Inhibiting cyclin-dependent kinases (CDK) offers an important arsenal for cancer treatments by interfering with apoptotic proteins related to cancer. Novel selective cyclin-dependent kinases inhibitors using the Quinazoline as the cap with multiple electronic donating (EDG) and/or electron withdrawing group (EWG) substituted Aniline chain at the C-2 position were designed, synthesized, and evaluated for activity against liver cancer. Among the tested compounds, compounds B34 and B35 emerged as potent candidates in the series, with IC50 values of 0.102 ± 0.04 µM and 0.058 ± 0.003 µM, respectively. They also suppressed the enzymatic activity of CDK2/cyclinA2 selectively. Further biological studies revealed that compounds B34 and B35 arrested the cell cycle, and induced apoptosis in HepG-2 cancer cells through a Caspase-mediated mechanism, facilitating the release of Cyt-c through modulation of Caspase-3 expression. More importantly, compounds B34 and B35 suppressed the xenografted tumor growth in mice in a dose-dependent manner. Finally, through a molecular docking study, it was confirmed that compoundsB34 andB35 retained crucial hydrogen bonding and hydrophobic interactions with CDK receptor, rationalizing their higher efficacy compared to other compounds in the series. Taken together, the Quinazoline derivatives B34 and B35 may serve as novel chemotherapeutic agents through inhibition of CDK.

The adenosine A2A receptor (A2AR) has been identified as a therapeutic target for treating neurodegenerative diseases and cancer. In recent years, we have highlighted the 2-aminoquinazoline heterocycle as an promising scaffold for designing new A2AR antagonists, exemplified by 6-bromo-4-(furan-2-yl)quinazolin-2-amine 1 (Ki (hA2AR) = 20 nM). Here, we report the synthesis of new 2-aminoquinazoline derivatives with substitutions at the C6- and C7-positions, and the introduction of aminoalkyl chains containing tertiary amines at the C2-position to enhance antagonist activity and solubility properties. Compound 5m showed a high affinity for hA2AR with a Ki value of 5 nM and demonstrated antagonist activity with an IC50 of 6 µM in a cyclic AMP assay. Introducing aminopentylpiperidine and 4-[(piperidin-1-yl)methyl]aniline substituents maintained the binding affinities (9x, Ki = 21 nM; 10d, Ki = 15 nM) and functional antagonist activities (9x, IC50 = 9 µM; 10d, IC50 = 5 µM) of the synthesized compounds while improving solubility. This study provides insights into the future development of A2AR antagonists for therapeutic applications.

A series of new piperidine-4-carbohydrazide derivatives bearing a quinazolinyl moiety were prepared and evaluated for their fungicidal activities against agriculturally important fungi. Among these derivatives, the chemical structure of compound A45 was clearly verified by X-ray crystallographic analysis. The antifungal bioassays revealed that many compounds in this series possessed good to excellent inhibition effects toward the tested fungi. For example, compounds A13 and A41 had EC50 values of 0.83 and 0.88 μg/mL against Rhizoctonia solani in vitro, respectively, superior to those of positive controls Chlorothalonil and Boscalid (1.64 and 0.96 μg/mL, respectively). Additionally, the above two compounds also exhibited notable inhibitory activities against Verticillium dahliae (with EC50 values of 1.12 and 3.20 μg/mL, respectively), far better than the positive controls Carbendazim and Chlorothalonil (19.3 and 11.0 μg/mL, respectively). More importantly, compound A13 could potently inhibit the proliferation of R. solani in the potted rice plants, showing good in vivo curative and protective efficiencies of 76.9% and 76.6% at 200 μg/mL, respectively. Furthermore, compound A13 demonstrated an effective inhibition of succinate dehydrogenase (SDH) activity in vitro with an IC50 value of 6.07 μM. Finally, the molecular docking study revealed that this compound could be well embedded into the active pocket of SDH via multiple noncovalent interactions, involving residues like SER39, ARG43, and GLY46.

