Tail approach synthesis of novel benzenesulfonamides incorporating 1,3,4-oxadiazole hybrids as potent inhibitor of carbonic anhydrase I, II, IX, and XII isoenzymes

doi:10.1016/j.ejmech.2020.112219

European Journal of Medicinal Chemistry

Volume 193, 1 May 2020, 112219

https://doi.org/10.1016/j.ejmech.2020.112219 Get rights and content

Highlights

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Two series of 1,3,4-oxadiazole based benzenesulfonamides 3a–j and 4a–j having carbonyl and amide tail/linker were synthesized.
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Inhibitory efficacy of 3a–j and 4a–j was evaluated towards hCA I, II, IX, and XII isoforms.
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Compound 4j (K_I = 70.7 nM, 7.9 nM, 16.3 nM) emerged as the most potent inhibitor of hCA I, II and IX respectively as compared to AAZ.
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4c and 3b were found to be the most selective hCA IX and XII inhibitors over hCA I.

Abstract

Two new series of 1,3,4-oxadiazole benzenesulfonamide hybrids 3 and 4, having twenty novel compounds, have been designed and synthesized in order to assess their inhibition potential as CAIs against hCA I, II, IX, and XII. ‘Tail approach’ strategy has been used to design the aromatic sulfonamide scaffolds with carbonyl and amide linker. Excellent inhibitory activity against hCA I has been exhibited by compounds 3g and 4j, 3.5 magnitude of order better than reference drug AAZ (K_I = 250 nM). Moreover, compound 4j (K_I = 7.9 nM) effectively inhibited glaucoma-associated hCA II isoform as well as tumor-associated hCA IX isoform with K_I = 16.3 nM. Further hCA XII was weakly inhibited by all the compounds with K_I values ranging from 0.23 μM to 3.62 μM. Interestingly structure-activity relationship (SAR) study indicates that N-(3-nitrophenyl)-2-((5-(4-sulfamoylphenyl)-1,3,4-oxadiazol-2-yl)thio)acetamide (4j) is a potent compound to be investigated further for antiglaucoma and antitumor activity. The chemistry of the nature of different substitutions on the 1,3,4-oxadiazole bearing benzenesulfonamide substituted aromatic ring for potency and selectivity over one hCA isoform versus others is deliberated in the present study. In this context, the 1,3,4-oxadiazole motif can be a valuable tool worth developing for the procurement of novel and potent selective CAIs potentially useful for the management of a variety of diseases as chemotherapeutic agents.

Graphical abstract

Introduction

World Health Organization cited cancer as a major public health problem worldwide with one in six deaths globally attributed to cancer [1]. Cancer is a generic term for an enormous cluster of diseases that matures by the genetic and epigenetic mutations transforming normal healthy cells into malignant phenotypes and the process is referred as metastasizing [1]. Undoubtedly, investigations in the arena of pioneering anti-cancer drug discovery focused on cancer treatment with more effective and less toxic agents are highly desired.

The carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes having the core of Zn²⁺ ion in the active center present all over the phyla of the animal kingdom [[2], [3], [4], [5], [6]]. The CAs catalyze the reversible and fundamental biochemical reaction, hydration of CO₂ into HCO₃⁻ and H⁺ ions as well as other hydrolytic reactions by the metal hydroxide nucleophilic mechanism [7,8]. This simple reaction is crucial for many physiological mechanisms including electrolyte secretion, respiration, acid-base tuning, bone resorption, tumorigenesis, calcification and biosynthesis of important molecules such as urea, glucose, and lipids, which require HCO₃⁻ as a substrate [[9], [10], [11]]. CAs have been developed as eight genetically different enzyme families ɑ-, β-, γ-, δ-, ζ-, η-, θ-, and ι-CAs, [12,13]. Further α-CA isoforms existing in human have been divided into sixteen sub-isoforms that differ by molecular features, oligomeric arrangement, cellular localization, distribution in organs and tissues, expression levels, kinetic properties and response to different classes of inhibitors [[14], [15], [16], [17], [18]]. Various dysfunctions, and/or over-expression of hCAs in different human physiological as well as pathological processes are responsible for many ailments in body such as mental disorders (hCA II, VII, VIII, XIV), obesity (hCA VA, VB), edema (hCA I, II) and glaucoma (hCA II, IV, XII) [[19], [20], [21]]. The eminent transmembrane isoforms hCA IX and XII are overexpressed in hypoxic tumors, with limited expression in most normal cells [14,19,22,23]. These tumor-associated proteins help in pH regulation in tumors, proliferation, angiogenesis, and metastasis of variety of cancer cells, their selective inhibition can lead to the development of new generation anticancer agents [24,25]. It is noteworthy that ubiquitous hCA I and II are the main off-target isoforms because these are involved in many physiological processes [2].

