One-pot multicomponent synthesis of novel 3, 4-dihydro-3-methyl-2(1H)-quinazolinone derivatives and their biological evaluation as potential antioxidants,enzyme inhibitors,antimicrobials, cytotoxic and anti-inflammatory agents

A series of novel 3, 4-dihydro-3-methyl-2(1H)-quinazolinone derivatives with substituted amine moieties (1–13) and substituted aldehyde (S) were designed and synthesized by a reflux condensation reaction in the presence of an acid catalyst to get N-Mannich bases. Mannich bases were evaluated pharmacologically for their antioxidant, α-amylase enzyme inhibition, antimicrobial, cell cytotoxicity and anti-inflammatory activities. Most of the compounds exhibited potent activities against these bioassays. Among them, SH1 and SH13 showed potent antioxidant activity against DPPH free radical at IC₅₀ of 9.94 ± 0.16 µg/mL and 11.68 ± 0.32 µg/mL, respectively. SH7, SH10 and SH13 showed significant results in TAC and TRP antioxidant assays, comparable to that of ascorbic acid. SH2 and SH3 showed potent activity in inhibiting α-amylase enzyme at IC₅₀ of 10.17 ± 0.23 µg/mL and 9.48 ± 0.17 µg/mL, respectively, when compared with acarbose (13.52 ± 0.19 µg/mL). SH7 was the most active against gram-positive and gram-negative bacterial strains, SH13 being the most potent against P. aeruginosa by inhibiting its growth up to 80% (MIC = 11.11 µg/mL). SH4, SH5 and SH6 exhibited significant activity against some fungal strains. Among the thirteen synthesized compounds (SH1-SH13), four were screened out based on the results of brine shrimp lethality assay (LD₅₀) and cell cytotoxicity assay (IC₅₀), to determine their anti-cancer potential against Hep-G2 cells. The study was conducted for 24, 48, and 72 h. SH12 showed potent results at IC₅₀ of 6.48 µM at 72 h when compared with cisplatin (2.56 µM). An in vitro nitric oxide (NO) assay was performed to shortlist compounds for in vivo anti-inflammatory assay. Among shortlisted compounds, SH13 exhibited potent anti-inflammatory activity by decreasing the paw thickness to the maximum compared to the standard, acetylsalicylic acid (ASA).     

Design,synthesis, docking and mechanistic studies of new thiazolyl/thiazolidinylpyrimidine-2,4-dione antiproliferative agents

In this article, we display on the synthesis and biological evaluation of a new series of thiazolylpyrimidine 3a-l and thiazolidinylpyrimidine derivatives 5a-e. The structures of the new compounds were confirmed by using different spectral techniques including NMR, IR, mass spectroscopy in addition to elemental analyses. The cell viability of the new compounds was assessed against normal human mammary gland epithelial (MCF-10A) cell line. Data revealed that none of the compounds examined exhibited cytotoxic effects, and the cell viability for the compounds examined at 50 µM was greater than 87%. The antiproliferative activity of 3a-l and 5a-e was evaluated against four human cancer cell lines where the compounds showed promising activity. The most potent derivatives were compounds 3a, 3c, 3f, 3i, and 5b with GI₅₀ values ranging from 0.90 µM to 1.70 µM against the four cancer cell lines in comparison to doxorubicin (GI₅₀ = 1.10 µM). Compounds 3a, 3c and 3i showed potent antiproliferative activity with dual inhibitory action against EGFR and BRAF^V600E. Compounds 3a, 3c, and 3i demonstrated promising AutoDock scores towards EGFR and BRAF^V600E with values of ? 9.1 and ? 8.6, ?9.0 and ? 8.5, and ? 8.4 and ? 8.0 kcal/mol, respectively. The physicochemical and pharmacokinetic characteristics of 3a, 3c, and 3i were anticipated, demonstrating their oral bioavailability.     

