Discovery of novel benzimidazole derivatives as potent HDACs inhibitors against leukemia with (Thio)Hydantoin as zinc-binding moiety: Design, synthesis, enzyme inhibition, and cellular mechanistic study.

Based on the well-established pharmacophoric features required for histone deacetylase (HDAC) inhibition, a novel series of easy-to-synthesize benzimidazole-linked (thio)hydantoin derivatives was designed and synthesized as HDAC6 inhibitors. All target compounds potently inhibited HDAC6 at nanomolar levels with compounds 2c, 2d, 4b and 4c (IC50s = 51.84-74.36 nM) being more potent than SAHA reference drug (IC50 = 91.73 nM). Additionally, the most potent derivatives were further assessed for their in vitro cytotoxic activity against two human leukemia cells. Hydantoin derivative 4c was equipotent/superior to SAHA against MOLT-4/CCRF-CEM leukemia cells, respectively and demonstrated safety profile better than that of SAHA against non-cancerous human cells. 4c was also screened against different HDAC isoforms. 4c was superior to SAHA against HDAC1. Cell-based assessment of 4c revealed a significant cell cycle arrest and apoptosis induction. Moreover, western blotting analysis showed increased levels of acetylated histone H3, histone H4 and α-tubulin in CCRF-CEM cells. Furthermore, docking study exposed the ability of title compounds to chelate Zn2+ located within HDAC6 active site. As well, in-silico evaluation of physicochemical properties showed that target compounds are promising candidates in terms of pharmacokinetic aspects.

Recent Methods for the Synthesis of Quinoxaline Derivatives and their Biological Activities.

Quinoxaline derivatives have been incorporated into numerous marketed drugs used for the treatment of various diseases. Examples include glecaprevir (Mavyret), voxilaprevir (Vosevi), Balversa (L01EX16) (erdafitinib), carbadox, XK469R (NSC698215), and becampanel (AMP397). These quinoxaline derivatives exhibit a diverse range of pharmacological activities, including antibacterial, antitubercular, antiviral, anti-HIV, anti-inflammatory, antifungal, anticancer, antiproliferative, antitumor, kinase inhibition, antimicrobial, antioxidant, and analgesic effects. Recognizing the significance of these bioactive quinoxaline derivatives, researchers have dedicated their efforts to developing various synthetic methods for their production. This review aimed to compile the most recent findings on the synthesis and biological properties of quinoxaline derivatives from 2015 to 2023.

The most recent compilation of reactions of enaminone derivatives with various amine derivatives to generate biologically active compounds.

Heterocyclic derivatives serve as the fundamental components of both natural and synthetic drugs. Enaminones play a crucial role as foundational units in the synthesis of numerous bioactive heterocyclic compounds, including pyrazoles, pyridines, oxazoles, isoxazoles, as well as fused heterocyclic structures like indoles, carbazoles, quinolines, acridines, and phenanthridines. These diverse heterocyclic rings are well-known for their various therapeutic activities, encompassing anticancer, anti-inflammatory, antimicrobial, antidepressant, and antiviral properties. By reacting with nitrogen-based nucleophiles, enaminones can generate bioactive azoles, azines, and their fused systems. This comprehensive review article focuses on the recent advancements in enaminone reactions with (a) nitrogen-based nucleophiles, such as aliphatic amines, derivatives of aniline, heterocyclic amines, hydroxylamine, hydrazine derivatives, guanidine derivatives, urea, and thiourea derivatives, and (b) nitrogen-based electrophiles, such as diazonium salts. These reactions have led to the synthesis of a wide range of bioactive fused heterocyclic compounds from 2010 to the end of 2022.

Novel benzimidazole-linked (thio)barbiturates as non-hydroxamate HDAC6 inhibitors targeting leukemia: Design, synthesis, and structure-activity relationship.