A facile C-H amination of quinazoline employing N-fluorobenzenesulfonimide (NFSI) as the amination source has been disclosed in the absence of any metal, oxidant or additive. The methodology shows a board range of quinazolines with different functional groups in moderate to good yields up to 87%. Furthermore, gram-scale reaction, desulfonylation to amine and synthesis of pharmaceutical intermediate were also investigated, which demonstrates potential applications in medicinal chemistry. A plausible amination mechanism is proposed via F+ transfer accompanied by the removal of one molecule of PhSO2F. DFT studies with experimental work suggest that the mechanism via F+ transfer is more favorable than the free radical one.

Two new sets of quinazoline-oxindole 8a-l and quinazoline-dioxoisoindoline 10a-d hybrids were designed as type II angiokinase inhibitors and anticancer agents. The design strategy was adjusted to account for the quinazoline scaffold\'s placement in the target kinases\' hinge region, where it would form hydrogen bonding and hydrophobic interactions with the important amino acids to stabilize it, and the amide group\'s occupation in the gate region, which would direct the oxindole scaffold toward the hydrophobic back pocket. The two sets of quinazolines 8a-l and 10a-d displayed pronounced inhibitory activity on VEGFR-2 (IC50 = 0.46-2.20 µM). The quinazoline-oxindole hybrids 8d, 8f, and 8h displayed IC50 = 0.46, 0.49, and 0.49 µM, respectively. Compound 8f demonstrated potent multikinase activity with IC50 values of 0.95 and 0.67 µM against FGFR-1 and BRAF, respectively. Additionally, compound 8f showed significant anticancer activity against National Cancer Institute\'s cancer cell lines, with GI50 reaching 1.21 µM. Analysis of the impact of compound 8f on the MDA-MB-231 cell line\'s cell cycle and apoptosis revealed that 8f stalled the cell cycle at the G2/M phase and promoted its necrosis.

A ninhydrin-based colorimetric chemosensor (LH) was synthesized using 3-hydroxy-2-naphthoic hydrazide and 11H-indeno[1,2-b]quinoxalin-11-one. It was characterized by spectroscopic and single crystal X-ray diffraction techniques. In a semi-aqueous (MeOH/HEPES) system, LH displayed a characteristic chromogenic change from colorless to yellow upon adding Cu2+ ion, with the appearance of a new peak at λmax = 460 nm. A 1:1 binding stoichiometry between LH and Cu2+ ion has been found, with LOD = 2.3 μM (145 ppb) and LOQ = 8 μM (504 ppb). Based on experimental results the formula of [Cu(L)Cl(H2O)2] (1) was assigned and this in-situ generated 1 was found to exhibit a discoloration of upon gradual addition of cysteine (LOD = 60 nM) as well as ATP (LOD = 130 nM) having 1:2 and 1:1 stoichiometry respectively. The LH was useful for recognition of Cu2+ ion in real water samples and on filter paper strips. A two-input-two-output logic gate circuitry was also constructed by employing 1 and cysteine. The DFT/TDDFT calculations performed on LH and 1 were consistent with experimental findings. The binding affinity of LH towards HSA and BSA were determined with HSA having greater affinity than BSA, which was also supported by theoretical calculations.

Alzheimer\'s disease is the most prevalent neurodegenerative disorder characterized by significant memory loss and cognitive impairments. Studies have shown that the expression level and activity of the butyrylcholinesterase enzyme increases significantly in the late stages of Alzheimer\'s disease, so butyrylcholinesterase can be considered as a promising therapeutic target for potential Alzheimer\'s treatments. In the present study, a novel series of 2,4-disubstituted quinazoline derivatives (6a-j) were synthesized and evaluated for their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinestrase (BuChE) enzymes, as well as for their antioxidant activities. The biological evaluation revealed that compounds 6f, 6h, and 6j showed potent inhibitory activities against eqBuChE, with IC50 values of 0.52, 6.74, and 3.65 µM, respectively. These potent compounds showed high selectivity for eqBuChE over eelAChE. The kinetic study demonstrated a mixed-type inhibition pattern for both enzymes, which revealed that the potent compounds might be able to bind to both the catalytic active site and peripheral anionic site of eelAChE and eqBuChE. In addition, molecular docking studies and molecular dynamic simulations indicated that potent compounds have favorable interactions with the active sites of BuChE. The antioxidant screening showed that compounds 6b, 6c, and 6j displayed superior scavenging capabilities compared to the other compounds. The obtained results suggest that compounds 6f, 6h, and 6j are promising lead compounds for the further development of new potent and selective BuChE inhibitors.

