Compounds 5r Research Articles

Design, synthesis, QSAR modelling and molecular dynamic simulations of N-tosyl-indole hybrid thiosemicarbazones as competitive tyrosinase inhibitors

Tyrosinase is an enzyme crucial for the progression of melanogenesis. Immoderate production of melanin may be the cause of hyperpigmentation and darkening leading to skin diseases. Tyrosinase is the most researched target for suppressing melanogenesis since it catalyzes the rate-limiting stage of melanin production. Thiosemicarbazones have been reported to possess strong inhibition capability against tyrosinase. We have designed and synthesized eighteen N-tosyl substituted indole-based thiosemicarbazones as competitive tyrosinase inhibitors in the current work. All the compounds exhibited outstanding to good potency with half maximal inhibitory concentration in the range of 6.40 ± 0.21 µM to 61.84 ± 1.47 µM. The compound 5r displayed the top-tier inhibition amongst the entire series with IC50 = 6.40 ± 0.21 µM. Compounds, 5q and 5r exhibited competitive inhibitions in concentration dependent manner with Ki = 3.42 ± 0.03 and 10.25 ± 0.08 µM respectively. The binding mode of 5r was evaluated through in silico molecular dynamics simulations and molecular docking, while ADME assessment studies predicted the drug-like characteristics of the derivatives. The newly synthesized derivatives may serve as a structural guide for designing and developing novel tyrosinase inhibitors.

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.

Synthesis and antimicrobial activity of benzoxazine/benzothiazine appended 1,2,3-triazole hybrids

In the present context to rationalize the search for new effective antimicrobial agents against the infections caused by microbes, a series of benzoxazine/benzothiazine appended 1,2,3-triazole hybrids were designed and synthesized via click reaction with ingredients of two or more bioactive moieties through the concept of molecular hybridization. Various spectral techniques such as FTIR, 1H NMR, 13C NMR, 2D NMR and HRMS were utilized for structural elucidation of the synthesized hybrids. The serial dilution method was employed for performing the antimicrobial activity of synthesized triazoles against four bacterial (S. aureus, B. subtilis, E. coli, K. pneumoniae) and two fungal (C. albicans, A. niger) strains. The antibacterial results demonstrated that a couple of hybrids show noteworthy outcomes related to standard medication. Compound 4r was indicated great action against E. coli with MIC values 0.0259 µmol/mL. Based on outcomes of antibacterial activity, molecular docking study was carried out with E. coli DNA gyrase to understand the binding behavior. To check out the drug-likeness, in silico ADME (Absorption, Distribution, Metabolism and Excretion) studies of synthesized hybrids were also analyzed and found that compounds can be developed as potential oral drug candidates.

Barbiturate-sulfonate hybrids as potent cholinesterase inhibitors: design, synthesis and molecular modeling studies.

Aim: Design and synthesis of a series of 5-benzylidene(thio)barbiturates 3a-r.Methodology: Evaluation of the inhibitory activity of the new chemical entities on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using Donepezil as the standard reference.Results & Conclusion: Compound 3r emerged as the most potent AChE inhibitor (IC50=9.12μM), while compound 3q exhibited the highest inhibitory activity against BChE (IC50=19.43μM). Toxicological bioassays confirmed the absence of cytotoxicity for the most potent compounds at the tested doses. Molecular docking analysis demonstrated that the tested derivatives effectively bind to the active sites of both enzymes. Overall, this study sheds light on the potential of barbiturate-sulfonate conjugates as promising drug candidates.