Traditional primary carbonic anhydrase sulfonamide inhibitors have been used over the last few decades in clinics for the treatment of glaucoma, epilepsy, obesity, and as diuretics [26]. Acetazolamide (AAZ), Methazolamide (MZA) and Ethoxzolamide (EZA) (Fig. 1) are the prototypical first and second-generation drugs [19,27]. The sulfonamide based hCA IX and XII inhibitor SLC-0111 is under clinical investigations [28]. Since most of the CA epitopes are nonspecific, a major challenge in therapeutic antitumor applications of hCA IX and XII sulfonamide-based inhibitors is to the risk of a plethora of undesired side effects [29].

The first choice in the field of specific CAI chemotypes is the zinc-binding group (ZBG) primary sulfonamide [23]. The ring and tail approach strategies have been used for the design of isoform-selective sulfonamide based CAIs [23]. The CAIs consisting of modulating moieties with various steric demands were directly attached to the sulfonamide group and appended with different tails to the aromatic/heterocyclic ring in the scaffold of the ZBG in order to target selectively the rim of the active site of CA, a region with significant amino acid difference between isoenzymes [30]. The sulphonamide moiety and the aromatic ring are attached through carbonyl/amide linker (Fig. 2.).

Several studies have been extensively performed on 1,3,4-oxadiazole moiety, which shows diverse biological activities including antiviral [31], analgesic [32], antitumor [33], and anti-inflammatory [34] activity. The biological potential of these heterocycles against cancer cells has been reported with different mechanisms of action, such as inhibition of tubulin, mitogenesis, angiogenesis, metastasis in tumors, focal adhesion kinase inhibition, telomerase inhibition, interacting with several receptors involved in proliferation, cell growth, and DNA biosynthesis [32,[35], [36], [37], [38], [39]]. Azole group present in the 1,3,4-oxadiazole make it more lipophilic and, therefore, more liable to pass through the cell membrane [40].

In previous years, our research group has explored N containing heterocyclic compounds such as 1,2,3-triazoles, 1,2,4 triazoles, pyrazoles and pyrazolines 1 containing benzenesulfonamides as CAIs (Fig. 3) that show moderate to excellent inhibition potential against hCA IX and XII [[41], [42], [43], [44]]. Recently, we reported the synthesis of benzenesulfonamides containing triazole moietiy 2 that showed excellent inhibition against hCA I, II, IV, and IX [45]. In order to explore the heterocyclic scaffolds as CAIs, we report herein the design and synthesis of new sets of twenty novel 1,3,4-oxadiazole containing benzenesulfonamides 3a–j and 4a–j to study the effect of the incorporation of amide and carbonyl linker between the aromatic ring and main 1,3,4-oxadiazole benzenesulfonamide moiety on their inhibition potential against physiologically relevant isoforms hCA I and II as well as tumor-associated isoforms hCA IX and XII (Fig. 3).

