l, while L. multiflorum responded most to triazoles 4c and 4l, with effectiveness comparable to that of the herbicide glyphosate. All derivatives, except 4l, exhibited aneugenic mechanisms of action, and 4a, 4b, 4c, 4e, 4f, and 4g showed clastogenic effects. This study demonstrated the potential of triazoles as effective agents against weed growth, with mechanisms that warrant further investigation for agricultural applications.

Unprecedented synthesis of indole-linked tetra-substituted alkenes by catalyst-free domino reaction

Herein, we report a simple, efficient catalyst-free green domino reaction of indole, arylglyoxal, and cyclic 1,3-dicarbonyls such as barbituric acid derivatives/dimedone at 100oC in dimethylformamide medium in open air condition. In this reaction, one C-C and one C=C bonds have been formed in one-pot without using any additive or metal based reagent. Considering the presence of indole, benzoyl and cyclic 1,3-dicarbonyl moieties in the products, it is expected that they will exhibit interesting medicinal properties. All the synthesized products were characterized by recording FTIR, 1H NMR, 13C NMR, and HRMS. Moreover, a single crystal XRD of compound 4i was recorded to confirm the structure of the product. Operational simplicity, gram-scale synthesis, mild reaction conditions, good yields, and wide substrate scope are the salient features of this methodology.

Indole analogs as potential anti-breast cancer agents: Design, synthesis, in-vitro bioevaluation with DFT, molecular docking and ADMET studies

Being a belligerent malignancy, triple-negative breast cancer poses unmet clinical challenges due to lack of targeted therapy, rapid growth rate and metastasis, high heterogeneity, and increased risk of recurrence. Diverse 1-(1H-indol-1-yl)-2-((5-aryl-4H-1,2,4-triazol-3-yl)thio))ethanones have been synthesized in substantial yield (81-87 %) by clubbing 1-(chloroacetyl)indoles with substituted triazoles under refluxing conditions of 4-5 h. The indole integrates demonstrated substantial antitumor efficacy in the MTT assay against the MDA-MB-231 cell line and substituting indole moiety with a halogen (bromo) significantly improves the anti-breast cancer action of the synthesized hybrids compared to the unsubstituted ring. Compound 4i featuring halogen substituent on both the indole and phenyl moieties displayed the highest anticancer action with an IC50 value of 2.121 μM The synthetic variants exhibited a notable binding propensity against the EGFR-TK receptor (PDB ID:1M17). Through in-silico ADMET screening, the pharmacological proclivity of the title compounds has been convicted. The notable bioactivity of the indole hybrids projects them as a potential lead in developing anti-breast cancer medications, especially against TNBC.

Synthesis and Evaluation of Thiazolyl-indole-2-carboxamide Derivatives as Potent Multitarget Anticancer Agents.

Cancer is a complex disease driven by the dysregulation of multiple signaling pathways and cellular processes. The development of compounds capable of exerting multitarget actions against these key pathways involved in cancer progression is a promising therapeutic approach. Here, a series of novel (E/Z)-N-(4-(2-(2-(substituted)hydrazineyl)-2-oxoethyl)thiazol-2-yl)-1H-indole-2-carboxamide derivatives (6a-6z) were designed, synthesized, and evaluated for their biological activity. Compounds 6e, 6i, 6q, 6v, 7a, and 7b exhibited exceptional cytotoxicity against various cancer cell lines, particularly 6i (IC50 = 6.10 ± 0.4 μM against MCF-7 cell lines) and 6v (IC50 = 6.49 ± 0.3 μM against MCF-7 cell lines). These potent compounds inhibited key protein kinases like EGFR, HER2, VEGFR-2, and CDK2, induced cell cycle arrest at the G2/M phase, and promoted apoptosis. Docking studies revealed improved binding affinity of 6i and 6v with target proteins compared to reference drugs. These findings highlight the promising potential of 6i and 6v as multitarget cancer therapeutics deserving further development.