Synthesis, biological evaluation, theoretical calculations, QSAR and molecular docking studies of novel arylaminonaphthols as potent antioxidants and BChE inhibitors

A completely green protocol was developed for the synthesis of a series of arylaminonaphthol derivatives in the presence of N-ethylethanolamine (NEEA) as a catalyst under ultrasonic irradiation and solventless conditions. The major assets of this methodology were the use of non-toxic organic medium, available catalyst, mild reaction condition, and good to excellent yield of desired products. All of the synthesized products were screened for their in vitro antioxidant activity using DPPH, ABTS, and Ferric-phenanthroline assays and it was found that most of them are potent antioxidant agents. Also, their butyrylcholinesterase inhibitory activity has been investigated in vitro. All tested compounds exhibited potential inhibitory activity toward BuChE when compared to standard reference drug galantamine, however, compounds 4r, 4u, 4 g and 4x gave higher butyrylcholinesterase inhibitory with IC50 values of 14.78 ± 0.65 µM, 16.18 ± 0.50 µM, 20.00 ± 0.50 µM, and 20.28 ± 0.08 µM respectively. On the other hand, we employed density functional theory (DFT), calculations to analyze molecular geometry and global reactivity descriptors, and MESP analysis to predict electrophilic and nucleophilic attacks. A quantitative structure–activity relationship (QSAR) investigation was conducted on the antioxidant and butyrylcholinesterase properties of 25 arylaminonaphthol derivatives, resulting in robust and satisfactory models. To evaluate their anti-Alzheimer’s activity, compounds 4 g, 4q, 4r, 4u, and 4x underwent docking simulations at the active site of the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), revealing why these compounds displayed superior activity, consistent with the biological findings.

Synthesis, Nematicidal Activity, and Molecular Docking of Some New Pyrazole-5- carboxamide Derivatives with Flexible Chain

A series of new pyrazole-5-carboxamide derivatives was synthesized containing flexible chain moiety. The synthetic route involved four-step approach starting from ethyl 3-ethyl-1-methyl-1H-pyrazole-5-carboxylate (1). The primarily nematicidal bioassay results have shown that some of them exhibited moderate activity against Meloidogyne incognita at 10 mg/L. In addition, the molecular docking simulation results indicated that compound 5r interacts with succinate dehydrogenase (SDH) through p-cation, p-p, and hydrogen bond interaction, which may provide useful information to further design novel nematicides.. KEYWORDS :Molecular docking, Nematicidal activity, Pyrazole carboxamide, Synthesis.

1,2,3-Triazole-totarol conjugates as potent PIP5K1α lipid kinase inhibitors

The human phosphatidylinositol 4-phosphate 5-kinase type I α (hPIP5K1α) plays a key role in the development of prostate cancer. In this work, seventeen derivatives of the natural diterpene totarol were prepared by copper(I)-catalysed Huisgen 1,3-dipolar cycloaddition reaction of the correspondingO-propargylated totarol with aryl or alkyl azides and screened for their inhibitory activities toward hPIP5K1α. Five compounds, 3a, 3e, 3f, 3i, and 3r, strongly inhibited the enzyme activity with IC50 values of 1.44, 0.46, 1.02, 0.79, and 3.65 µM, respectively, with the most potent inhibitor 3e 13-[(1-(3-nitrophenyl)triazol-4yl)methoxy]-totara-8,11,13-triene). These compounds were evaluated on their antiproliferative effects in a panel of prostate cancer cell lines. Compound 3r inhibited the proliferation of LNCaP, PC3 and DU145 cells at 20 µM, strongly, but also has strong cytotoxic effects on all tested cells.

Design, synthesis, and biological evaluation of novel benzimidazole derivatives as anti-cervical cancer agents through PI3K/Akt/mTOR pathway and tubulin inhibition

