Sulfonamide Moiety Research Articles

N-sulfonyl peptide-hybrids as a new class of dengue virus protease inhibitors.

Dengue virus (DENV) from the Flaviviridae family causes an epidemic disease that seriously threatens human life. The viral serine protease NS2B-NS3 is a promising target for drug development against DENV and other flaviviruses. We here report the design, synthesis, and in-vitro characterization of potent peptidic inhibitors of DENV protease with a sulfonyl moiety as N-terminal cap, thereby creating sulfonamide-peptide hybrids. The in-vitro target affinities of some synthesized compounds were in the nanomolar range, with the most promising derivative reaching a Ki value of 78nM against DENV-2 protease. The synthesized compounds did not have relevant off-target activity nor cytotoxicity. The metabolic stability of compounds against rat liver microsomes and pancreatic enzymes was remarkable. In general, the integration of sulfonamide moieties at the N-terminus of peptidic inhibitors proved to be a promising and attractive strategy for further drug development against DENV infections.

Anticancer Potential of Sulfonamide Moieties via In-Vitro and In-Silico Approaches: Comparative Investigations for Future Drug Development.

Several kinds of anticancer drugs are presently commercially accessible, but low efficacy, solubility, and toxicity have reduced the overall therapeutic indices. Thus, the search for promising anticancer drugs continues. The interactions of numerous essential anticancer drugs with DNA are crucial to their biological functions. Here, the anticancer effects of N-ethyl toluene-4-sulphonamide (8a) and 2,5-Dichlorothiophene-3-sulphonamide (8b) on cell lines from breast and cervical cancer were investigated. The study also compared how these substances interacted with the hearing sperm DNA. The most promising anticancer drug was identified as 2,5-Dichlorothiophene-3-sulfonamide (8b), which showed GI50 of 7.2 ± 1.12 µM, 4.62 ± 0.13 µM and 7.13 ± 0.13 µM against HeLa, MDA-MB231 and MCF-7 cells, respectively. Moreover, it also exhibited significant electrostatic and non-electrostatic contributions to the binding free energy. The work utilized computational techniques, such as molecular docking and molecular dynamic (MD) simulations, to demonstrate the strong cytotoxicity of 2,5-Dichlorothiophene-3-sulfamide (8b) in comparison to standard Doxorubicin and cisplatin, respectively. Molecular docking experiments provided additional support for a role for the minor groove in the binding of the 2,5-Dichlorothiophene-3-sulfamide (8b)-DNA complex. The molecular docking studies and MD simulation showed that both compounds revealed comparable inhibitory potential against standard Doxorubicin and cisplatin. This study has the potential to lead to the discovery of new bioactive compounds for use in cancer treatment, including metallic and non-metallic derivatives of 2,5-Dichlorothiophene-3-sulfonamide (8b). It also emphasizes the worth of computational approaches in the development of new drugs and lays the groundwork for future research.

Design, synthesis, and antiviral activities evaluation of novel quinazoline derivatives containing sulfonamide moiety

Abstract A series of novel quinazoline derivatives bearing sulfonamide moiety was designed and synthesized, and their structure were characterized by 1H NMR, 13C NMR, and HRMS techniques. Among them, the structure of compound E1 was further confirmed through X-ray single-crystal diffraction analyses. Their anti-Tobacco mosaic virus (TMV) activities were evaluated through half-leaf method. The bioassay results showed that E8 and E19 possess excellent inhibitory activity towards TMV. The EC50 of curative activities, protective activities, and inactivating activities of E8 and E19 are 132.1, 152.8, 57.4 mg/L and 278.0, 165.3, 94.5 mg/L, respectively, which are far superior than Ribavirin (318.2, 201.5, 128.6 mg/L, respectively).