Synthesis, cytotoxic evaluation, and in silico studies of novel benzenesulfonamide-thiazolidinone derivatives against colorectal carcinoma

Thirteen new benzenesulfonamide derivatives containing 4-thiazolidinone were synthesized. Their cytotoxic properties were tested on colorectal carcinoma (HT-29, DLD-1, COLO-205) and normal colon fibroblast (CCD-986Sk) cell lines. Compounds 3l (IC50=114.62 µM), 3a (IC50=25.82 µM), 3k (IC50=30.99 µM), and 3i (IC50=62.94 µM) showed the highest cytotoxicity on HT-29, DLD-1, COLO-205, and CCD-986Sk cell lines, respectively. Compound 3e (IC50=1075.4 µM) exhibited the least cytotoxicity against CCD-986Sk. The apoptosis profile of 5-FU at 5 µM was similar to that of compound 3e at 30 µM. Molecular docking and MD simulations showed stable interactions for compounds 3i and 3e. Molecular docking and MD simulations revealed that compounds 3i and 3e exhibit stable interactions with key cancer-related protein targets, particularly TGFβ2. These interactions suggest their potential as therapeutic agents. The predicted ADME parameters further highlighted compounds 3e and 3i for their favorable lipophilicity, solubility, permeability, and oral absorption profiles, supporting their promise as candidates for future drug development.

Design, synthesis and evaluation of novel LpxC inhibitors containing a hydrazone moiety as Gram-negative antibacterial agents

LpxC inhibitors are new-type antibacterial agents developed in the last twenty years, mainly against Gram-negative bacteria infections. To enable the development of novel LpxC inhibitors with potent antibacterial activities, several series of compounds were designed and synthesized and their antibacterial activities were evaluated against E. coli ATCC25922, P. aeruginosa ATCC27853, P. aeruginosa clinical isolate PAE 22-1, K. pneumoniae ATCC700603, K. pneumoniae clinical isolate KPN+22-1 in vitro. Compound 6i exhibited significant antibacterial activities against above five Gram-negative bacteria except P. aeruginosa ATCC27853. Moreover, compound 6i exhibited moderate liver microsomal stability and a promising pharmacokinetic profile (AUC0-t = 1050 ng h mL−1, oral bioavailability of 13.3 %) in Sprague-Dawley rats, acceptable PPB, low risk of drug-drug interactions and non-cytotoxic activity against hepatic cell. Collectively, compound 6i could be a promising Gram-negative antibacterial agent for further investigation.

Design and synthesis of spiro[pyrrolidine-3,3′-quinoline]-2,2′-dione derivatives as novel antifungal agents targeting chitin synthase

A novel spiro [pyrrolidine-3′,3′-quinoline]-2,2′-dione scaffold was constructed using fragments of quinoline and pyrrolidine. Subsequently, two series of derivatives were designed based on this scaffold. The enzyme inhibition experiments revealed that all designed compounds had moderate to good inhibitory activity against chitin synthase (CHS). The inhibitory effects of compounds 5i, 5j, 8i and 8n were approximately equal to that of control drug polyoxin B (PB, IP = 86.4 ± 2.9 %, IC50 = 0.082 ± 0.013 mM) which is a well-established CHS inhibitor. The results from enzyme kinetic parameters assays proved that these compounds act as non-competitive inhibitors of CHS. The sorbitol protection experiments demonstrated the tested compounds disrupted the synthesis of cell wall, which further verified that the target of these compounds is CHS. The experiments of antimicrobial showed that compounds 5b, 5f, 5i, 5j, 8f, 8i, 8m, 8n and 8o had strong antifungal activity against the four tested pathogenic fungi strains frequently emerging in clinical setting, with MIC values ranging from 4 to 32 μg/mL, which were either superior to or comparable with those of PB or fluconazole. Furthermore, these compounds displayed synergistic or additive effects when combined with fluconazole and these active compounds also showed promising activity against fluconazole-resistant and micafungin-resistant fungi variants. The result of antimicrobial experiments indicated that these compounds had minimal activity to tested bacterial strains. This suggests that they had selective antifungal activity. The results of ADME prediction, in conjunction with the cytotoxicity assay results, indicated that these compounds had favorable pharmacokinetic profiles and low toxicity. In addition, molecular docking studies illustrated that the compound had a strong affinity with the CHS, which was consistent with the results of enzymatic assays. These findings indicated that the designed compounds are non-competitive inhibitors of CHS with good selectivity and broad-spectrum antifungal activity, and possess significant antifungal activity against drug-resistant fungi, suggesting their potential as lead compounds for the development of novel drugs against drug-resistant fungi.