Phosphatidylinositol 3-kinase (PI3K) is one of the most attractive therapeutic targets for cervical cancer treatment. In this study, we designed and synthesized a series of benzimidazole derivatives and evaluated their anti-cervical cancer activity. Compound 4r exhibited strong antiproliferative activity in different cervical cancer cell lines HeLa, SiHa and Ca Ski, and relative lower cytotoxicity to normal hepatic and renal cell lines LO2 and HEK-293t (IC50 values were at 21.08 μM and 23.96 μM respectively). Its IC50 value was at 3.38 μM to the SiHa cells. Further mechanistic studies revealed that 4r induced apoptosis, arrested cell cycle in G2/M phase, suppressed PI3K/Akt/mTOR pathway and inhibit the polymerization of tubulin. Molecular docking study suggested that 4r formed key H-bonds action with PI3Kα (PDB ID:8EXU) and tubulin (PDB ID:1SA0). Zebrafish acute toxicity experiments showed that high concentrations of 4r did not cause death or malformation of zebrafish embryos. All these results demonstrated that 4r would be a promising lead candidate for further development of novel PI3K and tubulin dual inhibitors in cervical cancer treatment.

Microwave accelerated green access to functionalized pyrazolo[5,1-b]quinazoline-3-carboxylate scaffold and their pharmacological screening

Herein, we explored an environmentally benign synthesis of pyrazolo[5,1-b]quinazoline-3-carboxylate derivatives 4(a-u) as potential antimicrobial, antitubercular as well as antimalarial agents. Our approach employed microwave-assisted PEG-400 as a biodegradable reaction medium to expedite the one-pot fusion of 1,3-dicarbonyl compounds 1(a-c), substituted aldehydes 2(a-g), and ethyl-3-aminopyrazole-4-carboxylate (3a). The current protocol offers the advantages of a low E-factor, high atom economy, mild reaction condition, reusability of PEG-400 and produce water as a byproduct with a favorable yield (up to 96 % yield) in a short reaction time. Compared to the MIC values of standard antibiotics against their respective strains, compound 4g exhibited superior activity against Bacillus subtilis while compound 4r demonstrated a more favorable MIC against Pseudomonas aeruginosa. Against Candida albicans, compounds 4c, 4f, 4i, 4o, 4r, and 4u showed excellent antifungal activity as compared standard medications griseofulvin and fluconazole. Compounds 4d and 4p showed significant antitubercular activity against Mycobacterium tuberculosis H37Rv whereas compounds 4d, 4e, 4p and 4q showed good antimalarial activity against Plasmodium falciparum in contrast to standard drug ciprofloxacin and quinine respectively. In vitro cytotoxicity assay against S. pombe cells indicated that the majority of tested compounds exhibit more than 80 % cell viability, suggesting their non-toxic nature. A molecular docking study was conducted to elucidate the potential interactions between compound 4u and the active site of DNA gyrase. Based on the noteworthy findings from the investigation of drug-like properties and ADMET predictions, these derivatives depict an efficient multifunctional action and offer prospective access for future discoveries of antimicrobial, antitubercular, as well as antimalarial studies.

Novel dual-target FAAH and TRPV1 ligands as potential pharmacotherapeutics for pain management

Dual-acting drugs that simultaneously inhibit fatty acid amide hydrolase (FAAH) and antagonize the transient receptor potential vanilloid 1 (TRPV1) is a promising stronger therapeutic approach for pain management without side effects associated with single-target agents. Here, several series of dual FAAH/TRPV1 blockers were designed and synthesized through rational molecular hybridization between the pharmacophore of classical TRPV1 antagonists and FAAH inhibitors. The studies resulted in compound 2r, which exhibited strong dual FAAH/TRPV1 inhibition/antagonism in vitro, exerted powerful analgesic effects in formalin-induced pain test (phase II, in mice), desirable anti-inflammatory activity in carrageenan-induced paw edema in rats, no TRPV1-related hyperthermia side effect, and favorable pharmacokinetic properties. Meanwhile, the contributions of TRPV1 and FAAH to its antinociceptive effects were verified by target engagement and molecular docking studies. Overall, compound 2r can serve as a new scaffold for developing FAAH/TRPV1 dual-activie ligands to counteract pain.