Discovery of novel sulfonamide chromone-oxime derivatives as potent indoleamine 2,3-dioxygenase 1 inhibitors

A series of chromone-oxime derivatives containing piperazine sulfonamide moieties were designed, synthesized and evaluated for their inhibitory activities against IDO1. These compounds displayed moderate to good inhibitory activity against IDO1 with IC50 values in low micromolar range. Among them, compound 10m bound effectively to IDO1 with good inhibitory activities (hIDO1 IC50 = 0.64 μM, HeLa IDO1 IC50 = 1.04 μM) and were selected for further investigation. Surface plasmon resonance analysis confirmed the direct interaction between compound 10m and IDO1 protein. Molecular docking study of the most active compound 10m revealed key interactions between 10m and IDO1 in which the chromone-oxime moiety coordinated to the heme iron and formed several hydrogen bonds with the porphyrin ring of heme and ALA264, consistent with the observation by UV–visible spectra that 10m induced a Soret peak shift from 403 to 421 nm. Moreover, compound 10m exhibited no cytotoxicity at its effective concentration in MTT assay. Consistently, in vivo assays results demonstrated that 10m displayed potent antitumor activity with low toxicity in CT26 tumor–bearing Balb/c mice, in comparison with 1-methyl-l-tryptophan (1-MT) and 4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (IDO5L). In brief, the results suggested that chromone-oxime derivatives containing sulfonamide moieties might serve as IDO1 inhibitors for the development of new antitumor agents.

Synthesis, antimicrobial and antibiofilm activities of some novel 7-methoxyquinoline derivatives bearing sulfonamide moiety against urinary tract infection-causing pathogenic microbes

Synthesis, antimicrobial and antibiofilm activities of some novel 7-methoxyquinoline derivatives bearing sulfonamide moiety against urinary tract infection-causing pathogenic microbes

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.

Discovery of novel benzenesulfonamides incorporating 1,2,3-triazole scaffold as carbonic anhydrase I, II, IX, and XII inhibitors

Sulfonamides are among the most promising potential inhibitors for carbonic anhydrases (CAs), which are pharmaceutically relevant targets for treating several disease conditions. Herein, a series of benzenesulfonamides bearing 1,2,3-triazole moiety as inhibitors of human (h) α-CAs (hCAs) were designed using the tail approach. The design method combines a benzenesulfonamide moiety with a tail of oxime and a zinc-binding group on a 1,2,3-triazole scaffold. Among the synthesized derivatives, the naphthyl (6m, KI of 68.6 nM, SI of 10.3), and methyl (6a, KI of 56.3 nM, SI of 11.7) derivatives (over hCA IX) and propyl (6c, KI of 95.6 nM, SI of 2.7), and pentyl (6d, KI of 51.1 nM, SI of 6.6) derivatives (over hCA XII) displayed a noticeable selectivity for isoforms hCA I and II, respectively. Meanwhile, derivative 6e displayed a potent inhibitory effect versus the cytosolic isoform hCA I (KI of 47.8 nM) and tumor-associated isoforms hCA IX and XII (KIs of 195.9 and 116.9 nM, respectively) compared with the reference drug acetazolamide (AAZ, KIs of 451.8, 437.2, and 338.9 nM, respectively). Derivative 6b showed higher potency (KI of 33.2 nM) than AAZ (KI of 327.3 nM) towards another cytosolic isoform hCA II. Nevertheless, substituting the lipophilic large naphthyl tail to the 1,2,3-triazole linked benzenesulfonamides (6a-n) raised inhibitory effect versus hCA I and XII and selectivity towards hCA I and II isoforms over hCA IX. Evaluation of the cytotoxic potential of the synthesized derivatives was conducted in L929, MCF-7, and Hep-3B cell lines. Several compounds in the series demonstrated significant antiproliferative activity and minimal cytotoxicity. In the molecular docking study, the sulfonamide moiety interacted with the zinc-ion and neatly fit into the hCAs active sites. The extension of the tail was found to participate in diverse hydrophilic and hydrophobic interactions with adjacent amino acids, ultimately influencing the effectiveness and specificity of the derivatives.

Development of Macrocyclic Mn(II)−Bispyridine Complexes as pH‐Responsive Magnetic Resonance Imaging Contrast Agents

AbstractIn this study, macrocyclic complexes of Mn (II) with pH‐responsive relaxivities were developed. The ligands were based on the rigid MPi platform, which was composed of a triazacyclononane (TACN) macrocycle and two picolyl pendant arms. An aryl sulfonamide moiety introduced in the skeleton of MPi endowed the final Mn complex (Mn−MPA) with pH‐sensitive relaxivities. Mn−MPA showed a ∼3‐fold increase in longitudinal relaxivity associated with the protonation and decoordination of the sulfonamide group in an acidic environment. We found that it was feasible to tune the pH window of the complexes by choosing proper substituents on the aromatic ring or modifying on the picolyl pendants. Considering the good kinetic inertness, rapid and efficient response to pH stimuli, and easy modulation characteristics, Mn−MPAs can be considered ideal candidates for use as acidic microenvironment‐specific MRI contrast agents.

