Targeting the interplay between MMP-2, CA II and VEGFR-2 via new sulfonamide-tethered isomeric triazole hybrids; Microwave-assisted synthesis, computational studies and evaluation.

Recently, the interest in targeting metalloenzymes is obviously growing for halting various tumor progression events and surmounting the resistance due to routine chemotherapy regimen. In this regard, attention to MMP-2 and CA II has been drawn as validated druggable anticancer targets that share vital signaling pathways. The vast majority of MMP and CA inhibitors are designed to function as directed single-target agents. In spite of their transient efficacy, they are often susceptible to tumor resistance. Hence, several dual inhibitors of correlated MMPs and CAs were introduced. This set the stage to simultaneously target the common vital signaling nodes as well. VEGFR-2 is considered central to various tumorigenesis processes involving both MMP-2 and CA II. Herein, we report concomitant inhibition of MMP-2, CA II, and VEGFR-2 via rationally designed 1,2,3- and 1,2,4-triazole hybrids bearing various sulfonamide appendages following pharmacophore hybridization strategy. The designed adducts were efficiently elaborated in an almost quantitative yield utilizing microwave-assisted click 1,3-dipolar cycloaddition reaction between various alkynes-based 1,2,4-triazole and 4-azido benzensulfonamides. All derivatives were evaluated for their anticancer potential against three human cancer cell lines (Caco-2, MDA-MB-231, and HepG-2) after safety assessment on normal human cells (Wi-38). Amongst those click adducts, 8d and 8e were the most potent and safest anticancer agents exhibiting low range nanomolar IC50 (7.37-11.96 nM) and high selectivity (SI = 3.01-4.46), against the studied cancer cell lines, hence superior to doxorubicin concerning potency (IC50 = 10.63-48.25 nM) and selectivity (SI = 0.43-1.93). They significantly elevated the expression level of the tumor suppressor p53 in the three tested cancer cell lines up to 3 folds and induced apoptosis in HepG-2 cells with higher potential to 8d over 8e. Enzymatic evaluation showed that both derivatives were potent dual MMP-2/VEGFR-2 inhibitors, particularly 8d (MMP-2; IC50 = 5.66 nM and VEGFR-2; IC50 = 6.65 nM), relative to the reference MMP-2 inhibitor NNGH (IC50 = 299.50 nM) and VEGFR-2 inhibitor sorafenib (IC50 = 4.92 nM). Both 8d and 8e exhibited relatively moderate activity against the human CA II isoform (IC50 = 116.9 and 187.5 nM, respectively) relative to the reference (IC50 = 27.3 nM). Docking studies clearly explained the superior in vitro enzymatic inhibition profiles of 8d over 8e and predicted the structural determinants of activity. Nevertheless, 8d displayed promising in silico ADMET properties and ligand efficiency metrics. These findings evidently demonstrated the sulfatriazole 8d as an auspicious multi-target-directed ligand that deserves further optimization for developing novel antitumor agents.

Novel scaffold hopping of potent benzothiazole and isatin analogues linked to 1,2,3-triazole fragment that mimic quinazoline epidermal growth factor receptor inhibitors: Synthesis, antitumor and mechanistic analyses.

A series of benzothiazole/isatin linked to 1,2,3-triazole moiety and terminal sulpha drugs 5a-e and 6a-e were synthesized and evaluated for cytotoxic activity against a panel of cancer cell lines. The novel compounds showed variable IC50 range of activity and some of them were potent compared to reference drug. The promising compounds were subjected as postulated the mimicry proposal for quinazoline-based EGFR inhibitors for their inhibitory profile against EGFR TK enzyme. That data obtained revealed that most of these compounds were potent EGFR TK inhibitors at nanomolar concentrations. Among these, compounds 5a and 5b showed more potent activity on EGFR compared to erlotinib (IC50 103 and 104 versus 67.6 nM). Based upon the results, molecular docking analysis was performed on EGFR receptor and proved the strong contribution of fragments; benzothiazole, isatin, and triazole to the binding ATP pocket. When these selected compounds 5a and 5b were tested in an HepG2 model, they could effectively inhibited tumor growth, strongly induced cancer cell apoptosis, and suppressed cell cycle progression leading to DNA fragmentation. Well-DMET profile of the most active derivatives was presented and compared to the reference drugs. Taken together, we introduced novel triazole-sulpha drug hybrid for the first time as EGFR inhibitors and the results of our studies indicate that the newly discovered inhibitors have significant potential for anticancer treatment.

