Benzothiazole derivatives in the design of antitumor agents.

Benzothiazoles are a class of heterocycles with multiple applications as anticancer, antibiotic, antiviral, and anti-inflammatory agents. Benzothiazole is a privileged scaffold in drug discovery programs for modulating a variety of biological functions. This review focuses on the design and synthesis of new benzothiazole derivatives targeting hypoxic tumors. Cancer is a major health problem, being among the leading causes of death. Tumor-hypoxic areas promote proliferation, malignancy, and resistance to drug treatment, leading to the dysregulation of key signaling pathways that involve drug targets such as vascular endothelial growth factor, epidermal growth factor receptor, hepatocyte growth factor receptor, dual-specificity protein kinase, cyclin-dependent protein kinases, casein kinase 2, Rho-related coil formation protein kinase, tunica interna endothelial cell kinase, cyclooxygenase-2, adenosine kinase, lysophosphatidic acid acyltransferases, stearoyl-CoA desaturase, peroxisome proliferator-activated receptors, thioredoxin, heat shock proteins, and carbonic anhydrase IX/XII. In turn, they regulate angiogenesis, proliferation, differentiation, and cell survival, controlling the cell cycle, inflammation, the immune system, and metabolic alterations. A wide diversity of benzothiazoles were reported over the last years to interfere with various proteins involved in tumorigenesis and, more specifically, in hypoxic tumors. Many hypoxic targets are overexpressed as a result of the hypoxia-inducible factor activation cascade and may not be present in normal tissues, providing a potential strategy for selectively targeting hypoxic cancers.

Development of Penicillin-Based Carbonic Anhydrase Inhibitors Targeting Multidrug-Resistant Neisseria gonorrhoeae.

The development of antibacterial drugs with new mechanisms of action is crucial in combating the rise of antibiotic-resistant infections. Bacterial carbonic anhydrases (CAs, EC 4.2.1.1) have been validated as promising antibacterial targets against pathogens such as Helicobacter pylori, Neisseria gonorrhoeae, and vancomycin-resistant enterococci. A multitarget strategy is proposed to design penicillin-based CA inhibitor hybrids for tackling resistance by targeting multiple bacterial pathways, thereby resensitizing drug-resistant strains to clinical antibiotics. The sulfonamide derivatives potently inhibited the CAs from N. gonorrhoeae and Escherichia coli with KI values in the range of 7.1-617.2 nM. Computational simulations with the main penicillin-binding protein (PBP) of N. gonorrhoeae indicated that these hybrid derivatives maintained the mechanism of action of the lead ß-lactams. A subset of derivatives showed potent PBP-related antigonococcal effects against multidrug-resistant N. gonorrhoeae strains, with several compounds significantly outperforming both the lead ß-lactam and CA inhibitor drugs (MIC values in the range 0.25 to 0.5 µg/mL).

Synthetic Approaches to Novel Human Carbonic Anhydrase Isoform Inhibitors Based on Pyrrol-2-one Moiety.

New dihydro-pyrrol-2-one compounds, featuring dual sulfonamide groups, were synthesized through a one-pot, three-component approach utilizing trifluoroacetic acid as a catalyst. Computational analysis using density functional theory (DFT) and condensed Fukui function explored the structure-reactivity relationship. Evaluation against human carbonic anhydrase isoforms (hCA I, II, IX, XII) revealed potent inhibition. The widely expressed cytosolic hCA I was inhibited across a range of concentrations (KI 3.9-870.9 nM). hCA II, also cytosolic, exhibited good inhibition as well. Notably, all compounds effectively inhibited tumor-associated hCA IX (KI 1.9-211.2 nM) and hCA XII (low nanomolar). Biological assessments on MCF7 cancer cells highlighted the compounds' ability, in conjunction with doxorubicin, to significantly impact tumor cell viability. These findings underscore the potential therapeutic relevance of the synthesized compounds in cancer treatment.

Exploration of 3-aryl pyrazole-tethered sulfamoyl carboxamides as carbonic anhydrase inhibitors.

Herein, we report the design and synthesis of two series of pyrazole-tethered sulfamoyl phenyl acetamides and pyrazole-tethered sulfamoyl phenyl benzamides. The synthesized compounds were investigated for inhibiting two human carbonic anhydrases, human carbonic anhydrases (hCA) I and II, and those of the bacterial pathogen Mycobacterium tuberculosis, mtCA 1-3. The results indicate that, among the synthesized compounds, pyrazoles with 4-aminobenzene sulfonamide were more selective toward hCA I and II over mtCAs, and compounds with 3-aminobenzene sulfonamide were selective toward mtCA 1-3 over hCA I, II. Compound 6g showed significant and selective inhibition toward hCA I and II, with Ki values of 0.0366 and 0.0310 µM, respectively. Compound 5g exhibited the best inhibition toward mtCA 2, with a Ki value of 0.0617 µM. Among the benzamides, compound 9b exhibited significant activity toward mtCA 2, with a Ki value of 0.0696 µM. Selectivity of these compounds was further supported by docking studies. When tested for antitubercular activity, many compounds showed moderate to good inhibition against the Mtb H37Rv strain, with minimum inhibitory concentration (MIC) values in the range of 4-128 µg/mL.