Design,synthesis, biological activity evaluation and mechanism of action of myricetin derivatives containing thioether quinazolinone

Plant bacteria and viruses have a huge negative impact on food crops in the world. Therefore, it is important to create new and efficient green pesticides. In this paper, a series of myricetin derivatives containing quinazolinone sulfide were introduced. Good antibacterial and antiviral activities of the drug molecules 2-((3-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)propyl)thio)-6-fluoro-3-phenylquinazolin-4(3H)-one (T5) and 2-((4-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)butyl)thio)-6-methyl-3-phenylquinazolin-4(3H)-one (T15) respectively were found by biological activity screening. The value of dissociation constant (K_d) of compound T15 to TMV CP was 0.024 ± 0.006 μM, determined by Microscale thermophoresis (MST), which was far less than the value of 8.491 ± 2.027 μM of commercial drug ningnanmycin (NNM). The interaction between compound T15 and TMV CP was further verified by molecular docking. Compound T15 formed strong hydrogen bonds with residues SER:49 and SER:15 (1.92 Å, 2.20 Å, respectively), which were superior to the traditional hydrogen bonds formed by NNM with residue SER:215 (3.64 Å). In addition, the effects of compound T15 on the contents of chlorophyll and peroxidase (POD) in tobacco were studied, and the results indicated that compound T15 could enhance the disease resistance of tobacco plants to a certain extent.     

Integrating approach to discover novel bergenin derivatives and phenolics with antioxidant and anti-inflammatory activities from bio-active fraction of Syzygium brachythyrsum

Syzygium brachythyrsum is an important folk medicinal and edible plant in Yunnan ethnic minority community of China, however, little is known about the chemical and bio-active properties. The present study is aimed to identify the bioactive constituents with antioxidant and anti-inflammatory properties by an integrating approach. First, two new bergenin derivatives, brachythol A (1) and brachythol B (2), together with eleven known phenolic compounds (3–13) were isolated from bioactive fractions by phytochemical method. Among these isolated chemicals, five bergenin derivatives, along with 3 phenolics were found in Syzygium genus for the first time. Then, a further chemical investigation based on ultra-high-performance liquid chromatography-Q Exactive Orbitrap mass spectrometry resulted in a total of 107 compounds characterized in the bio-active fractions, including 50 bergenin derivatives, among which 14 bergenin derivatives and 14 phenolics were potential new natural chemicals. Most of the isolated compounds showed obvious antioxidant activities, while compounds 11, 12, and 13 had favorable performance. Eight compounds (2–5, 7, and 9–11) showed good inhibitory activity on nitric oxide (NO) production in macrophage RAW 264.7 cells. The structure–activity correlation analysis indicated that the antioxidation and anti-inflammatory activities enhanced when bergenin was esterified with gallic acid, caffeic acid or ferulic acid. This is the first report of bergenins in Syzygium genus and the richness in new bio-active bergenins and gallic acid derivatives indicated that Syzygium brachythyrsum is a promising functional and medicinal resource.     

Synthesis,anticancer activity and docking studies of pyrazoline and pyrimidine derivatives as potential epidermal growth factor receptor (EGFR) inhibitors

A search for anticancer agents has prompted the design and synthesis of new chalcone, pyrazoline and pyrimidine derivatives as potential epidermal growth factor receptor (EGFR) kinase inhibitors. These derivatives’ binding affinities were predicted by AutoDock, which showed that chalcone, pyrazoline and pyrimidine derivatives as EGFR-kinase inhibitors have good binding energies, ranging from ?10.91 to ?7.32 kcal/mol. These compounds were synthesized and characterized using elemental analysis (CHN analysis) and spectroscopic techniques (FTIR and NMR). Among the pyrazoline derivatives, 4Aiii has revealed a superior in vitro activity, inhibiting the EGFR kinase even at a low concentration of 0.19 μM compared to the pyrimidine derivative, 5Bii. In contrast, the cytotoxic effect of these derivatives was studied against hormonal and non-hormonal breast cancer cell lines. Most of the pyrazoline derivatives were able to express their cytotoxic effect efficiently against hormonal breast cancer but only one pyrimidine derivative managed to express its activity against hormonal breast cancer.     

Synthesis,pharmacological evaluation,and molecular modeling studies of novel isatin hybrids as potential anticancer agents

A novel series of isatin hybrids 5a-g was designed, synthesized, and characterized spectroscopically. The synthesized compounds were evaluated for their cytotoxic activity against the human breast cancer cell line (MCF-7) by in vitro MTT assay. Amongst the tested compounds, 5e compound bearing benzyl moiety at N₄ piperazine was found to be the most active with the promising IC₅₀ (12.47 µM). Moreover, the active compounds 5e and 5g were subjected to antitumor evaluation (in vivo) against Dalton’s ascitic lymphoma (DAL) cell line and the results suggested that the best active compound 5e can normalize the blood picture in comparison to the standard drug. An in silico molecular docking study using the crystal structure of Hsp90 protein described the role of significant protein–ligand interactions and revealed more insights into the binding mode. The drug-likeliness of the compounds was predicted based on Lipinski's rule of five and pharmacokinetic ADME parameters. Hence, the synthesized isatin hybrids could be novel starting point anticancer lead compounds demonstrating drug-like properties which can be explored further for anticancer drug discovery.     