Section snippets

Chemistry

The synthesis of the novel derivatives of 1,3,4-oxadiazole bearing benzenesulfonamide 3a–j and 4a–j is outlined in Scheme 1. Initially, the 4-sulfamoylbenzoic acid (6) was prepared by the oxidation of 4-methylbenzenesulfonamide (5) in the presence of KMnO₄ that was further converted into methyl 4-sulfamoylbenzoate (7) using usual Fischer esterification reaction [46]. Refluxing methyl ester derivatives with hydrazine monohydrate in ethanol afforded corresponding hydrazide 8 [46]. The acid

Conclusions

As a part of our research aiming to design selective novel carbonic anhydrase inhibitors, we have synthesized two series of twenty compounds 3a–j and 4a–j containing 1,3,4-oxadiazole bearing benzenesulfonamide. These compounds were examined for their inhibition potential against the two dominant cytosolic isoforms hCA I/II and the tumor-associated isoforms hCA IX/XII and compared with that of reference drug acetazolamide AAZ, a standard inhibitor. The hCA I was relatively weakly inhibited by

General

All the reagents and solvents were purchased from commercial suppliers and were used as received unless otherwise indicated. All the solvents were dried and/or purified according to standard procedures prior to use. All the air or moisture-sensitive reactions were performed under a nitrogen atmosphere using dried glassware and syringes techniques to transfer solutions. Analytical thin-layer chromatography (TLC) was performed on MERCK precoated silica gel on F₂₅₄ aluminium plates using a mixture

CA inhibition assay

An SX.18 MV-R Applied Photophysics (Oxford, UK) stopped-flow instrument has been used to assay the inhibition of various CA isozymes [50]. Phenol Red (at a concentration of 0.2 mM) has been used as an indicator, working at the absorbance maximum of 557 nm, with 10 mM Hepes (pH 7.4) as a buffer, 0.1 M Na₂SO₄ or NaClO₄ (for maintaining constant the ionic strength; these anions are not inhibitory in the used concentration), following the CA-catalyzed CO₂ hydration reaction for a period of 5–10 s.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

One of the authors (Vikas Sharma) is grateful to the Council of Scientific and Industrial Research, New Delhi, India for the award of Junior Research Fellowship and the other (Rajiv Kumar), is thankful to University Grants Commission, New Delhi, India for the award of Senior Research Fellowship.

Acknowledgment

The authors are thankful to Materials Research Centre, MNIT Jaipur for providing HRMS facility and Guru Jambheshwar University of Science & Technology, Hisar-Haryana for NMR facility.

References (50)

H.I. Gul et al.
New phenolic Mannich bases with piperazines and their bioactivities
Bioorg. Chem.
(2019)
M. Tugrak et al.
Synthesis and biological evaluation of some new mono Mannich bases with piperazines as possible anticancer agents and carbonic anhydrase inhibitors
Bioorg. Chem.
(2019)
M. Şentürk et al.
Carbonic anhydrase inhibitors. Inhibition of human erythrocyte isozymes I and II with a series of antioxidant phenols
Bioorg. Med. Chem.
(2009)
P. Khloya et al.
4-Functionalized 1,3-diarylpyrazoles bearing benzenesulfonamide moiety as selective potent inhibitors of the tumor associated carbonic anhydrase isoforms IX and XII
Eur. J. Med. Chem.
(2014)
B.Z. Kurt et al.
Synthesis, biological activity and multiscale molecular modeling studies of bis-coumarins as selective carbonic anhydrase IX and XII inhibitors with effective cytotoxicity against hepatocellular carcinoma
Bioorg. Chem.
(2019)
N. Chiaramonte et al.
Sulfonamides incorporating piperazine bioisosteres as potent human carbonic anhydrase I, II, IV and IX inhibitors
Bioorg. Chem.
(2019)
A. Akıncıoğlu et al.
Discovery of potent carbonic anhydrase and acetylcholine esterase inhibitors: novel sulfamoylcarbamates and sulfamides derived from acetophenones
Bioorg. Med. Chem.
(2015)
A. Yıldırım et al.
N-Acylsulfonamides strongly inhibit human carbonic anhydrase isoenzymes I and II
Bioorg. Med. Chem.
(2015)
S. Akin et al.
Synthesis of 1,2,4-triazole-5-on derivatives and determination of carbonic anhydrase II isoenzyme inhibition effects
Bioorg. Chem.
(2019)
H.A. Allam et al.
Application of hydrazino and hydrazido linkers to connect benzenesulfonamides with hydrophilic/phobic tails for targeting the middle region of human carbonic anhydrases active site: selective inhibitors of hCA IX
Eur. J. Med. Chem.
(2019)

H.S. Ibrahim et al.