Based on the well-established pharmacophoric features required for histone deacetylase (HDAC) inhibition, novel easy-to-prepare benzimidazole-linked (thio)barbiturate derivatives were designed and synthesized as HDAC6 inhibitors. The proposed structures of the title compounds were confirmed based on their spectral data and elemental analyses. The newly synthesized compounds were screened in vitro against HDAC6. All tested compounds showed potent HDAC6 inhibition at the nanomolar level. Several compounds displayed a remarkable HDAC6 inhibitory activity (IC50 = 48.85-75.62 nM), superior to that of the reference drug suberoylanilide hydroxamic acid (SAHA; IC50 = 91.73 nM). The most potent derivatives were further assessed for their in vitro anticancer activity against two human leukemia cell lines. Thiobarbiturate 3e was two times more potent than SAHA against the tested cells. The detailed structure-activity relationship was also described. Furthermore, molecular docking simulation revealed the ability of the title compounds to chelate the catalytic Zn+2 ion located within the binding pocket of HDAC6. In silico evaluation of physicochemical properties indicated that the target compounds are promising candidates in terms of pharmacokinetic aspects.

The patent review of the biological activity of tropane containing compounds.

INTRODUCTION: Tropane-derived medications have historically played a substantial role in pharmacotherapy. Both natural and synthetic derivatives of tropane find application in addressing diverse medical conditions. Prominent examples of tropane-based drugs include hyoscine butylbromide, recognized for its antispasmodic properties, atropine, employed as a mydriatic, maraviroc, known for its antiviral effects. trospium chloride, utilized as a spasmolytic for overactive bladder, and ipratropium, a bronchodilator. AREAS COVERED: We compiled patents pertaining to the biological activity of substances containing tropane up to the year 2023 and categorized them according to the specific type of biological activity they exhibit. ScienceFinder, ScienceDirect, and Patent Guru were used to search for scientific articles and patent literature up to 2023. EXPERT OPINION: Pharmaceutical researchers in academic and industrial settings have shown considerable interest in tropane derivatives. Despite this, there remains a substantial amount of work to be undertaken. A focused approach is warranted for the exploration and advancement of both natural and synthetic bioactive molecules containing tropane, facilitated through collaborative efforts between academia and industry. Leveraging contemporary techniques and technologies in medicinal and synthetic chemistry, including high throughput screening, drug repurposing,and biotechnological engineering, holds the potential to unveil novel possibilities and accelerate the drug discovery process for innovative tropane-based pharmaceuticals.

Novel thiazole derivatives incorporating phenyl sulphonyl moiety as potent BRAFV600E kinase inhibitors targeting melanoma.

Novel thiazole derivatives possessing phenyl sulfonyl moiety were designed and synthesized as B-RAFV600E kinase inhibitors based on the clinically-approved anticancer drug, dabrafenib. All target compounds showed significant inhibition of B-RAFV600E kinase enzyme at nanomolar levels. Compounds 7b and 13a revealed excellent B-RAFV600E inhibitory activity, superior to that of dabrafenib with IC50 values of 36.3 ± 1.9, 23.1 ± 1.2, and 47.2 ± 2.5 nM, respectively. Moreover, the title compounds were much more selective toward B-RAFV600E kinase than B-RAF wild type. In addition, the most potent compounds were further evaluated for their anticancer activity against B-RAFV600E-mutated and wild type melanoma cells. A positive correlation between the cytotoxic activity and selectivity for B-RAF V600E over B-RAF wild type was clearly observed for compounds 7b, 11c, 13a, and 17. All the screened compounds potently inhibited the growth of WM266.4 melanoma cells with IC50 values in the range from 1.24 to 17.1 µM relative to dabrafenib (IC50 = 16.5 ± 0.91 µM). Compounds 7b, 11a and 11c, 13a, and 17 were much more potent than dabrafenib against B-RAFV600E-mutated WM266.4 melanoma cells. Furthermore, compound 7b suppressed the phosphorylation of downstream ERK1/2 from WM266.4 cells. Also, the docking study revealed the proper orientation and well-fitting of the title compounds into the ATP binding site of B-RAFV600E kinase.

Discovery of new 1H-pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents targeting EGFRWT and EGFRT790M.