Design,synthesis, crystal structures and biological evaluation of some 1,3-thiazolidin-4-ones as dual CDK2/EGFR potent inhibitors with potential apoptotic antiproliferative effects

A series of novel thiazolidine-4-one derivatives was synthesized by reacting 1,4-disubstituted hydrazine carbothioamides with diethyl azodicarboxylate. The structures were confirmed by spectroscopic data as well as single-crystal X-ray analyses. The antiproliferative activity of the synthesized compounds was investigated against four human cancer cell lines using an MTT assay. Compounds 5d, 5e, and 5f revealed the most potent antiproliferative activity with GI₅₀ values ranging from 0.70 µM to 1.20 µM, compared to doxorubicin GI₅₀ value = 1.10 µM. Compounds 5d, 5e, and 5f were further investigated for their inhibitory activities against CDK2 and EGFR as potential targets for their molecular mechanism. Compounds 5e and 5f have showed potent inhibitory activity to CDK2 enzyme with IC₅₀ values of 18 and 14 nM, which is more potent than the reference dinaciclib (IC₅₀ = 20 nM). Moreover, compounds 5e and 5f were the most potent EGFR inhibitors, with IC₅₀ values of 93 and 87 nM, respectively, compared to the reference erlotinib (IC₅₀ = 70 nM). In addition, the most potent derivatives were tested for their apoptotic activity against caspases 3, 8, and 9, and the results showed that compounds 5d, 5e, and 5f revealed a greater increase in active caspases 3,8 and 9 than doxorubicin. Also, compounds 5d, 5e, and 5f elevated cytochrome C levels in the MCF-7 human breast cancer cell line by about 15.5, 15.8, and 16.5 times, respectively. Finally, a molecular docking study was performed to investigate the binding sites of these compounds within the active sites of CDK2 and EGFR targets, and the results confirmed that the most potent CDK2 and EGFR inhibitor 5h also have showed the highest docking score.     

Synthesis,bioactivity and preliminary mechanism of action of novel trifluoromethyl pyrimidine derivatives

In this study, a series of trifluoromethyl pyrimidine derivatives 5a-5v were designed and synthesized. All synthetic compounds were original. Bioassay results showed that some of the target compounds were proved to have higher antiviral and antifungal activities than those of commercial agents. Especially, EC₅₀ values of the curative activity of compound 5j and the protection activity of compound 5m were 126.4 and 103.4 µg/mL, respectively, which were lower than that of ningnanmycin. Microscale thermophoresis experiment proved that there was a good interaction between compound 5m and TMV-CP. Meanwhile, the antifungal activity results showed that compound 5u had a significant on in vitro against Rhizoctonia solani (RS) activity, with the EC₅₀ value of 26.0 µg/mL, which was equal to that of azoxystrobin. As well, in vivo experiments on rice leaves showed that compound 5u could effectively control RS, and the effect of 5u on the cell morphology of RS was observed by scanning electron microscopy.     

Eco-friendly synthesis of size-controlled silver nanoparticles by using Areca catechu nut aqueous extract and investigation of their potent antioxidant and anti-bacterial activities