Design, synthesis, ADME prediction and pharmacological evaluation of novel benzimidazole-1,2,3-triazole-sulfonamide hybrids as antimicrobial and antiproliferative agents.

BACKGROUND: Nitrogen heterocyclic rings and sulfonamides have attracted attention of several researchers. RESULTS: A series of regioselective imidazole-based mono- and bis-1,4-disubstituted-1,2,3-triazole-sulfonamide conjugates 4a-f and 6a-f were designed and synthesized. The first step in the synthesis was a regioselective propargylation in the presence of the appropriate basic catalyst (Et3N and/or K2CO3) to afford the corresponding mono-2 and bis-propargylated imidazoles 5. Second, the ligation of the terminal C≡C bond of mono-2 and/or bis alkynes 5 to the azide building blocks of sulfa drugs 3a-f using optimized conditions for a Huisgen copper (I)-catalysed 1,3-dipolar cycloaddition reaction yielded targeted 1,2,3-triazole hybrids 4a-f and 6a-f. The newly synthesized compounds were screened for their in vitro antimicrobial and antiproliferative activities. Among the synthesized compounds, compound 6a emerged as the most potent antimicrobial agent with MIC values ranging between 32 and 64 µg/mL. All synthesized molecules were evaluated against three aggressive human cancer cell lines, PC-3, HepG2, and HEK293, and revealed sufficient antiproliferative activities with IC50 values in the micromolar range (55-106 µM). Furthermore, we conducted a receptor-based electrostatic analysis of their electronic, steric and hydrophobic properties, and the results were in good agreement with the experimental results. In silico  ADMET prediction studies also supported the experimental biological results and indicated that all compounds are nonmutagenic and noncarcinogenic. CONCLUSION: In summary, we have successfully synthesized novel targeted benzimidazole-1,2,3-triazole-sulfonamide hybrids through 1,3-dipolar cycloaddition reactions between the mono- or bis-alkynes based on imidazole and the appropriate sulfonamide azide under the optimized Cu(I) click conditions. The structures of newly synthesized sulfonamide hybrids were confirmed by means of spectroscopic analysis. All newly synthesized compounds were evaluated for their antimicrobial and antiproliferative activities. Our results showed that the benzimidazole-1,2,3-triazole-sulfonamide hybrids inhibited microbial and fungal strains within MIC values from 32 to 64 µg/mL. The antiproliferative evaluation of the synthesized compounds showed sufficient antiproliferative activities with IC50 values in the micromolar range (55-106 µM). In conclusion, compound 6a has remarkable antimicrobial activity. Pharmacophore elucidation of the compounds was performed based on in silico ADMET evaluation of the tested compounds. Screening results of drug-likeness rules showed that all compounds follow the accepted rules, meet the criteria of drug-likeness and follow Lipinski's rule of five. In addition, the toxicity results showed that all compounds are nonmutagenic and noncarcinogenic.

Synthesis and crystal structure of a new pyridinium bromide salt: 4-methyl-1-(3-phen-oxy-prop-yl)pyridinium bromide.

In the cation of the title mol-ecular salt, C15H18NO+·Br-, the pyridinium and phenyl rings are inclined to one another by 11.80 (8)°. In the crystal, the Br- anion is linked to the cation by a C-H⋯Br hydrogen bond. The cations stack along the b-axis direction and are linked by further C-H⋯Br inter-actions, and offset π-π inter-actions [inter-centroid distances = 3.5733 (19) and 3.8457 (19) Å], forming slabs parallel to the ab plane. The effects of the C-H⋯X- inter-action on the NMR signals of the ortho- and meta-pyridinium protons in a series of related ionic liquids, viz. 4-methyl-1-(4-phen-oxy-but-yl)pyridin-1-ium salts, are reported and discussed.