Nontuberculous mycobacteria (NTM), which include the Mycobacterium avium complex, are classified as difficult-to-treat pathogens due to their ability to quickly develop drug resistance against the most common antibiotics used to treat NTM infections. The overexpression of efflux pumps (EPs) was demonstrated to be a key mechanism of clarithromycin (CLA) resistance in NTM. Therefore, in this work, 24 compounds from an in-house library, characterized by chemical diversity, were tested as potential NTM EP inhibitors (EPIs) against Mycobacterium smegmatis mc2 155 and M. avium clinical isolates. Based on the acquired results, 12 novel analogs of the best derivatives 1b and 7b were designed and synthesized to improve the NTM EP inhibition activity. Among the second set of compounds, 13b emerged as the most potent NTM EPI. At a concentration of 4 µg/mL, it reduced the CLA minimum inhibitory concentration by 16-fold against the clinical isolate M. avium 2373 overexpressing EPs as primary mechanism of CLA resistance.

A library of new quinazoline pharmacophores bearing benzenesulfonamide moiety was designed and synthesized. Compounds 3a-n were screened for their in vitro antimicrobial activity against eight multidrug-resistant clinical isolates. Compounds 3d and 3n exhibited prominent antibacterial activity, specifically against MRSA. After exhibiting relative in vitro and in vivo safety, compound 3n was selected to assess its anti-inflammatory activity displaying promising COX-2 inhibitory activity compared to Ibuprofen. In vivo experimental MRSA pneumonia model was conducted on immunodeficient (irradiated) mice to reveal the antimicrobial and anti-inflammatory responses of compound 3n compared to azithromycin (AZ). Treatment with compound 3n (10 and 20 mg/kg) as well as AZ resulted in a significant decrease in bacterial counts in lung tissues, suppression of serum C-reactive protein (CRP), lung interleukin-6 (IL-6), myeloperoxidase activity (MPO) and transforming growth factor-β (TGF-β). Compound 3n showed a non-significant deviation of lung TGF-β1 from normal values which in turn controlled the lung inflammatory status and impacted the histopathological results. Molecular docking of 3n showed promising interactions inside the active sites of TGF-β and COX-2. Our findings present a new dual-target quinazoline benzenesulfonamide derivative 3n, which possesses significant potential for treating MRSA-induced pneumonia in an immunocompromised state.

Lung cancer (LC) is the most common cancer in males. As per GLOBOCAN 2020, 8.1 % of deaths and 5.9 % of cases of LC were reported in India. Our laboratory has previously reported the significant anticancer potential of 5H-benzo[h]thiazolo[2,3-b]quinazoline analogues. In this study, we have explored the anticancer potential of 7A {4-(6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-7-yl)phenol} and 9A {7-(4-chlorophenyl)-9-methyl-6,7-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazoline}by using in-vitro and in-vivo models of LC. In this study, we investigated the antiproliferative potential of quinazoline analogues using A549 cell line to identify the best compound of the series. The in-vitro and molecular docking studies revealed 7A and 9A compounds as potential analogues. We also performed acute toxicity study to determine the dose. After that, in-vivo studies using urethane-induced LC in male albino Wistar rats carried out further physiological, biochemical, and morphological evaluation (SEM and H&E) of the lung tissue. We have also evaluated the antioxidant level, inflammatory, and apoptotic marker expressions. 7A and 9A did not demonstrate any signs of acute toxicity. Animals treated with urethane showed a significant upregulation of oxidative stress. However, treatment with 7A and 9A restored antioxidant markers near-normal levels. SEM and H&E staining of the lung tissue demonstrated recovered architecture after treatment with 7A and 9A. Both analogues significantly restore inflammatory markers to normal level and upregulate the intrinsic apoptosis protein expression in the lung tissue. These experimental findings demonstrated the antiproliferative potential of the synthetic analogues 7A and 9A, potentially due to their anti-inflammatory and apoptotic properties.