Silver nanoparticles (AgNPs) have attracted considerable attention owing to their unique biological applications. AgNPs synthesized by plant extract is considered as a convenient, efficient and eco-friendly material. In this work, the aqueous extract of Areca catechu L. nut (ACN) was used as the reducing and capping agents for one-pot synthesis of AgNPs, and their antioxidant and antibacterial activities were investigated. UV (Ultra Violet)-visible spectrum and dynamic light scattering (DLS) analysis revealed that the size of AgNPs was sensitive to the synthesis conditions. The synthesized AgNPs were composed of well-dispersed particles with an small size of about 10 nm under the optimal conditions (pH value of extract was 12.0; AgNO₃ concentration was 1.0 mM; reaction time was 90 min). In addition, scanning electron microscope with energy dispersive X-ray (SEM-EDX), transmission electron microscopy (TEM) and X-ray diffraction (XRD) results further verified that the synthesized AgNPs had a stable and well-dispersed form (Zeta potential value of ?30.50 mV and polydispersity index of 0.328) and a regular spherical shape (average size of 15–20 nm). In addition, Fourier transform infrared spectrometry (FTIR) results revealed that phytochemical constituents in ACN aqueous extract accounted for Ag⁺ ion reduction, capping and stabilization of AgNPs. The possible reductants in the aqueous extract of Areca catechu L. nut were identified by high-performance liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry (HPLC-ESI-qTOF/MS) method. More importantly, the synthesized AgNPs indicated excellent free radical scavenging activity of 1,1-diphenyl-2-picrylhydrazyl (DPPH, IC₅₀ = 11.75 ± 0.29 μg/mL) and 2,2-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS⁺, IC₅₀ = 44.85 ± 0.37 μg/mL), which were significant higher than that of ascorbic acid. Moreover, AgNPs exhibited an enhanced antibacterial activity against six selected common pathogens (especially Escherichia coli and Staphylococcus aureus) compared with AgNO₃ solution. In a short, this study showed that the Areca catechu L. nut aqueous extract could be applied for eco-friendly synthesis of AgNPs.     

Efficient synthesis of magnetic nanoparticle-Musa acuminata peel composite for the adsorption of anionic dye

The impregnation of magnetite (Mt) nanoparticle (NPs) onto Musa acuminata peel (MApe), to form a novel magnetic combo (MApe-Mt) for the adsorption of anionic bromophenol blue (BPB) was studied. The SEM, EDX, BET, XRD, FTIR and TGA were used to characterize the adsorbents. The FTIR showed that the OH and CO groups were the major sites for BPB uptake onto the adsorbent materials. The average Mt crystalline size on MApe-Mt was 21.13 nm. SEM analysis revealed that Mt NPs were agglomerated on the surface of the MApe biosorbent, with an average Mt diameter of 25.97 nm. After Mt impregnation, a decrease in BET surface area (14.89 to 3.80 m²/g) and an increase in pore diameter (2.25–3.11 nm), pore volume (0.0052–0.01418 cm³/g) and pH point of zero charge (6.4–7.2) was obtained. The presence of Pb(II) ions in solution significantly decreased the uptake of BPB onto both MApe (66.1–43.8%) and MApe-Mt (80.3–59.1%), compared to other competing ions (Zn(II), Cd(II), Ni(II)) in the solution. Isotherm modeling showed that the Freundlich model best fitted the adsorption data (R² > 0.994 and SSE < 0.0013). In addition, maximum monolayer uptake was enhanced from 6.04 to 8.12 mg/g after Mt impregnation. Kinetics were well described by the pseudo-first order and liquid film diffusion models. Thermodynamics revealed a physical, endothermic adsorption of BPB onto the adsorbents, with ΔH^o values of 15.87–16.49 kJ/mol, corroborated by high desorption (over 90%) of BPB from the loaded materials. The viability of the prepared adsorbents was also revealed in its reusability for BPB uptake.     

Synthesis,antifungal activity and in vitro mechanism of novel 1-substituted-5-trifluoromethyl-1H-pyrazole-4-carboxamide derivatives

Inspired by the wide application of amides in plant pathogens, a series of novel 1-substituted-5-trifluoromethyl?1H?pyrazole-4-carboxamide derivatives were designed and synthesized. Bioassay results indicated that some target compounds exhibited excellent and broad-spectrum in vitro and certain in vivo antifungal activities. Among them, the in vitro EC₅₀ values of Y₁₃ against G. zeae, B. dothidea, F. prolifeatum and F. oxysporum were 13.1, 14.4, 13.3 and 21.4 mg/L, respectively. The in vivo protective activity of Y₁₃ against G. zeae at 100 mg/L was 50.65%. SAR analysis revealed that the phenyl on the 1-position of the pyrazole ring was important for this activity. An antifungal mechanism study of Y₁₃ against G. zeae demonstrated that this compound may disrupt the cell membrane of mycelium, thus inhibiting the growth of fungi. These mechanistic study results were inconsistent with those for traditional amides and may provide a novel view for deep study of this series of pyrazole carboxamide derivatives.     

