Sulfonamide-phosphonate hybrids as new carbonic anhydrase inhibitors: In vitro enzymatic inhibition, molecular modeling, and ADMET prediction

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    A new series of sulfonamide-phosphonate hybrids 4a-m was designed and synthesized.

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    Structures of new compounds 4a-m were confirmed by 1H NMR, 13C NMR, and IR spectroscopy.

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    Compounds were evaluated for their in vitro anti-hCA activity.

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    Compounds 4l and 4j proved to possess high inhibitory activity against hCAI and hCAII.

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    Docking study revealed that compounds 4l and 4j as well fit into hCAI and hCAII active sites.

Abstract

In the presented work, we report the synthesis of a new series of sulfonamide-phosphonate hybrids 4a-m. These newly synthesized compounds were assessed for their inhibitory effects toward two human carbonic anhydrase isoforms I and II (hCA I and II). These examined isoforms were as well inhibited by the most of prepared sulfonamide-phosphonates in comparison to standard inhibitor acetazolamide. Obtained data exhibited that compounds 4b-m with Ki values in the range of 8.11–48.08 nM were more potent than standard drug acetazolamide with Ki value of 64.52 Nm against hCA I. Moreover, all the synthesized compounds (Ki values = 7.08–64.24 nM), with the exception of compound 4b, were more potent than acetazolamide (Ki value = 75.36) against hCA II. In particular, sulfonamide-phosphonates 4l and 4j, respectively, with substituents 5‑chloro-2-nitro and 2,3-dichloro emerged as the most potent hCA inhibitors. Thereafter, the molecular docking of compounds 4l and 4j at hCA I and II active sites was performed and the obtained results revealed that these compounds interacted whit the important amino acids of the active site. Finally, the predicted parameters of Lipinski's rule of five, ADME, and toxicity analysis showed that compounds 4l and 4j had good drug-likeness and acceptable physicochemical properties. Therefore, the hybridization of the sulfonamide and phosphonate moieties could be promising strategy for achieve to potent lead compounds for inhibition of hCA.

Introduction

Carbonic anhydrases (CA) are zinc containing metallo-enzymes in known sixteen isoforms which differ in function, tissue expression patterns, and kinetic properties [1]. The overexpression and sluggishness of various types of CA isoforms related to many diseases in human [2]. Two main isoforms of CA are CA I (located in gastrointestinal tract (GT) and tract erythrocytes) and CA II (located in brain, eye, GT, erythrocytes, kidney, lung, bone osteoclasts, and testis) that involved in important physiological processes such as gas-exchange, regulation of the acid-base homeostasis, and ion transportation [3], [4], [5]. The effect of these isoforms on acid-base homeostasis leads to their use in treatment of glaucoma, epilepsy, peptic ulcer, and cerebral edema [6], [7], [8]. Thus, design of safe and potent CA inhibitors and preparation of them simple methods are attractive subjects for medicinal chemists [9], [10], [11], [12], [13], [14].

Our research group for a long time is involved in the design of novel classes of enzyme inhibitors with treatment applications and synthesis of them by simple and efficient chemical reactions. One of the important strategies for design of our new compounds is molecular hybridization of effective pharmacophore. Recently, we became interested in the synthesis and evaluation of CA inhibitors [15], [16], [17], [18]. In this regard, very recently, we reported CA inhibitory effects of a new series of sulfonamide derivatives [19]. Moreover, a survey on the structures of clinically important CA inhibitors acetazolamide, methazolamide, ethoxzolamide, dorzolamide, brinzolamide, and pazopanib revealed that sulfonamide moiety is present in all of them [20], [21], [22]. Therefore, sulfonamide is a reasonable pharmacophore for the design of new CA inhibitors [23], [24], [25], [26], [27]. On the other hand, phosphonates moiety found in the several series of the potent CA inhibitors [28,29].

In this work, on the basis of the mentioned points, we designed a new series of sulfonamide-phosphonate derivatives as CA inhibitors by molecular hybridization. The target compounds were synthesized by a one-step simple reaction and evaluated against hCA I and hCA II in vitro and in silico. In order to study the structure–activity relationship (SAR) and optimization of inhibitory activity against studied CA isoforms, thirteen derivatives with electron donating groups such as methyl, hydroxyl, methoxy, and electron withdrawing groups such as fluoro, chloro, bromo, and nitro were synthesized.

Section snippets

Chemistry

The designed sulfonamide-phosphonates 4a-m were synthesized by a Kabachnik-fields reaction, which provides an effective route to latter compounds through a one-step reaction according to Scheme 1 [30]. Therefore, compounds 4a-m were obtained from reaction of 4-aminobenzenesulfonamide 1, trimethyl phosphite 2, and benzaldehydes 3a-m in methanol.

A possible mechanism for the formation of sulfonamide-phosphonates 4a-m is proposed in Scheme 2 [30]. Initially, imine derivatives 5a-m were formed of

Conclusion

hCAs are a group of zinc-binding enzymes that catalyzed the reversible hydration of CO2 to bicarbonate. Importance of the inhibition of these enzymes in the several diseases such as glaucoma, peptic ulcer, epilepsy, and cerebral edema was as well documented. Therefore, we decided to design of hybrid derivatives in order to inhibition of hCAs. Based on the presence of sulfonamide moiety in the clinically important hCA inhibitors and new potent anti-CA agents, sulfonamide was selected as the

General procedure for the synthesis of sulfonamide-phosphonates 4a-m

A suspension of 4-aminobenzenesulfonamide 1 (1 mmol), trimethyl phosphite 2 (1 mmol), and benzaldehyde derivatives 3a-m (1 mmol) in methanol (15 mL) was stirred at room 80 °C for 3 h. After completion of the reaction (checked by TLC), methanol was evaporated under reduced pressure and the residue was recrystallized by ethyl acetate.

Credit author statement

All authors have contributed to this manuscript.

Declaration of Competing Interest

The authors declare that there is no conflict of interest.

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