Synthesis of anthraquinone-connected coumarin derivatives via grindstone method and their evaluation of antibacterial, antioxidant, tyrosinase inhibitory activities with molecular docking, and DFT calculation studies

Anthraquinones and coumarins have excellent pharmacological activities and are an important class of natural plant metabolites with various biological activities. In this study, anthraquinone-9,10-dione and coumarin derivatives were combined to develop a novel anthraquinone-connected coumarin-derivative sequence. The synthesised novel anthraquinone-connected coumarin derivatives (1a-t) were screened for in vitro antibacterial, antioxidant, and tyrosinase inhibitory activities. The antibacterial activities of the synthesised compounds (1a–t) were tested against both gram-positive and gram-negative bacteria. Specifically, compound 1t was more active against E. aerogenes than ciprofloxacin. With regard to antioxidant activity, compound 1o (50.68 % at 100 μg/mL) was highly active compared to the other compounds, whereas it was less active than the standard BHT (76.74 % at 100 μg/mL). In terms of compound 1r (9.31 ± 0.45 μg/mL) was highly active against tyrosinase inhibitory activity compared with kojic acid (10.42 ± 0.98 μg/mL). In the molecular docking study, compound 1r had a higher docking score (−8.8 kcal mol−1) than kojic acid (−1.7 kcal mol−1). DFT calculations were performed to determine the energy gap of highly active compound 1r (ΔE = 0.11) and weakly active compound 1a (ΔE = 0.12). In this study, we found that every molecule displayed significant antibacterial, antioxidant, and tyrosinase inhibitory properties. Based on these reports, compounds 1r and 1t may act as multi-target agents.

Novel 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide based thiosemicarbazides as potent and selective inhibitors of tumor-associated human carbonic anhydrase IX and XII: Synthesis, cytotoxicity, and molecular modelling studies

In the pursuit of discovering new selective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, a small collection of novel thiosemicarbazides (5a-5t) were designed and synthesized starting from 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide which was evaluated as a potent inhibitor of different CA isoforms in a previous study. The newly synthesized compounds were examined against four human carbonic anhydrases (hCA), namely transmembrane tumor-related hCA IX/XII and cytosolic widespread off-targets hCA I/II. In enzyme inhibition assays, all nineteen compounds display up to ∼340-fold selectivity for hCA IX/XII over off-target isoforms hCA I/II. Four compounds have enzyme inhibition values (Ki) lower than 10 nM against tumor-associated isoforms hCA IX/XII including two compounds in the subnanomolar range (5r and 5s; hCA XII; Ki: 0.69 and 0.87 nM). The potential binding interactions of the most potent compounds against hCA IX and XII, compounds 5s and 5r, respectively, were investigated using ensemble docking and molecular dynamics studies. Cell viability assays using human colorectal adenocarcinoma cell line HT-29 and healthy skin fibroblasts CCD-86Sk show that compound 5e selectively inhibits HT-29 cancer cell proliferation (IC50: 53.32 ± 7.74 µM for HT-29; IC50: 74.64 ± 14.15 µM for CCD-986Sk). Finally, Western blot assays show that compounds 5e and 5r significantly reduce the expression of hCA XII in HT-29 cells. Moreover, 5e shows better cytotoxic activity in hypoxia compared to normoxic conditions. Altogether, the newly designed compounds show stronger inhibition of the tumor-associated hCA IX and XII isoforms and several tested compounds show selective cytotoxicity as well as downregulation of hCA XII expression.

Synthesis and catalytic properties of palladium(II) complexes with P,π-chelating ferrocene phosphinoallyl ligands and their non-tethered analogues.