Pharmacophore model-aided virtual screening combined with comparative molecular docking and molecular dynamics for identification of marine natural products as SARS-CoV-2 papain-like protease inhibitors

Targeting SARS-CoV-2 papain-like protease using inhibitors is a suitable approach for inhibition of virus replication and dysregulation of host anti-viral immunity. Engaging all five binding sites far from the catalytic site of PLpro is essential for developing a potent inhibitor. We developed and validated a structure-based pharmacophore model with 9 features of a potent PLpro inhibitor. The pharmacophore model-aided virtual screening of the comprehensive marine natural product database predicted 66 initial hits. This hit library was downsized by filtration through a molecular weight filter of ≤ 500 g/mol. The 50 resultant hits were screened by comparative molecular docking using AutoDock and AutoDock Vina. Comparative molecular docking enables benchmarking docking and relieves the disparities in the search and scoring functions of docking engines. Both docking engines retrieved 3 same compounds at different positions in the top 1 % rank, hence consensus scoring was applied, through which CMNPD28766, aspergillipeptide F emerged as the best PLpro inhibitor. Aspergillipeptide F topped the 50-hit library with a pharmacophore-fit score of 75.916. Favorable binding interactions were predicted between aspergillipeptide F and PLpro similar to the native ligand XR8-24. Aspergillipeptide F was able to engage all the 5 binding sites including the newly discovered BL2 groove, site V. Molecular dynamics for quantification of Cα-atom movements of PLpro after ligand binding indicated that it exhibits highly correlated domain movements contributing to the low free energy of binding and a stable conformation. Thus, aspergillipeptide F is a promising candidate for pharmaceutical and clinical development as a potent SARS-CoV-2 PLpro inhibitor.     

Semisynthetic derivatives of haemanthamine and their in vitro antiproliferative activity evaluation against a panel of human cell lines

In this study, a new series of aliphatic, cyclic, and heterocyclic derivatives of haemanthamine was designed and synthesized to enhance its inhibitory effect on the proliferation and viability of cancer cells. A library of haemanthamine derivatives was subjected to 10 μM single-dose cytotoxicity screening against a panel of human cell lines of various histotypes. Initial cytotoxicity evaluation of the parent haemanthamine (1) and a series of twenty-nine (2–30) semisynthetic analogues showed that for some of the newly formed derivatives, a certain cytotoxic effect was observed, in one case even higher than that of the parent compound. Specifically, 11-O-(4-chloro-3-nitrobenzoyl)haemanthamine (21) showed an enhanced antiproliferative effect, where the mean growth percent (GP) value was 5% compared to haemanthamine, leading to a decrease in the GP to 25%. Among ten cell lines tested, derivative 21, bearing a substituted aromatic ester bond via C-11 of haemanthamine, had excellent activity for inhibiting the growth of HeLa (IC₅₀ = 0.2 ± 0.1 μM), A549 (IC₅₀ = 1.7 ± 0.1 μM) and HT-29 (IC₅₀ = 2.2 ± 0.1 μM) cells. When evaluating response kinetics, we found that 21 and haemanthamine dose- and time-dependently suppressed the proliferation of A549 cells. In contrast to haemanthamine (1), Trypan blue and lactate dehydrogenase (LDH) release assay revealed that 21 was capable of reducing the survival of A549 cells.     

SAR studies of quinoline and derivatives as potential treatments for Alzheimer’s disease

Quinoline analogs are an important class of N-based heterocyclic compounds, which have received extensive attention because of their use in medicinal chemistry and organic synthesis. Over the past few decades, several new scaffold-based functionalization synthesis strategies have been reported for quinolines. Quinoline derivatives have a wide range of biological activities, including anti-Alzheimer’s disease activity. Herein, we review research on quinoline and related analogs as anti-Alzheimer’s disease agents from 2001 to 2022 and particularly highlight the structure–activity relationships and molecular binding modes. This review provides information for the rational design of more effective and target-specific drugs for Alzheimer's disease.     

