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Derivatives with tetrahydrobenzo[ h ]quinoline chemotype were synthesized via one-pot reactions and evaluated for their antileishmanial, antimalarial and antitubercular activities. Based on a structure-guided approach, they were designed to possess antileishmanial activity through antifolate mechanism, via targeting Leishmania major pteridine reductase 1 (Lm -PTR1). The in vitro antipromastigote and antiamastigote activity are promising for all candidates and superior to the reference miltefosine, in a low or sub micromolar range of activity. Their antifolate mechanism was confirmed via the ability of folic and folinic acids to reverse the antileishmanial activity of these compounds, comparably to Lm -PTR1 inhibitor trimethoprim. Molecular dynamics simulations confirmed a stable and high potential binding of the most active candidates against leishmanial PTR1. For the antimalarial activity, most of the compounds exhibited promising antiplasmodial effect against P. berghei with suppression percentage of up to 97.78%. The most active compounds were further screened in vitro against the chloroquine resistant strain P. falciparum, (RKL9) and showed IC 50 value range of 0.0198–0.096 μM, compared to IC 50 value of 0.19420 μM for chloroquine sulphate. Molecular docking of the most active compounds against the wild-type and quadruple mutant pf DHFR-TS structures rationalized the in vitro antimalarial activity. Some candidates showed good antitubercular activity against sensitive Mycobacterium tuberculosis in a low micromolar range of MIC, compared to 0.875 μM of isoniazid. The top active ones were further tested against a multidrug-resistant strain (MDR) and extensively drug-resistant strain (XDR) of Mycobacterium tuberculosis. Interestingly, the in vitro cytotoxicity test of the best candidates displayed high selectivity indices emphasizing their safety on mammalian cells. Generally, this work introduces a fruitful matrix for new dual acting antileishmanial-antimalarial chemotype graced with antitubercular activity. This would help in tackling drug-resistance issues in treating some Neglected Tropical Diseases. [Display omitted] • New tetrahydrobenzo[ h ]quinoline chemotype were synthesized via one-pot reactions. • They were designed to possess antileishmanial activity via antifolate mechanism. • Dual antileishmanial-antimalarial graced with antitubercular activity were observed. • Molecular docking and dynamics rationalized the observed antileishmanial activity. • Most actives candidates showed low toxicity and high safety. [ABSTRACT FROM AUTHOR]

Abstract: Two series of 4,6-diaryl-2-imino-1,2-dihydropyridine-3-carbonitriles and their isosteric 4,6-diaryl-2-oxo-1,2-dihydropyridine-3-carbonitriles were synthesized through a combinatorial approach. The prepared analogues were evaluated for their in vitro capacity to inhibit PDE3A and the growth of the human HT-29 colon adenocarcinoma tumor cell line. Compound 6-(4-bromophenyl)-4-(2-ethoxyphenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (Id) exhibited the strongest PDE3 inhibition when cGMP but not cAMP is the substrate with a IC50of 27μM, which indicates a highly selective mechanism of enzyme inhibition. On the other hand, compound 6-(1,3-benzodioxol-5-yl)-4-(2-ethoxyphenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (Ii) was the most active in inhibiting colon tumor cell growth with a IC50 of 3μM. The electronic effects, steric effects and conformational aspects of Id seem to be the most crucial for the PDE3 inhibition. Meanwhile, steric factors and the H-bonding capability seem to be the most important factors for tumor cell growth inhibitory activity. Conversely, there is no direct correlation between PDE3 inhibition and anticancer activity for the prepared compounds. An in silico docking experiment indicates the potential involvement of other potential molecular targets such as PIM-1 kinase to explain its tumor cell growth inhibitory activity. [Copyright &y& Elsevier]