Discovery of Novel Hydroxyimine-Tethered Benzenesulfonamides as Potential Human Carbonic Anhydrase IX/XII Inhibitors.

To discover novel carbonic anhydrase (CA, EC 4.2.1.1) inhibitors for cancer treatment, a series of 4-{4-[(hydroxyimino)methyl]piperazin-1-yl}benzenesulfonamides were designed and synthesized using SLC-0111 as the lead molecule. The developed novel compounds 27-34 were investigated for the inhibition of human (h) isoforms hCA I, hCA II, hCA IX, and hCA XII. The hCA I was inhibited by compound 29 with a Ki value of 3.0 nM, whereas hCA II was inhibited by compound 32 with a Ki value of 4.4 nM. The tumor-associated hCA IX isoform was inhibited by compound 30 effectively with an Ki value of 43 nM, whereas the activity of another cancer-related isoform, hCA XII, was significantly inhibited by 29 and 31 with a Ki value of 5 nM. Molecular modeling showed that drug molecule 30 participates in significant hydrophobic and hydrogen bond interactions with the active site of the investigated hCAs and binds to zinc through the deprotonated sulfonamide group.

Inhibition Studies on Human and Mycobacterial Carbonic Anhydrases with N-((4-Sulfamoylphenyl)carbamothioyl) Amides.

A library of structurally diverse N-((4-sulfamoylphenyl)carbamothioyl) amides was synthesized by selective acylation of easily accessible 4-thioureidobenzenesulfonamide with various aliphatic, benzylic, vinylic and aromatic acyl chlorides under mild conditions. Inhibition of three α-class cytosolic human (h) carbonic anhydrases (CAs) (EC 4.2.1.1); that is, hCA I, hCA II and hCA VII and three bacterial ß-CAs from Mycobacterium tuberculosis (MtCA1-MtCA3) with these sulfonamides was thereafter investigated in vitro and in silico. Many of the evaluated compounds displayed better inhibition against hCA I (KI = 13.3-87.6 nM), hCA II (KI = 5.3-384.3 nM), and hCA VII (KI = 1.1-13.5 nM) compared with acetazolamide (AAZ) as the control drug (KI values of 250, 12.5 and 2.5 nM, respectively, against hCA I, hCA II and hCA VII). The mycobacterial enzymes MtCA1 and MtCA2 were also effectively inhibited by these compounds. MtCA3 was, on the other hand, poorly inhibited by the sulfonamides reported here. The most sensitive mycobacterial enzyme to these inhibitors was MtCA2 in which 10 of the 12 evaluated compounds showed KIs (KI, the inhibitor constant) in the low nanomolar range.

Five-Membered Heterocyclic Sulfonamides as Carbonic Anhydrase Inhibitors.

The development of heterocyclic derivatives has progressed considerably over the past decades, and many new carbonic anhydrase inhibitors (CAIs) fall into this field. In particular, five-membered heterocyclic sulfonamides have been generally shown to be more effective inhibitors compared to six-membered rings ones. Despite the importance of oxygen and nitrogen five-membered heterocyclic aromatic rings in medicinal chemistry, the installation of sulfonamide moiety on such heterocycles has not received much attention. On the other hand, 1,3,4-thiadiazole/thiadiazoline ring-bearing sulfonamides are the scaffolds which have been widely used in a variety of pharmaceutically important CAIs such as acetazolamide, metazolamide and their many derivatives obtained by using the tail approach. Here, we reviewed the field focusing on the diverse biological activities of these CAIs, such as antiglaucoma, antiepileptic, antitumor and antiinfective properties. This review highlights developments involving five-membered heterocyclic sulfonamides over the last years, with a focus on their pharmacological/clinical applications.

Selenium-analogs based on natural sources as cancer-associated carbonic anhydrase isoforms IX and XII inhibitors.

In the relentless search for new cancer treatments, organoselenium compounds, and carbonic anhydrase (CA) inhibitors have emerged as promising drug candidates. CA isoforms IX and XII are overexpressed in many types of cancer, and their inhibition is associated with potent antitumor/antimetastatic effects. Selenium-containing compounds, particularly selenols, have been shown to inhibit tumour-associated CA isoforms in the nanomolar range since the properties of the selenium atom favour binding to the active site of the enzyme. In this work, two series of selenoesters (1a-19a and 1b-19b), which gathered NSAIDs, carbo/heterocycles, and fragments from natural products, were evaluated against hCA I, II, IX, and XII. Indomethacin (17b) and flufenamic acid (19b) analogs exhibited selectivity for tumour-associated isoform IX in the low micromolar range. In summary, selenoesters that combine NSAIDs with fragments derived from natural sources have been developed as promising nonclassical inhibitors of the tumour-associated CA isoforms.