New 1H-pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesised to act as epidermal growth factor receptor inhibitors (EGFRIs). The synthesised derivatives were assessed for their in vitro anti-proliferative activities against A549 and HCT-116 cancer cells. Compounds 8, 10, 12a, and 12b showed potent anti-proliferative activities. Compound 12b was the most promising member with IC50 values of 8.21 and 19.56 µM against A549 and HCT-116, respectively. Compounds 8, 10, 12a, and 12b were evaluated for their kinase inhibitory activities against wild EGFR (EGFRWT). Compound 12b was the most potent member showing an IC50 value of 0.016 µM. In addition, compound 12b showed noticeable activity against mutant EGFR (EGFRT790M) (IC50 = 0.236 µM). Flow cytometric analyses revealed that compound 12b is a good apoptotic inducer and can arrest the cell cycle at S and G2/M phases. Furthermore, it produced an 8.8-fold increase in BAX/Bcl-2 ratio. Molecular docking studies were carried out against EGFRWT and EGFRT790M.

An updated patent review of VEGFR-2 inhibitors (2017-present).

Introduction: Angiogenesis is a vital process for cellular functions in both physiological and pathophysiological conditions and is one of the hallmarks of cancer progression and metastasis. VEGF/VEGFR-2 signaling pathway has been recognized as the most critical factor in promoting angiogenesis. Hence, several VEGFR-2 inhibitors have been clinically tested and/or approved for the treatment of angiogenesis-related diseases.Areas covered: This review covered reports in the patent literature in the period 2017 to the end of 2020 on the small-molecule inhibitors and antibodies of VEGFR-2 and their potential use as therapeutics for several types of cancers, angiogenesis-related disorders, and Parkinson's and Alzheimer's diseases.Expert opinion: VEGF inhibition has attracted considerable attention as a potential approach for antiangiogenic therapy during the last two decades. However, the effectiveness of this approach may be limited by several issues such as weak response, resistance development, and serious adverse effects. Therefore, the combination of anti-angiogenic therapy with chemotherapy and/or immunotherapy, together with the proper utilization of nanomedicine-based approaches, may have a synergistic effect on improving the efficiency of therapy, reducing side effects and lowering the cost.

Novel thiobarbiturates as potent urease inhibitors with potential antibacterial activity: Design, synthesis, radiolabeling and biodistribution study.

Urease enzyme is a virulence factor that helps in colonization and maintenance of highly pathogenic bacteria in human. Hence, the inhibition of urease enzymes is well-established to be a promising approach for preventing deleterious effects of ureolytic bacterial infections. In this work, novel thiobarbiturate derivatives were synthesized and evaluated for their urease inhibitory activity. All tested compounds effectively inhibited the activity of urease enzyme. Compounds 1, 2a, 2b, 4 and 9 displayed remarkable anti-urease activity (IC50 = 8.21-16.95 µM) superior to that of thiourea reference standard (IC50 = 20.04 µM). Moreover, compounds 3a, 3g, 5 and 8 were equipotent to thiourea. Among the tested compounds, morpholine derivative 4 (IC50 = 8.21 µM) was the most potent one, showing 2.5 folds the activity of thiourea. In addition, the antibacterial activity of the synthesized compounds was estimated against both standard strains and clinical isolates of urease producing bacteria. Compound 4 explored the highest potency exceeding that of cephalexin reference drug. Moreover, biodistribution study using radiolabeling approach revealed a remarked uptake of 99mTc-compound 4 into infection induced in mice. Furthermore, a molecular docking analysis revealed proper orientation of title compounds into the urease active site rationalizing their potent anti-urease activity.

Synthesis of novel 2-aminobenzothiazole derivatives as potential antimicrobial agents with dual DNA gyrase/topoisomerase IV inhibition.

Novel benzothiazole-based compounds were designed and synthesized as potential antimicrobial agents with dual DNA gyrase/topoisomerase IV inhibitory activity. The structures of the newly synthesized compounds were established on the basis of spectral (IR, NMR, MS) and elemental analyses. Most of the studied compounds possessed significant antimicrobial activity against tested bacteria and fungi. Compounds 4b and 7a were much more potent than reference standard ciprofloxacin against methicillin-resistant Staphylococcus aureus (MRSA) and a multi-drug resistant clinical isolate of Enterococcus faecium. Moreover, 7a was equipotent to nystatin against clinical isolate of Candida albicans. Both 4b and 7a inhibited DNA gyrase and topoisomerase IV at low micromolar levels and also displayed safety profiles much better than that of novobiocin in cytotoxicity assay.