Herein we introduce new compounds as conjugates of arylnicotinic acids with aryl (thio)semicarbazide derivatives. Based on a structure-guided approach, they were designed to possess anti-leishmanial activity through anti-folate mechanism, via targeting Leishmania major pteridine reductase 1 (Lm -PTR1). The in vitro anti-promastigote and anti-amastigote activity were promising for many thiosemicarbazide derivatives and superior to the reference miltefosine. The most active compounds 8i and 8j exhibited their anti-amastigote activity with IC 50 values of 4.2 and 3.3 μM, respectively, compared to reference miltefosine (IC 50 value of 7.3). Their anti-folate mechanism was confirmed via the ability of folic and folinic acids to reverse the anti-leishmanial activity of these compounds, comparably to Lm -PTR1 inhibitor trimethoprim. Interestingly, the in vitro cytotoxicity test of the most active compounds displayed higher selectivity indices than that of miltefosine emphasizing their safety on mammalian cells. Furthermore, the docking experiments on Lm -PTR1 as a putative target rationalized the in vitro anti-leishmanial activity. The in silico predictions exhibited promising pharmacokinetics and drug-likeness profiles of the most active compounds. Generally, this work introduces a fruitful matrix for new anti-leishmanial chemotype which would extend the chemical space for the anti-leishmanial activity. Image 1 • Certain arylnicotinic acids conjugated with aryl (thio)semicarbazides were designed to target folate pathway of L. major , especially Lm -PTR1. • Reversal of anti-leishmanial activity of the most active compounds by folic acid and folinic acid validated the anti-folate mechanism. • The in vitro cytotoxicity test of the most active compounds displayed higher selectivity indices than that of miltefosine. • Docking experiments on Lm-PTR1 as a putative target rationalized the in vitro antileishmanial activity. • In silico predictions exhibited promising pharmacokinetics and drug-likeness profiles of the most active compounds. [ABSTRACT FROM AUTHOR]

Abstract In search for effective multi-targeting drug ligands (MTDLs) to address low-grade inflammatory changes of metabolic disorders, we rationally designed some novel glitazones-like compounds. This was achieved by incorporating prominent pharmacophoric motifs from previously reported COX-2, 15-LOX and PPARγ ligands. Challenging our design with pre-synthetic docking experiments on PPARγ showed encouraging results. In vitro tests have identified 4 compounds as simultaneous partial PPARγ agonist, potent COX-2 antagonist (nanomolar IC 50 values) and moderate 15-LOX inhibitor (micromolar IC 50 values). We envisioned such outcome as a prototypical balanced modulation of the 3 inflammatory targets. In vitro glucose uptake assay defined six compounds as insulin-sensitive and the other two as insulin-independent glucose uptake enhancers. Also, they were able to induce PPARγ nuclear translocation in immunohistochemical analysis. Their anti-inflammatory potential has been translated to effective inhibition of monocyte to macrophage differentiation, suppression of LPS-induced inflammatory cytokine production in macrophages, as well as significant in vivo anti-inflammatory activity. Ligand co-crystallized PPARγ X-ray of one of MTDLs has identified new clues that could serve as structural basis for its partial agonism. Docking of the most active compounds into COX-2 and 15-LOX active sites, pinpointed favorable binding patterns, similar to those of the co-crystallized ligands. Finally, in silico assessment of pharmacokinetics, physicochemical properties, drug-likeness and ligand efficiency indices was performed. Hence, we anticipate that the prominent biological profile of such series will rationalize relevant anti-inflammatory drug development endeavors. Graphical abstract Prototypical balanced modulation of 3 inflammatory targets offered by some novel glitazone-like compounds. Image 1 Highlights • 1,2,3-triazolyl-thiazolidinedione/rhodanine hybrids were rationally designed as PPARγ partial agonists/COX-2 and 15-LOX inhibitors. • COX-2 and 15-LOX in vitro assays identified 10 compounds as dual inhibitors. • Glucose uptake assay recognized 6 compounds as insulin-sensitive and 2 compounds as insulin-independent uptake enhancers, while PPARγ agonistic activity was confirmed via reporter assay and immunohistochemical analysis. • 4 Compounds showed potent inhibition of monocyte to macrophage differentiation as well as high in vivo anti-inflammatory activity. • Crystal structure of PPARγ ligand binding domain (LBD) in complex with the most active compound has been solved and demonstrated partial agonistic behavior. [ABSTRACT FROM AUTHOR]