Dual-tail arylsulfone-based benzenesulfonamides differently match the hydrophobic and hydrophilic halves of human carbonic anhydrases active sites: selective inhibitors for the tumor-associated hCA IX isoform

Eur. J. Med. Chem.

(2018)

W. Wu et al.

Synthesis and antiviral activity of 2-substituted methylthio-5-(4-amino-2-methylpyrimidin-5-yl)-1,3,4-oxadiazole derivatives

Bioorg. Med. Chem. Lett

(2015)

K. Manjunatha et al.

Synthesis and biological evaluation of some 1,3,4-oxadiazole derivatives

Eur. J. Med. Chem.

(2010)

A.G. Banerjee et al.

Synthesis, characterization, evaluation and molecular dynamics studies of 5, 6-diphenyl-1,2,4-triazin-3(2H)-one derivatives bearing 5-substituted 1,3,4-oxadiazole as potential anti-inflammatory and analgesic agents

Eur. J. Med. Chem.

(2015)

S.A. Shahzad et al.

Synthesis and biological evaluation of novel oxadiazole derivatives: a new class of thymidine phosphorylase inhibitors as potential anti-tumor agents

Bioorg. Med. Chem.

(2014)

J. Sun et al.

Synthesis and antitumor activity of 1,3,4-oxadiazole possessing 1,4-benzodioxan moiety as a novel class of potent methionine aminopeptidase type II inhibitors

Bioorg. Med. Chem. Lett

(2013)

W. Caneschi et al.

Synthesis and anticancer evaluation of new lipophilic 1,2,4 and 1,3,4-oxadiazoles

Eur. J. Med. Chem.

(2019)

L. Vats et al.

Synthesis of novel 4-functionalized 1,5-diaryl-1,2,3-triazoles containing benzenesulfonamide moiety as carbonic anhydrase I, II, IV and IX inhibitors

Eur. J. Med. Chem.

(2018)

V. Sharma et al.

Synthesis of novel benzenesulfonamide bearing 1,2,3-triazole linked hydroxy-trifluoromethylpyrazolines and hydrazones as selective carbonic anhydrase isoforms IX and XII inhibitors

Bioorg. Chem.

(2019)

R. Kumar et al.

Design and synthesis of novel benzenesulfonamide containing 1,2,3-triazoles as potent human carbonic anhydrase isoforms I, II, IV and IX inhibitors

Eur. J. Med. Chem.

(2018)

L. Vats et al.

Continued exploration and tail approach synthesis of benzenesulfonamides containing triazole and dual triazole moieties as carbonic anhydrase I, II, IV and IX inhibitors

Eur. J. Med. Chem.

(2019)

R. Kumar et al.

Benzenesulfonamide bearing imidazothiadiazole and thiazolotriazole scaffolds as potent tumor associated human carbonic anhydrase IX and XII inhibitors

Bioorg. Med. Chem.

(2017)

X. Guo et al.

Discovery of 1-aryloxyethyl piperazine derivatives as Kv1.5 potassium channel inhibitors

Eur. J. Med. Chem.

(2014)

M. Tanc et al.

6-Substituted 1,2-benzoxathiine-2,2-dioxides are isoform-selective inhibitors of human carbonic anhydrases IX, XII and VA

Org. Biomol. Chem.