A dual-reaction-site and dual-channel fluorescent-on probe for selectively monitoring mitochondrial glutathione

Glutathione (GSH) is the most abundant endogenous antioxidant and serves critical cellular functions in living system. As a results, it is of great significant to disclose GSH-specific fluorescent probe to deeply understand its biological functions. In this study, we developed a dual-reaction-site and dual-channel turn-on fluorescent probe Cyan-S-Nap for GSH by installing the sensing groups of thiophenol and sulfonamide moieties into the dyes of heptamethine cyanine and naphthalimide, respectively. The probe displayed selective response to GSH by the two independent fluorescent channels in visible (λem = 492 nm) and near-infrared (λem = 810 nm) regions. The dual emissions feature endows the probe with the ability to precisely detect the concentration fluctuation of GSH. In addition, the biological utilities of Cyan-S-Nap suggested that the probe was capable of imaging mitochondrial GSH in dual channels in a synchronous and independent manner, as well as monitoring the changes of GSH levels modulated by exogenous/endogenous reactive oxygen species in living cells and zebrafish.

Terminators or Guardians? Design, Synthesis, and Cytotoxicity Profiling of Chalcone-Sulfonamide Hybrids.

With a "less is more" philosophy, a series of 15 chalcone-sulfonamide hybrids were designed anticipating synergistic anticancer activity. The aromatic sulfonamide moiety was included as a known direct inhibitor of carbonic anhydrase IX activity through its zinc chelating property. The chalcone moiety was incorporated as an electrophilic stressor to indirectly inhibit carbonic anhydrase IX cellular activity. Screening by the Developmental Therapeutics Program of the National Cancer Institute, NCI-60, revealed that 12 derivatives were potent inhibitors of cancer cell growth in multiple cell lines and were promoted to the five-dose screen. The cancer cell growth inhibition profile indicated sub- to two-digit micromolar potency (GI50 down to 0.3 μM and LC50 as low as 4 μM) against colorectal carcinoma cells, in particular. Unexpectedly, most compounds demonstrated low to moderate potency as direct inhibitors of carbonic anhydrase catalytic activity in vitro, with 4d being the most potent, having an average Ki value of 4 μM. Compound 4j showed ca. six-fold selectivity to carbonic anhydrase IX over the other tested isoforms in vitro. Cytotoxicity of both 4d and 4j in live HCT116, U251, and LOX IMVI cells under hypoxic conditions confirmed their targeting of carbonic anhydrase activity. Elevation of oxidative cellular stress was stipulated from the increase in Nrf2 and ROS levels in 4j-treated colorectal carcinoma, HCT116, cells compared to the control. Compound 4j arrested the cell cycle of HCT116 cells at the G1/S phase. In addition, both 4d and 4j showed up to 50-fold cancer cell selectivity compared to the non-cancerous HEK293T cells. Accordingly, this study presents 4d and 4j being new, synthetically accessible, simplistically designed derivatives as potential candidates to be further developed as anticancer therapeutics.

Photoinduced Vicinal 1,2-Difunctionalization of Olefins for the Synthesis of Alkyl Sulfonamides.

Alkyl sulfonamides are an important class of bioactive molecules. Historical syntheses have relied on multistep sequences incorporating harsh reaction conditions. Photochemical methods have been limited to hydrosulfamoylation, installing only one substituent across an olefin. Herein, radical/polar crossover (RPC) is used to establish the first multicomponent 1,2-difunctionalization reaction incorporating a sulfonamide moiety and a second reaction partner. This protocol, exemplified on a range of olefins, utilizes various commercial sulfamoyl chlorides and organotrifluoroborates as coupling partners.

Sulfonamide Moiety as "Molecular Chimera" in the Design of New Drugs.