In a search for new drug candidates for one of the neglected tropical diseases, leishmaniasis, twenty quinoline-isatin hybrids were synthesized and tested for their in vitro antileishmanial activity against Leishmania major strain. All the synthesized compounds showed promising in vitro activity against the promastigote form in a low micromolar range (IC 50 = 0.5084–5.9486 μM) superior to the reference miltefosine (IC 50 = 7.8976 μM). All the target compounds were then tested against the intracellular amastigote form and showed promising inhibition effects (IC 50 = 0.60442–8.2948 μM versus 8.08 μM for miltefosine). Compounds 4e , 4b and 4f were shown to possess the highest antileishmanial activity against both promastigote and amastigote forms. The most active compounds were proven to exhibit their significant antileishmanial effects through antifolate mechanism, targeting DHFR-TS and PTR1. To evaluate the safety profile of the most active derivatives 4e , 4b and 4f, the in vitro cytotoxicity test was carried out and displayed higher selectivity indices than the reference miltefosine. Molecular docking within putative target protein PTR1 confirmed the high potentiality of the most active compounds 4e , 4b and 4f to block the catalytic activity of Lm-PTR1. [Display omitted] • New quinoline-isatin hybrids were synthesized as antileishmanial agents. • Compounds 4e , 4b and 4f showed the highest in vitro activity. • The most active derivatives acted as DHFR-TS/PTR1 inhibitors. • The promising compounds displayed low toxicity in VERO cells. • In silico studies of the promising compounds showed high docking scores. [ABSTRACT FROM AUTHOR]

Pharmacologic inhibition of the oncogenic protein kinases using small molecules is a promising strategy to combat several human malignancies. CDK1 is an example of such a valuable target for the management of pancreatic ductal adenocarcinomas (PDAC); its overexpression in PDAC positively correlates with the size, histological grade and tumor aggressiveness. Here we report the identification of novel series of 1-piperazinyl-4-benzylphthalazine derivatives (8a-g , 10a-i and 12a-d) as promising anticancer agents with CDK1 inhibitory activity. The anti-proliferative activity of these agents was first screened on a panel of 11 cell lines representing 5 cancers (pancreas, melanoma, leukemia, colon and breast), and then confirmed on two CDK1-overexpressing PDAC cell lines (MDA-PATC53 and PL45 cells). Phthalazines 8g , 10d and 10h displayed potent activity against MDA-PATC53 (IC 50 = 0.51, 0.88 and 0.73 μM, respectively) and PL45 (IC 50 = 0.74, 1.14 and 1.00 μM, respectively) cell lines. Furthermore, compounds 8g , 10d and 10h exhibited potent and selective inhibitory activity toward CDK1 with IC 50 spanning in the range 36.80–44.52 nM, whereas they exerted weak inhibitory effect on CDK2, CDK5, AXL, PTK2B, FGFR, JAK1, IGF1R and BRAF kinases. Western blotting of CDK1 in MDA-PATC53 cells confirmed the ability of target phthalazines to diminish the CDK1 levels, and cell cycle analyses revealed their ability to arrest the cell cycle at G2/M phase. In conclusion, a panel of potent and selective CDK1 inhibitors were identified which can serve as lead compounds for designing further CDK1 inhibitors. • Novel 1-piperazinyl-4-benzylphthalazine derivatives (8a-g , 10a-I, 12a-d) were developed. • They displayed potent anti-proliferative activity against two CDK1-overexpressing PDAC cell lines. • Compounds 8g , 10d and 10h exhibited potent and selective inhibitory activity toward CDK1. • They weakly inhibited CDK2, CDK5, AXL, PTK2B, FGFR, JAK1, IGF1R, BRAF kinases. • Molecular docking for the target phthalazines in CDK1 active site was carried out. [ABSTRACT FROM AUTHOR]