Organocatalytic[3 + 2]Cycloaddition: Synthesis of Quinazoline Containing Sulfonyl 1,2,3‐Triazoles as Potent EGFR Targeting Anti‐Breast Cancer Agents

ABSTRACTA general strategy was developed for the synthesis of new fully decorated 1,2,3‐triazoles (4a–4m and 5a–5g) containing quinazolines from 1‐(4‐nitrophenyl)‐2‐(quinazolin‐8‐ylsulfonyl) ethan‐1‐one and several azides using Ramachary organocatalytic azide‐ketone cycloaddition method. This reaction is reported for the synthesis of fully substituted sulfonyl‐1,2,3‐triazolyl quinazolins at a temperature of 100°C and the yields of the products produced are satisfactory to excellent. In vitro anticancer activity of all these derivatives demonstrated that six compounds, 4d, 4f, 4i, 4j, 5d, and 5e, were effective against two human breast cancer cell lines, MCF‐7 and MDA‐MB‐231. Compounds 4f, 4j, and 5d had more action against both cell lines than Erlotinib. Later, the findings of inhibitory assays of potent compounds 4d, 4f, 4i, 4j, 5d, and 5e against the tyrosine kinase EGFR revealed that compound 5d proved more potent than the reference erlotinib, while 4f and 4j had comparable efficacy. In silico molecular docking studies were also performed on six strong medicines to identify interactions with the EGFR receptor, and the energy estimations were shown to be comparable with the observed IC50 values. Ultimately, using SWISS/ADME and pkCSM, the in silico pharmacokinetic profile of potent compounds 4d, 4f, 4i, 4j, 5d, and 5e was predicted. All of the compounds precisely followed the principles established by Lipinski, Veber, Egan, and Muegge.

Development of new pyrazoles as class I HDAC inhibitors: Synthesis, molecular modeling, and biological characterization in leukemia cells.

Class I histone deacetylases (HDACs) are considered promising targets in current cancer research. To obtain subtype-selective and potent HDAC inhibitors, we used the aminobenzamide scaffold as the zinc-binding group and prepared new derivatives with a pyrazole ring as the linking group. The synthesized compounds were analyzed in vitro using an enzymatic assay against HDAC1, -2, and -3. Compounds 12b, 15b, and 15i were found to be potent HDAC1 inhibitors, also in comparison to the reference compounds entinostat and tacedinaline, with IC50 values of 0.93, 0.22, and 0.68 μM, respectively. The best compounds were measured for their cellular effect and target engagement in acute myeloid leukemia (AML) cells. In addition, we studied the interaction of the compounds with HDAC subtypes using docking and molecular dynamic simulations. In summary, we have developed a new chemotype of HDAC1 inhibitors that can be used for further structure-based optimization.

Synthesis, antimicrobial activity, molecular docking and MD simulation studies, in silico ADME investigations and thermo-acoustic studies of heterocyclic dihydropyrimidine substituted 1,3,4-thiadiazole scaffolds

The connections between the chemical structures and antibacterial properties of different functional groups including organic molecules were examined in this study. we have synthesized a novel series of 1,3,4-thiadiazole hybrids (5a-o) based on 3,4-dihydropyrimidines. After an effective synthesis, the compounds' structure was confirmed by using spectrum techniques like IR, 1H NMR, 13C NMR, and mass spectrometry. Elemental analyses were performed on a Perkin-Elmer 2400 CHN analyzer and the resulting data were within the accepted range (± 0.40) of the calculated values. The in vitro antimicrobial activity of the compounds against a range of bacterial and fungal species. Compound 5i showed potent inhibitory effects against P. aeruginosa with MIC values of 12.5 μg/ml S. aureus and A.niger were positively affected by compound 5k with MIC values of 12.5 μg/ml and 50 μg/ml, respectively. Based on the results, compounds 5a and 5o have moderate activity against C.albicans and E. coli with MIC values of 50 μg/ml and 62.5 μg/ml respectively. Furthermore, molecular docking and molecular dynamics simulations were used to identify the most stable conformation of newly discovered inhibitors. Thermo-acoustical properties of derivatives 5k and 5l in DMSO and DMF solvent have been determined at three different atmospheric pressure temperatures (298.15, 308.15, and 318.15)K. The components of the liquid mixture's molecular interactions have been taken into account to explain these results. The acquired results are interpreted in terms of interactions between solutes and solvents, providing insight into the compounds' potential to form or disrupt structures in DMSO and DMF solutions.