(2015)

R.G. Khalifah

The carbon dioxide hydration activity of carbonic anhydrase. I. Stop-flow kinetic studies on the native human isoenzymes B and C

J. Biol. Chem.

(1971)

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Design, synthesis and in silico insights of novel 1,2,3-triazole benzenesulfonamide derivatives as potential carbonic anhydrase IX and XII inhibitors with promising anticancer activity
2024, Bioorganic Chemistry
Novel 1,2,3-triazole benzenesulfonamide derivatives were designed as inhibitors for the tumor- related hCA IX and XII isoforms. Most of the synthesized compounds showed good inhibitory activity against hCA IX and hCA XII isoforms. Compounds 4d, 5h and 6b, exhibited remarkable activity as hCA IX inhibitors, with K_i values in the range of 0.03 to 0.06 µM, more potent than AAZ. Additionally, compounds 5b and 6d, efficiently inhibited hCA XII isoform, with K_i value of 0.02 µM, respectively, similar to AAZ. Further investigation for those potent derivatives against MCF-7, Hep-3B and WI-38 cell lines was achieved. Compounds 4d and 6d exerted dual cytotoxic activity against MCF-7 and Hep-3B cell lines, with IC₅₀ values of 3.35 & 2.12 µM against MCF-7 cell line and 1.72 & 1.56 µM against Hep-3B cell line, with high SI values ranged from 8.92 to 17.38 on both of the cell lines. Besides, they showed a high safety profile against normal human cell line, WI-38. Moreover, compound 5h had better cytotoxic effect on MCF-7 than the reference, DOX, with IC₅₀ value of 4.02 µM. While, compounds 5b and 6b showed higher activity against Hep-3B if compared to the reference drug, 5-FU.
From ADME study, compounds 4d, 5b, 6b and 6d obeyed Lipinski’s rule of five, and they might be orally active derivatives, while, compound 5h exerted less oral bioavailability than the reference standard acetazolamide. Molecular docking and MDS studies predicted the binding mode and the stability of the target compounds inside hCA IX and hCA XII active sites, especially for compounds 5b and 6b.
Discovery of novel benzenesulfonamides incorporating 1,2,3-triazole scaffold as carbonic anhydrase I, II, IX, and XII inhibitors
2023, International Journal of Biological Macromolecules
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, K_I of 68.6 nM, S_I of 10.3), and methyl (6a, K_I of 56.3 nM, S_I of 11.7) derivatives (over hCA IX) and propyl (6c, K_I of 95.6 nM, S_I of 2.7), and pentyl (6d, K_I of 51.1 nM, S_I 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 (K_I of 47.8 nM) and tumor-associated isoforms hCA IX and XII (K_Is of 195.9 and 116.9 nM, respectively) compared with the reference drug acetazolamide (AAZ, K_Is of 451.8, 437.2, and 338.9 nM, respectively). Derivative 6b showed higher potency (K_I of 33.2 nM) than AAZ (K_I 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.
A decade of tail-approach based design of selective as well as potent tumor associated carbonic anhydrase inhibitors
2022, Bioorganic Chemistry
Citation Excerpt :
Most of the synthesized compounds were low nanomolar to subnanomolar hCA II, IX and XII inhibitors and did not potently inhibit hCA I, and hence, showed selective inhibition against hCA IX and XII over hCA I but not over hCA II except compound 55 (Fig. 7), which was almost inactive on the cytosolic isoforms hCA I and II with Ki values of > 10000 nM, and potently and selectively inhibited hCA IX and hCA XII isoforms with Ki values of 12.1 and 10.2 nM. Furthermore, Sharma and co-workers [66,67,70,73,77,78,81–85] designed and synthesized various diverse azole derivatives, which were evaluated for their CA inhibition profile. Many of them showed potent inhibition for hCA IX and/or hCA XII isoforms, and some of them possessed selectivity upto significant extent for these tumor associated isoforms over ubiquitous main off-target isoforms hCA I and II [66,73,77,78].