A series of 36 pyrazol-4-yl pyridine derivatives (8a-i , 9a-i , 10a-i , and 11a-i) was designed, synthesized, and evaluated for its antiproliferative activity over NCI-60 cancer cell line panel and inhibitory effect against JNK isoforms (JNK1, JNK2, and JNK3). All the synthesized compounds were tested against the NCI-60 cancer cell line panel. Compounds 11b , 11c , 11g , and 11i were selected to determine their GI 50s and exerted a superior potency over the reference standard SP600125 against the tested cell lines. 11c showed a GI 50 of 1.28 μM against K562 leukemic cells. Vero cells were used to assess 11c cytotoxicity compared to the tested cancer cells. The target compounds were tested against h JNK isoforms in which compound 11e exhibited the highest potency against JNK isoforms with IC 50 values of 1.81, 12.7, and 10.5 nM against JNK1, JNK2, and JNK3, respectively. Kinase profiling of 11e showed higher JNK selectivity in 50 kinase panels. Compounds 11c and 11e showed cell population arrest at the G2/M phase, induced early apoptosis, and slightly inhibited beclin-1 production at higher concentrations in K562 leukemia cells relative to SP600125. NanoBRET assay of 11e showed intracellular JNK1 inhibition with an IC 50 of 2.81 μM. Also, it inhibited CYP2D6 and 3A4 with different extent and its hERG activity showed little cardiac toxicity with an IC 50 of 4.82 μM. h JNK3 was used as a template to generate the h JNK1 crystal structure to explore the binding mode of 11e (PDB ID: 8ENJ) with a resolution of 2.8 °A and showed a typical type I kinase inhibition against h JNK1. Binding energy scores showed that selectivity of 11e towards JNK1 could be attributed to additional hydrophobic interactions relative to JNK3. [Display omitted] • Compounds 11c exhibited GI 50 of 1.28 μM against NCI K562 cells. • Compound 11e showed some selectivity towards JNK1 with IC 50 of 1.81 nM at 1 μM ATP and showed high JNK selectivity among 50 kinases. • 11c and 11e exhibited G2/M phase arrest, early apoptosis and slight beclin-1 inhibition against K562 cells in comparison with SP600125. • 11e inhibited JNK1 in HEK293 cells, CYP2A6, and CYP3A4 and showed little hERG activity. • 11e showed type I kinase inhibition upon co-crystallization with JNK isoforms (PDB: 8ENJ). [ABSTRACT FROM AUTHOR]

New functionalized acrylamide derivatives bearing sulfisoxazole moiety were synthesized and evaluated for their in vitro antimicrobial activities. In vivo pharmacokinetic study was carried out. Molecular modeling studies indicated that these compounds were able to inhibit the microbial dihydropteroate synthase enzyme (DHPS). • Acrylamide derivatives bearing sulfisoxazole moiety were synthesized. • Target compounds were evaluated in vitro as antimicrobial agents. • DHPS is confirmed to be a putative target for these compounds. • Docking experiments against DHPS rationalized the observed activities. • 99mTc-5g complex could be used as a diagnostic radio imaging material. New functionalized acrylamide derivatives bearing sulfisoxazole moiety were designed to target bacterial dihydropteroate synthase (DHPS). The in vitro antimicrobial activities of these compounds were assessed. The E -configuration of compound 5b was proved by single crystal X-ray analysis. Compounds 5g and 5h displayed double the activity of ampicillin against B. subtilis. Also, 5h was two times more active than gentamycin against E. coli. Interestingly, compounds 5f-g , 7c , 8a, 8c exhibited two folds the potency of amphotericin B against S. racemosum while 5h displayed three folds the activity of amphotericin B against S. racemosum. Most of the synthesized compounds showed superior activities to the parent sulfisoxazole and were non-toxic to normal cells. DHPS is confirmed to be a putative target for our compounds via antagonizing their antibacterial activity by the folate precursor (p -aminobenzoic acid) and product (methionine) on E. coli ATCC 25922. Docking experiments against DHPS rationalized the observed antibacterial activity. Additionally, compound 5g was evaluated as a selective targeting vector for 99mTc that showed a remarkable uptake and targeting ability towards the infection site that was induced in mice. [ABSTRACT FROM AUTHOR]

In the current medical era, the utilization of a single small molecule to simultaneously target two distinct molecular targets is emerging as a highly effective strategy in the battle against cancer. Carbonic Anhydrase (CA) and Vascular-Endothelial Growth Factor (VEGF) are genes that are activated in response to low oxygen levels (hypoxia) and play a role in the development and progression of tumors in hypoxic conditions. Herein we report the design, synthesis, and biological assessment of a series of novel indolinone-based benzenesulfonamides (8a-k , 11a-d , 15a-d , and 16) as potential dual inhibitors for cancer-associated h CA IX/XII and VEGFR-2. All the synthesized sulfonamides were assessed for their inhibitory effect against four CA isoforms I, II, IX, and XII where they displayed varying degrees of h CA inhibition. The most effective and selective h CA IX and XII inhibitors 8g , 8j and 15b were chosen to be tested for their in vitro inhibitory impact against VEGFR-2 as well as their antiproliferative impact against VEGFR-2 overexpressing MDA-MB-231 and MCF-7 breast cancer cells. Furthermore, molecular docking studies were conducted within the h CA IX, XII, and VEGFR-2 active sites to explain the observed inhibitory results. [Display omitted] • Novel series of isatin-based benzenesulfonamides (8a-k , 11a-d , 15a-d , 16) were synthesized. • Inhibitory activities of all molecules were evaluated towards hCA I, II, IX and XII isoforms. • All isatins efficiently inhibited the cancer-related h CA IX and XII in the low nanomolar ranges. • Isatins 8g , 8j and 15b effectively inhibited VEGFR-2 with good IC 50 values. • 8g , 8j, 15b exerted potent antiproliferative impact against MDA-MB-231 and MCF-7 cell lines. [ABSTRACT FROM AUTHOR]