The -SO2NH- group is of great significance in modern pharmaceutical use since, in sulfa-drugs, it is possible to introduce easily chemical modifications, and even small changes may lead to an improved version of an already existing drug. This paper aims to describe updated information in the sulfonamide field with a particular focus on new mechanisms of action, especially if discovered by employing computational approaches. Research articles that focused on the use of the sulfonamide moiety for the design, synthesis, and in vitro/in vivo tests of various diseases were collected from various search engines like PubMed, Science Direct, Google Scholar, and Scopus, using keywords like sulfonamide moiety, aryl/heteroary lsulfonamides, alkyl sulfonamides, in silico drug design, etc. Conclusion: The more relevant reports highlighting the prominent role of sulfonamide moiety in drug discovery have been critically analyzed. Sulfonamides can be considered as "molecular chimera", which are found to form hydrogen bonds as well as interact with unipolar environments within proteins. Therefore, based on the analysis reported herein, it is strongly foresight that new entities can be developed easily to improve the available machinery helpful in the fight against new and emerging diseases.

Sulfonamides as tyrosine kinase modulators – A promising class of anticancer agents

Tyrosine kinases are significant mediators of the signaling cascade that play vital role in various biological processes. The involvement of tyrosine kinases in regulating and functioning various metabolic pathways in the body has encouraged scientists to study their role in cancer onset and progression extensively. The human genome consists of over 90 tyrosine kinases, making it a wider research domain. To date, drugs incorporating a wide variety of heterocyclic scaffolds have been developed against many tyrosine kinases. However, factors such as drug resistance, undesirable side effects, and toxicity shown by current anticancer agents are significant challenges. These shortcomings compelled medicinal chemists to ponder the development of variable scaffolds with proficient anticancer activity and minimum toxicity. After the discovery of prontosil (the first sulfonamide antibiotic), molecules with sulfonamide moiety were synthesized and tested for bacterial infections, diabetes, inflammation, glaucoma, etc. and soon sulfonamides with oncotherapeutic effects surfaced. ACK1/TNK, BTK, LMTK3, and EGFR, etc., are some of the enzymes belonging to receptor tyrosine kinase family which are customarily mutated or overexpressed in different types of cancer. These enzymes are now widely explored and modulators of these enzymes having the sulfonamide moiety are steadily being launched. In this review we sight to summarize the chemical and biological aspects of these sulfonamide containing compounds as tyrosine kinase modulators and their role in preventing and terminating the progression of cancer.

A new class of anti-proliferative activity and apoptotic inducer with molecular docking studies for a novel of 1,3-dithiolo[4,5-b]quinoxaline derivatives hybrid with a sulfonamide moiety.

A new series of 6-(pyrrolidin-1-ylsulfonyl)-[1,3]dithiolo[4,5-b]quinoxaline-2-ylidines 10a-f, 12, 14, 16, and 18 were designed, synthesized, and evaluated for their in vitro anticancer activity. The structures of the novel compounds were systematically characterized by 1H NMR, 13C NMR, and elemental analysis. The synthesized derivatives were evaluated for their in vitro antiproliferative activity against three human cancer cell lines (HepG-2, HCT-116, and MCF-7) with more sensitivity to MCF-7. Moreover, three derivatives 10c, 10f, and 12 were the most promising candidates with sub-micromole values. These derivatives were further evaluated against MDA-MB-231, and the results displayed significant IC50 values ranging from 2.26 ± 0.1 to 10.46 ± 0.8 μM and showed low cellular cytotoxicity against WI-38. Surprisingly, the most active derivative 12 revealed sensitivity towards the breast cell lines MCF-7 (IC50 = 3.82 ± 0.2 μM) and MDA-MB-231 (IC50 = 2.26 ± 0.1 μM) compared with doxorubicin (IC50 = 4.17 ± 0.2 and 3.18 ± 0.1 M). Cell cycle analysis showed that compound 12 arrests and inhibits the growth of MCF-7 cells in the S phase with values of 48.16% compared with the untreated control 29.79% and exhibited a significantly higher apoptotic effect in MCF-7 with a value of 42.08% compared to control cell at 1.84%. Furthermore, compound 12 decreased Bcl-2 protein 0.368-fold and activation on pro-apoptotic genes Bax and P53 by 3.97 and 4.97 folds, respectively, in MCF-7 cells. Compound 12 exhibited higher inhibitory activity to EGFRWt, EGFRL858R, and VEGFR-2 with IC50 values (0.19 ± 0.009, 0.026 ± 0.001, and 0.42 ± 0.021 μM) compared with erlotinib (IC50 = 0.037 ± 0.002 and 0.026 ± 0.001 μM) and sorafenib (IC50 = 0.035 ± 0.002 μM). Finally, in silico ADMET prediction presented that 1,3-dithiolo[4,5-b]quinoxaline derivative 12 obeys the Lipinski rule of five and the Veber rule with no PAINs alarms and moderately soluble properties. Additionally, toxicity prediction revealed that compound 12 demonstrated inactivity to hepatotoxic carcinogenicity, immunotoxicity, mutagenicity, and cytotoxicity. Moreover, molecular docking studies showed good binding affinity with lower binding energy inside the active site of Bcl-2 (PDB: 4AQ3), EGFR (PDB: 1M17), and VEGFR (PDB: 4ASD).