Hybrid phosphines usually combine a phosphine moiety with another heteroatom secondary donor group in their structures while compounds equipped with hydrocarbyl π-donor moieties remain uncommon. This contribution reports the synthesis and structural characterization of the first P/π-allyl-chelating complexes that were obtained using the structurally flexible and redox-active ferrocene unit as the scaffold, viz. [PdCl(R2PfcCHCHCH2-η3:κP)] (1R; R = Ph and cyclohexyl (Cy); fc = ferrocene-1,1'-diyl). These compounds were synthesized from the respective phosphinoferrocene carboxaldehydes R2PfcCHO via reaction with vinylmagnesium bromide to generate 1-(phosphinoferrocenyl)allyl alcohols, which were subsequently acetylated. The resulting allyl acetates reacted smoothly with [Pd2(dba)3]/[Et3NH]Cl (dba = dibenzylideneacetone) to produce the target compounds. Complexes 1R and their nontethered analogues [PdCl(η3-C3H5)(FcPR2-κP)] (5R; Fc = ferrocenyl) were evaluated as pre-catalysts for the Pd-catalysed allylic amination of cinnamyl acetate with aliphatic amines and Suzuki-Miyaura-type cross-coupling of 4-tolylboronic acid with benzoyl chloride. In these reactions, better results were achieved with compounds 5R (particularly with 5Ph), presumably because they form more stable LPd(0)-type catalysts.

Synthesis and characterization of 4(3-(4-Fluorophenyl)2-methyl-1-(4-(sulfonamidesubtituted)phenyl)-4-oxoazitidin-2-yl)-3-methyl-1-(p-tolyl)-1H-pyrazol-5(4H)One as Antibacterial, and Antioxidant Candidates

A series of all novels 4(3-(4-Fluorophenyl)2-methyl-1-(4-(sulfonamidesubtituted)phenyl)-4-oxoazitidin-2-yl)-3-methyl-1-(p-tolyl)-1H-pyrazol-5(4H) One 5a-5r poly functionalized derivatives were containing sulfonamide functionality united with 2-Azitidinone (Azitidin-2-one or β-lactam) group which designed and synthesized with moderate to good yield. The starting with 4-acyl-2-pyrazolin-5-one (APYZ) 1 which condensed with different sulfonamides 2 produced intermediate Schiff bases 4-(arylideneamino)-N-(thiazol-2-yl)benzensulfonamide 3a-r were cyclization with 2-(4-flourophenyl)chloroacetylchloride (F-CAC) 4 which produced targeted compounds 5a-5r of 2-Azitidinone versatile group in good yield. The isolated compounds were recognized by spectral and elemental investigation. The compounds 5f, 5l, 5n, and 5r showed excellent increased antibacterial activity compared to streptomycin standard drug and 5c, 5f, 5l, 5o, and 5r showed moderate to good antioxidant properties with used DPPH radical scavenging assay.

Zinc acetate-catalyzed, green and efficient synthesis of xanthene derivatives under ultrasound irradiation: X-ray crystallographic analysis and in silico study.

A simple, one-pot method using zinc acetate and ultrasound irradiation has been developed to synthesize xanthene derivatives from cyclic diketones and aromatic aldehydes, yielding good to excellent results. This method offers advantages like mild conditions, high atom economy, easy isolation, and a recyclable catalyst. All xanthene derivatives, including two new molecules, were confirmed using standard spectroscopic methods, with X-ray crystallographic data provided for compound 3r. The synthesized molecules were shown to inhibit the VEGFR-2 enzyme, confirmed by molecular docking studies. A 200 ns molecular dynamics simulation validated these findings, showing significant stability for the 3e-VEGFR-2 complex after 1 ns and the 3p-VEGFR-2 complex for 8 ns. DFT calculations were used to analyze electronic and geometric properties, including HOMO and LUMO bandgap energies and molecular electrostatic potential surfaces. Additionally, the absorption, distribution, metabolism, and excretion (ADME) properties of the synthesis compounds were assessed.