Hypoxia, a characteristic feature of solid tumors, develops as a result of excessive cell proliferation and rapid tumor growth exceeding the oxygen supply, and can result in angiogenesis activation, increased invasiveness, aggressiveness, and metastasis, leading to improved tumor survival and suppression of anticancer drug therapeutic impact. SLC-0111, a ureido benzenesulfonamide, is a selective human carbonic anhydrase (hCA) IX inhibitor in clinical trials for the treatment of hypoxic malignancies. Herein, we describe the design and synthesis of novel 6-arylpyridines 8a-l and 9a-d as structural analogues of SLC-0111, in the aim of exploring new selective inhibitors for the cancer-associated hCA IX isoform. The para -fluorophenyl tail in SLC-0111 was replaced by the privileged 6-arylpyridine motif. Moreover, both ortho- and meta- sulfonamide regioisomers, as well as an ethylene extended analogous were developed. All 6-arylpyridine-based SLC-0111 analogues were screened in vitro for their inhibitory potential against a panel of hCAs (hCA I, II, IV and IX isoforms) using stopped-flow CO 2 hydrase assay. In addition, the anticancer activity was firstly explored against a panel of 57 cancer cell lines at the USA NCI-Developmental Therapeutic Program. Compound 8g emerged as the best anti-proliferative candidate with mean GI% value equals 44. Accordingly, a cell viability assay (MTS) for 8g was applied on colorectal HCT-116 and HT-29 cancer cell lines as well as on the healthy HUVEC cells. Thereafter, Annexin V-FITC apoptosis detection, cell cycle, TUNEL, and qRT-PCR, colony formation, and wound healing assays were applied to gain mechanistic insights and to understand the behavior of colorectal cancer cells upon the treatment of compound 8g. Also, a molecular docking analysis was conducted to provide in silico insights into the reported hCA IX inhibitory activity and selectivity. [Display omitted] • New series of sulfonamide-tethered 6-arylpyridines 8a-l and 9a-d was designed and synthesized. • Inhibitory activities of all derivatives were evaluated toward hCA I, II, IV and IX isoforms. • The anticancer activity was explored against a panel of 57 cancer cell lines at the NCI-USA. • Compound 8g showed promising CA inhibitory and anti-proliferative activities. • A thorough investigation was done into the anticancer efficacy of 8g against colorectal cell lines. [ABSTRACT FROM AUTHOR]

Abstract New 1,3,4-trisubstituted pyrazole derivatives were synthesized and evaluated for their antiplasmodial activity. Compounds 4b , 4c , 7a and 7d were the most potent antiplasmodial agents against P. berghei with percent of suppression ranging from 90 to 100%. They were also screened for their in vitro antimalarial activity against the chloroquine resistant strain P. falciparum, (RKL9). Compound 4c displayed the highest in vitro antimalarial activity; 13-fold higher than standard chloroquine phosphate. Molecular docking of the most active compounds against the wildtype and quadruple mutant pf DHFR-TS structures rationalized the in vitro antimalarial activity. Furthermore, these compounds exhibited reasonable in silico drug-likeness and pharmacokinetic properties. Toxicity studies of the most active compounds revealed that all tested compounds were non-toxic and well-tolerated up to 150 mg/kg via oral route and 75 mg/kg via parentral route. According to RBC hemolysis assay, it was found that compound 7a was the most potent anti-inflammatory and least toxic derivative with IC 50 value 71-fold higher than IC 50 value related to the antimalarial activity. Moreover, cytotoxicity assessment revealed that compound 4c was the least toxic derivative with IC 50 value 70000-fold higher than IC 50 value related to the antimalarial activity. Graphical abstract Image 1 Highlights • 1,3,4-trisubstituted pyrazole derivatives were synthesized. • Promising antimalarial activity against P. berghei and chloroquine resistant RKL9. • Antimalarial activity is up to 13-fold higher than standard chloroquine phosphate. • Molecular docking experiments rationalized the observed antimalarial activity. • RBC hemolysis assay and cytotoxicity assessment showed low toxicity profile. [ABSTRACT FROM AUTHOR]