Cooperative assistance of a sulfonamide in a proline-mediated direct asymmetric aldol addition

A sulfonamide moiety was introduced at the C-4 position of proline, cis to the –COOH group, to examine a possible synergistic interaction between the two groups and the consequent influence on the enamine mediated asymmetric aldol reaction.

3-Hydroxy-2-oxindole Derivatives Containing Sulfonamide Motif: Synthesis, Antiviral Activity, and Modes of Action.

3-Hydroxy-2-oxindole motif constitutes a core structure in numerous natural products and imparts notable biological activities. Here, we describe the design and synthesis of four series of novel 3-substituted-3-hydroxy-2-oxindole derivatives containing sulfonamide moiety along with their antiviral activities against potato virus Y (PVY). Compound 10b displayed optimal antiviral activity and superior anti-PVY activity compared with the lead compound and commercial Ningnanmycin in terms of curative and protective effects. Additionally, 10b considerably inhibited PVY systemic infection in Nicotiana benthamiana. Physiological and biochemical analyses revealed that the activities of the four crucial defense-related enzymes increased in the tobacco plant following treatment with 10b. RNA-sequencing analysis revealed that 10b substantially induced the upregulation of 38 differentially expressed genes, which were enriched in the photosynthesis pathway. These findings suggest that 10b is a promising antiviral agrochemical that can effectively control PVY infection and trigger plant host immunity to develop virus resistance. This study provides novel molecular entities and ideas for developing new pesticides.

Design, Synthesis, and Biological Evaluation of Novel 1,4-Pentadien-3-one Derivatives Containing a Sulfonamide Moiety

Novel 1,4-pentadien-3-one derivatives containing a sulfonamide moiety were synthesized, and their antifungal, antibacterial, and antiviral activities were verified. These compounds exhibited better activity against five bacteria, with EC50 values ranging from 9.6 to 60.1 μg/mL, prominently, which are superior to those of the commercial agent. A great amount of compounds had excellent fungicidal activity in vitro at 100 μg/mL. Strikingly, compound E6 exhibited moderate activity against Phytophthora litchii than azoxystrobin, with the EC50 value of compound E6 (0.5 μg/mL) drawing near azoxystrobin (0.3 μg/mL). Furthermore, compound E17 had a marked impact on in vivo anti-tobacco mosaic virus, according to the data of microscale thermophoresis, with a Kd value of the intermolecular binding force of 0.002 ± 0.001 μM, which was better than the commercial agent of ningnanmycin (Kd = 0.121 ± 0.031 μM). In addition, the results of these studies suggest that the use of active splicing can improve the biological activity of natural compounds and provide further complement to the development of novel pesticides.

Structural hybrids of sulfonamide and thiazole moieties: Synthesis and evaluation of antimicrobial activity

For the discovery of new antimicrobial drugs, new derivatives of sulfonamide having thiazole ring were synthesized. The new series of sulfonamide derivatives were synthesized starting from 4-(arylsulfonamido)-acetophenone thiosemicarbazones 2a–f. Cyclization of thiosemicarbazone derivatives 2a–f by using ethyl chloroacetate and chloroacetone gave the thiazolidin-4-ones 3a–f and 4-methylthiazoles 4a–e, respectively. The antimicrobial properties of the synthesized compounds were investigated. The major thiosemicarbazone and thiazole derivatives gave no effect on most of the tested microorganisms. Incorporation phenyl group at both of the N-4 of thiosemicarbazones and the sulfonamide as in compound 2f gave moderate effects against most of the screened Gram-positive bacteria.