An Efficient Copper-Mediated Route for the Synthesis of 2-Substituted Benzothiazoles from Dithioesters and Investigation of Their Antibacterial Activities

AbstractAn efficient one-pot synthesis of 2-aryl/2-aroylbenzothiazoles through copper-mediated condensation of 2-chloroanilines with dithioesters has been developed. The method provides good isolated yields and exhibits broad functional group tolerance, accommodating both electron-donating and electron-withdrawing groups on the substrates. A series of synthesized compounds was evaluated for their antibacterial activity against Klebsiella pneumoniae, Pseudomonas aeruginosa, and Salmonella paratyphi. Among the series, three compounds exhibited a significant inhibitory effect against the tested pathogens, with one also demonstrating potential as an effective compound in both the agar well diffusion assay and broth microdilution assay. Additionally, the three compounds displayed strong inhibitory effects on biofilm formation of the pathogens in both the crystal violet assay and MTT assay at a concentration of 10 mM. These findings highlight the promising antimicrobial and antibiofilm properties of these compounds, indicating the potential for their further investigation as potential therapeutic agents against the tested pathogens.

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.

Synthesis and Antifungal Evaluation of New Azole Derivatives against Candida albicans.

In this study, we designed and prepared a series of new azole derivatives by recombination of fluconazole (FLC) and ketoconazole units, and in vitro antifungal activities against Candida albicans were evaluated. The results indicated that most azoles showed good antifungal activity against the drug-sensitive C. albicans strain, especially compounds 6a, 6e, 6n, 6p, 6r, 6s, 6t, and 6v, which displayed better antifungal activity (MIC50 < 1.0 μg/mL) than FLC against SC5314. The further mechanism study showed that compound 6r could significantly inhibit the formation of C. albicans biofilm, increase the permeability of the cell membrane, reduce the ergosterol level of the cell membrane, damage the membrane structure, and destroy the integrity of the cell structure to exert excellent antifungal activity. Subsequently, a molecular docking study indicated that azole compounds could inhibit cytochrome P450 14α-demethylase (CYP51). Therefore, these azole derivatives can be considered as potent antifungal drugs to treat fungal infections.

Biological evaluation of carbazoyl hydrazine derivatives as potential Pim-1 kinase inhibitors for the treatment of human liver cancer

In this study, we investigated the anticancer activity of novel carbazoyl hydrazine derivatives as inhibitors of Proviral Integration site for Moloney murine leukemia virus kinase 1 (Pim-1) in liver cancer cells in vitro. The obtained compounds were characterized using 1H NMR, 13C NMR, HRMS, and FTIR. Through computer-assisted screening, antitumor activity testing, and Pim-1 inhibitory activity testing, most of the compounds exhibited significant inhibitory activity against liver cancer cell lines. Among them, compound N'-(2-(9H-carbazol-9-yl)acetyl)-4-fluorobenzohydrazide (4r) demonstrated a remarkable anticancer effect by inducing G2/M phase cell cycle arrest and apoptosis. It was identified as a highly efficient lead compound in our screening process. Overall, our study provides valuable insights into the anticancer activity of novel carbazoyl hydrazine derivatives as Pim-1 inhibitors in liver cancer cells. The identified lead compound 4r demonstrates promising potential for further exploration and development in future studies for liver cancer treatment.

Exploration and Biological Evaluation of 1,3-Diamino-7H-pyrrol[3,2-f]quinazoline Derivatives as Dihydrofolate Reductase Inhibitors.

Dihydrofolate reductase (DHFR), a core enzyme of folate metabolism, plays a crucial role in the biosynthesis of purines and thymidylate for cell proliferation and growth in both prokaryotic and eukaryotic cells. However, the development of new DHFR inhibitors is challenging due to the limited number of scaffolds available for drug development. Hence, we designed and synthesized a new class of DHFR inhibitors with a 1,3-diamino-7H-pyrrol[3,2-f]quinazoline derivative (PQD) structure bearing condensed rings. Compound 6r exhibited therapeutic effects on mouse models of systemic infection and thigh infection caused by methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300. Moreover, methyl-modified PQD compound 8a showed a strong efficacy in a murine model of breast cancer, which was better than the effects of taxol. The findings showcased in this study highlight the promising capabilities of novel DHFR inhibitors in addressing bacterial infections as well as breast cancer.