Abstract Leishmaniasis affects over 150 million people all over the world, especially in subtropical regions. Currently used antileishmanial synthesized drugs are associated with some drawbacks such as resistance and cytotoxicity, which hamper the chances of treatment. Furthermore, effective leishmanial vaccines are not well developed. Promising chemotherapy, either from natural or synthetic compounds, was or still is the most promising treatment. This review focuses on recent findings in drugs used for the treatment of leishmaniasis including; chemical and natural antileishmanial moieties, different potential targets, as well as various trials of vaccination development. Special emphasis has been paid to the mechanisms of the drugs, their safety and where possible, the structure-activity relationship to enable guided future drug discovery. Graphical abstract Image 1 Highlights • Various herbal agents show promising antileishmanial activity. • Promising synthesized agents with various core substructures were reported. • New drugs are needed due to the toxicity and resistance to current treatments. • A need to develop an effective vaccine with broad protection against leishmaniasis. [ABSTRACT FROM AUTHOR]

The development of new COX-2 inhibitors with analgesic and anti-inflammatory efficacy as well as minimal gastrointestinal, renal and cardiovascular toxicity, is of vital importance to patients suffering from chronic course pain and inflammatory conditions. This study aims at evaluating the therapeutic activity and adverse drug reactions associated with the use of the newly synthesized pyrazole derivative, compound AD732, E -4-[3-(4- methylphenyl)-5- hydroxyliminomethyl - 1H - pyrazol -1- yl ]benzenesulfonamide, as compared to indomethacin and celecoxib as standard agents. Anti-inflammatory activity was assessed using carrageenan-induced rat paw edema and cotton pellet granuloma tests; formalin-induced hyperalgesia and hot plate tests were done to study analgesic activity. In vitro tests to determine COX-1/COX-2 selectivity and assessment of renal and gastric toxicity upon acute exposure to AD732 were also conducted. Compound AD732 exhibited promising results; higher anti-inflammatory and analgesic effects compared to standard agents, coupled with the absence of ulcerogenic effects and minimal detrimental effects on renal function. Additionally, compound AD732 was a less potent inhibitor of COX-2 in vitro than celecoxib, which may indicate lower potential cardiovascular toxicity. It may be concluded that compound AD732 appears to be a safer and more effective molecule with promising potential for the management of pain and inflammation. [Display omitted] [ABSTRACT FROM AUTHOR]

In the present study, we describe the design of different series of benzofuran-based derivatives as potential carbonic anhydrase inhibitors (CAIs). The adopted design is based on bioisosteric replacement for the p -fluorophenyl SLC-0111 tail with the lipophilic 2-methylbenzofuran or 5-bromobenzofuran tails to furnish the 2-methylbenzofuran (MBF) sulfonamides (MBFS; 9 , 11 and 13) and 5-bromobenzofuran (BBF) sulfonamides (BBFS; 27a-b , 28a-b and 29a-c), respectively. Thereafter, the urea spacer was either elongated to furnish MBFS (17 and 19), and BBFS (30) series, or replaced by a carbamate one to afford MBFS (15). All the designed compounds were synthesized and evaluated for their inhibitory activities against four human (h) CA isoforms: h CA I, II, IX and XII. MBFS (11b and 17) and BBFS (28b , 29a and 30) efficiently inhibited the tumor-related CA IX isoform in the single-digit nanomolar range (K I s = 8.4, 7.6, 5.5, 7.1 and 1.8 nM, respectively). In particular, MBFS 11b and BBFS 28b exhibited good selectivity toward hCA IX isoform over the main off-target hCA II isoform (S. I. = 26.4 and 58.9, respectively). As a consequence, 11b and 28b were examined for their anticancer and pro-apoptotic activities toward MDA-MB-231 and MCF-7 cancer cell lines. [Display omitted] • New series of 2-methyl/5-bromobenzofuran-based sulfonamides were designed and synthesized. • Inhibitory activities of all derivatives were evaluated toward hCA I, II, IX and XII isoforms. • Compounds 11b, 17 , 28b , 29a and 30 had single-digit nanomolar CA IX inhibitory activities. • Compounds 11b and 28b were examined for their potential anticancer activities. • Molecular modeling was done to acquire insights for the binding interactions and affinities. [ABSTRACT FROM AUTHOR]