Exploration of 1,2,3-triazole linked benzenesulfonamide derivatives as isoform selective inhibitors of human carbonic anhydrase

A novel series of 1,2,3-triazole benzenesulfonamide substituted 1,3-dioxoisoindolin-5-carboxylate (7a-l) inhibitors of human α-carbonic anhydrase (hCA) was designed using a tail approach. The design method relies on the hybridization of a benzenesulfonamide moiety with a tail of 1,3-dioxoisoindoline-5-carboxylate and a zinc-binding group on a 1,2,3-triazole scaffold. Among the synthesized analogues, 2‑iodophenyl (7f, KI of 105.00 nM and SI of 2.98) and 2‑naphthyl (7h, KI of 32.11 nM and SI of 3.48) analogues (over off-target hCA I) and phenyl (7a, KI of 50.13 nM and SI of 2.74) and 2,6‑dimethylphenyl (7d, KI of 50.60 nM and SI of 3.35) analogues (over off-target hCA II) exhibited a remarkable selectivity for tumor isoforms hCA IX and XII, respectively. Meanwhile, analogue 7a displayed a potent inhibitory effect against the tumor-associated isoform hCA IX (KI of 18.29 nM) compared with the reference drug acetazolamide (AAZ, KI of 437.20 nM), and analogue 7h showed higher potency (KI of 9.22 nM) than AAZ (KI of 338.90 nM) against another tumor-associated isoform hCA XII. However, adding the lipophilic large naphthyl tail to the 1,3-dioxoisoindolin-5-carboxylate analogues increased both the hCA inhibitory and selective activities against the target isoform, hCA XII. Additionally, these analogues (7a-l) showed IC50 values against the human lung (A549) adenocarcinoma cancer cell line ranging from 129.71 to 352.26 μM. The results of the molecular docking study suggested that the sulfonamide moiety fits snugly into the hCAs active sites and interacts with the Zn2+ ion. At the same time, the tail extension engages in various hydrophilic and hydrophobic interactions with the nearby amino acids, which affects the potency and selectivity of the hybrids.

Design and synthesis of new adamantyl derivatives as promising antiproliferative agents

A series of adamantyl carboxamide derivatives containing sulfonate or sulfonamide moiety were designed as multitargeted inhibitors of ectonucleotide pyrophosphatases/phosphodiesterases (NPPs) and carbonic anhydrases (CAs). The target compounds were investigated for their antiproliferative activity against NCI-60 cancer cell lines panel. Three main series composed of 3- and 4-aminophenol, 4-aminoaniline, and 5-hydroxyindole scaffolds were designed based on a lead compound (A). Compounds 1e (benzenesulfonyl) and 1i (4-fluorobenzenesulfonyl) of 4-aminophenol backbone exhibited the most promising antiproliferative activity. Both compounds exhibited a broad-spectrum and potent inhibition against all the nine tested cancer subtypes. Both compounds showed nanomolar IC50 values over several cancer cell lines that belong to leukemia and colon cancer such as K-562, RPMI-8226, SR, COLO 205, HCT-116, HCT-15, HT29, KM12, and SW-620 cell lines. Compounds 1e and 1i induced apoptosis in K-562 leukemia cells in a dose-dependent manner. Compound 1i showed the highest cytotoxic activity with IC50 value of 200 nM against HT29 cell line. In addition, compounds 1e and 1i were tested against normal breast cells (HME1) and normal skin fibroblast cells (F180) and the results revealed that the compounds are safe toward normal cells compared to cancers cells. Enzymatic assays against NPP1-3 and carbonic anhydrases II, IX, and XII were performed to investigate the possible molecular target(s) of compounds 1e and 1i. Furthermore, a molecular docking study was performed to predict the binding modes of compounds 1e and 1i in the active site of the most sensitive enzymes subtypes.