Human carbonic anhydrase (hCA) isoforms hCA IX and hCA XII are well established anticancer drug targets and their selective inhibition is highly desired for the proper treatment of cancer. Lack of isoform-selectivity in current clinically used CA inhibitors (CAIs) is a major concern as it leads to undesired side effects, associated with off-target inhibition. Thus, there is need to explore alternative approaches for the design of isoform-selective inhibitors and the leading promising approach for the design of isoform-selective CAIs is “the tail-approach”. Virtually, most drug design studies in the last decade were done by considering the tail-approach reported in 1999. The past decade of 2010–2020 witnessed progressive maturation of this approach as a large number of CAIs have been designed and synthesised based on it, many of which turned out to be effective as well as selective hCA IX and hCA XII inhibitors. This review covers the past decade (2010–2020) research, considering selective as well as potent inhibitors of tumor associated isoforms, hCA IX and hCA XII, which include newer generation inhibitors containing sulfonamides or their bioisosteres, non-classical inhibitors (including carboxylic acid/ester, coumarin and sulfocoumarin classes) and various other novel classes of inhibitors belonging to newly identified chemotypes/scaffolds.
Tail-approach based design and synthesis of Arylthiazolylhydrazono-1,2,3-triazoles incorporating sulfanilamide and metanilamide as human carbonic anhydrase I, II, IV and IX inhibitors
2022, Bioorganic Chemistry
Citation Excerpt :
No doubt the normal expression/regulated activity of these hCA isoforms play a pivotal role in many physiological processes (vide supra), but their contribution in numerous pathological processes is also well known due to their overexpression/deregulated activity which results into number of diseases. For example, overexpression of hCA I isoform is connected with cerebral/retinal edema; hCA II isoform is associated with edema, glaucoma, altitude sickness and epilepsy; hCA IV isoform is linked with stroke, retinitis pigmentosa, glaucoma; whereas overexpression of hCA IX isoform is associated with cancer [11,12,15,16]. It clearly demonstrates the importance of these isoforms as potential therapeutic drug targets.
A library of twenty-two arylthiazolylhydrazono-1,2,3-triazoles incorporating sulfanilamide and metanilamide moieties have been synthesized by utilizing tail-approach and characterized by their IR, ¹H NMR, ¹³C NMR, HRMS and single crystal studies. Further, these newly synthesized compounds were screened in-vitro for their inhibition efficacy against physiologically relevant hCA I, II, IV and IX isoforms. Inhibition data revealed that, in broader sense, sulfanilamide analogues (4a-4k) were comparatively better inhibitors of cytosolic hCA I and II isoforms than metanilamide analogues (5a-5k), whereas exactly opposite trend was observed in case of inhibition of membrane bound hCA IV and transmembrane hCA IX. For hCA I, more than half of the synthesized compounds were found to be moderate inhibitors and three compounds 4b, 5b and 5e (K_i of 40.6, 224.7 and 74.4 nM, respectively) appeared as better inhibitors than reference drug AAZ (K_i = 250 nM). hCA II was potently inhibited by 4e-4g and 5e with K_i of 18.1, 14.1, 14.9 and 17.8 nM, respectively. Interestingly, 4e-4g selectively inhibited hCA II with selectivity of > 15-fold over hCA I, IV and IX isoforms. All the compounds presented moderate to weak inhibition profiles against glaucoma associated hCA IV with K_i of 88 nM-8.87 μM and except 4f, 5k, significant inhibition profiles against tumor associated hCA IX isoform with K_i spanning in range of 0.113 μM-0.318 μM. Moreover, 5e was the only compound among the whole series which effectively inhibited all the tested isoforms.
The effect of benzenesulfonamide's side chains on their human carbonic anhydrase Ⅰ/Ⅱ inhibitory activities
2022, Journal of Molecular Structure
Benzenesulfonamides are well-known potent carbonic anhydrase inhibitors (CAIs). They are usually composed of benzenesulfonamide heads and hydrophobic side chain tails. However, hydrophobic side chain tails contribute to poor water solubility, which is a major challenge in the development of CAIs. Herein, to elaborate whether benzenesulfonamides with hydrophilic/hydrophobic tails are effective against carbonic anhydrases (CAs), 12 benzenesulfonamides containing hydrophilic tails and 16 benzenesulfonamides containing hydrophobic tails were designed and synthesized. Benzenesulfonamides with hydrophilic tails including 4b, 4c, and 5b and benzenesulfonamides with hydrophobic tails including 2e, 4b, and 4c are potent carbonic anhydrase Ⅰ/Ⅱ dual inhibitors whose Ki to CA