Novel aromatic carboxamides from dehydroabietylamine as potential fungicides: Design,synthesis and antifungal evaluation

The present study was carried out to design and synthesize a number of novel aromatic carboxamide derivatives of dehydroabietylamine. The preliminary antifungal assay indicated that most of title compounds displayed moderate to good antifungal activity toward the six fungal strains in vitro. Compounds 3i, 3q, 4b and 4d showed significant antifungal activity against Sclerotinia sclerotiorum, with EC₅₀ values ranging from 0.067 ～ 0.393 mg/L. Compounds 3i, 4b and 4d also showed pronounced mycelial growth inhibition activities against B. cinerea and A. solani. Furthermore, in the in vivo assay, compound 4b exhibited brilliant protective activity against S. sclerotiorum-infected rape leaves. Meanwhile, the in vivo bioassay on tomato plants infected by B. cinerea showed that compound 3i and 4d displayed excellent protective activity at 200 mg/L, which were near to boscalid. Primary mechanistic study revealed that 4b could inhibit sclerotia formation as well as reduce the exopolysaccharide level. SEM and TEM analysis indicated that 4b possessed a strong ability to destroy the surface morphology of mycelia, cell structure and seriously interfere with the growth of the fungal pathogen. In addition, 4b exhibited good inhibitory activity (IC₅₀ = 23.3 ± 1.6 μM) toward succinate dehydrogenase (SDH). Molecular modeling study confirmed the binding modes between compound 4b and SDH. The above antifungal results and fungicidal mechanism study revealed that this class of dehydroabietylamine derivatives could be potential SDH inhibitors and lead compounds for novel fungicides development.     

Ascorbic acid supported Carboxymethyl cellulose stabilized silver nanoparticles as optical nanoprobe for Au3+ detection in environmental sample

Heavy metals (HMs), pollution of major environmental matrices and its attendant effects on human health and the environment, continue to generate huge scientific interest, particularly in monitoring and detection. Herein, the optical property of carboxymethyl cellulose stabilized silver nanoparticles (CMC-AgNPs), supported with ascorbic acid, is exploited as a colorimetric probe for the detection of toxic Au³⁺ ion in solution. The as-synthesized CMC-AgNPs showed sharp absorption maximum at 403 nm, with sparkling yellow color and average particles size distribution less than 10 nm. It was further characterized using ATR-FTIR, TEM, FESEM/EDS, XRD and DLS/zeta potential analyzer. Au³⁺ ion detection strategy involves the addition of ascorbic acid (AA) to a pH adjusted CMC-AgNPs, followed by the analyte addition. AA would facilitate the reduction of Au³⁺ on CMC-AgNPs (seed), with resultant color perturbations from light yellow to yellow, orange, ruby red and purple red, under 8 min incubation, at room temperature (RT). The CMC-AgNPs could also serve as a catalyst, by promoting AA mediated reduction of Au³⁺, in-situ. Moreover, we propose, that the color and the absorption spectra change is attributed to the deposition of gold nanoparticles (AuNPs), on the CMC-AgNPs/AA probe, to form (CMC-Ag@Au) nanostructures, depending on the analyte concentration. Absorbance ratio (A₅₄₀/A₄₀₃) showed good linearity with Au³⁺ concentration from 0.25 to 100.0 µM, and an estimated LOD of 0.061 µM. The assay was applied to Au³⁺ detection in environmental wastewater sample, showing satisfactory real sample detection potentiality.     

Recent trends in the stereoselective synthesis of (poly)-substituted 2-oxo acids by biocatalyzed aldol reaction

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Recent progress in TiO2-based photocatalysts for hydrogen evolution reaction: A review

TiO₂ has gained tremendous attention as a cutting-edge material for application in photocatalysis. The performance of TiO₂ as a photocatalyst depends on various parameters including morphology, surface area, and crystallinity. Although TiO₂ has shown good catalytic activity in various catalysis systems, the performance of TiO₂ as a photocatalyst is generally limited due to its low conductivity and a wide optical bandgap. Numerous different studies have been devoted to overcome these problems, showing significant improvement in photocatalytic performance. In this study, we summarize the recent progress in the utilization of TiO₂ for the photocatalytic hydrogen evolution reaction (HER). Strategies for modulating the properties toward the high photocatalytic activity of TiO₂ for HER including structural engineering, compositional engineering, and doping are highlighted and discussed. The advantages and limitations of each modification approach are reviewed. Finally, the remaining obstacles and perspective for the development of TiO₂ as photocatalysts toward high efficient HER in the near future are also provided.