I and CA II were below 10 nM, and below 50 nM, respectively. However, the water solubility of 4b, 4c, and 5b was 52, 148, and 71 mg/100 g of water, respectively, which is much better than that of benzenesulfonamides with hydrophobic tails. In a hypoxic mouse model, compounds 4c and 5b extended the survival of mice by 34.46% and 28.23%, respectively, compared to the blank control. Treatment with 4c and 5b extended survival better than acetazolamide treatment did (16.86%). Moreover, 5b also has better anti-convulsant effect than AAZ. Molecular docking analysis demonstrated that hydrogen bonds between the oxygen atoms in the hydrophilic tails of 4b, 4c, and 5b and H₂O in hCA I and hCA II protein facilitated ligand-receptor binding. Therefore, considering the good water solubility and potent CA I/II inhibition, 4c and 5b are worth exploring as therapeutic options for acute mountain sickness. In conclusion, benzenesulfonamides containing hydrophilic tails could offer innovative opportunities for potent, water-soluble anti-AMS (Acute Mountain Sickness) compounds.
Molecular insights of oxadiazole benzene sulfonamides as human carbonic anhydrase IX inhibitors: Combined molecular docking, molecular dynamics, and 3D QSAR studies
2022, Journal of the Indian Chemical Society
Citation Excerpt :
The generated QSAR model with structural information helped in developing newer leads with better CA IX inhibitory activity. From literature review, interaction along hydrophobic and hydrophilic region of CA IX active site provided valuable information for designing inhibitors [20,21]. The designed compounds (Table 2) having diverse heterocyclic rings and oxadiazole chain linkers were geometry optimized to generate low energy conformers using Avogadro tool.
α - CA IX isozyme over-expression in hypoxic environment becomes an attractive target for the design of inhibitors targeting cancer particularly, tumor progression and invasion.
In the process of designing new scaffolds, oxadiazole benzene sulfonamide leads were explored and evaluated for the selective inhibition of tumor-associated hCA IX. The chemical dataset compounds with human carbonic anhydrase IX inhibition values were subjected to QSAR study for generating validated models.
The best statistically validated model with three descriptors MATSe1, GATSm6 and MoRSEM15 was utilized for designing compounds with improved bioactivity. Further new molecules were taken over for the molecular docking studies and the best lead for molecular dynamics simulation and binding free energy studies. The outcome of the QSAR and molecular docking studies resulted in the development of lead molecules. Among the designed compounds two molecules 35a and 38a were further studied for molecular interactions and observations led to the residues of active site region involving both hydrophilic and hydrophobic interactions.
Molecular dynamics simulation studies for the lead molecule 38a in comparison to the reference provided useful structural insights. Further, fluctuations of the residues, H-bond profiles and stability analysis by RMSD, RMSF, RoG were studied. In addition, MM-PBSA and MM-GBSA also affirms the docking results. We propose the designed compound 38a as the best theoretical lead which may further be experimentally studied for selective inhibition.

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Research paperTail approach synthesis of novel benzenesulfonamides incorporating 1,3,4-oxadiazole hybrids as potent inhibitor of carbonic anhydrase I, II, IX, and XII isoenzymes

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Conclusions

General

CA inhibition assay

Disclosure statement

Declaration of competing interest

Acknowledgment

Bioorg. Chem.

Bioorg. Chem.

Bioorg. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Chem.

Bioorg. Chem.

Bioorg. Med. Chem.

Bioorg. Med. Chem.

Bioorg. Chem.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Med. Chem. Lett

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Chem.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Med. Chem.

Eur. J. Med. Chem.

Org. Biomol. Chem.

J. Biol. Chem.

Research paper
Tail approach synthesis of novel benzenesulfonamides incorporating 1,3,4-oxadiazole hybrids as potent inhibitor of carbonic anhydrase I, II, IX, and XII isoenzymes