Design, synthesis and in vitro evaluation of novel thiazole-coumarin hybrids as selective and potent human carbonic anhydrase IX and XII inhibitors.

The coumarin is one of the most promising classes of non-classical carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. In continuation of our ongoing work on search of coumarin based selective carbonic anhydrase inhibitors, a new series of 6-aminocoumarin based 16 novel analogues of coumarin incorporating thiazole (4a-p) have been synthesized and studied for their hCA inhibitory activity against a panel of human carbonic anhydrases (hCAs). Most of these newly synthesized compounds exhibited interesting inhibition constants in the nanomolar range. Among the tested compounds, the compounds 4f having 4-methoxy substitution exhibited activity at 90.9 nM against hCA XII isoform. It is noteworthy to see that all compounds were specifically and selectively active against isoforms hCA IX and hCA XII, with Ki under 1000 nM range. It is anticipated that these newly synthesized coumarin-thiazole hybrids (4a-p) may emerge as potential leads candidates against hCA IX and hCA XII as selective inhibitors compared to hCA I and hCA II.

Design, synthesis, and biological evaluation of 3-benzenesulfonamide-linked 3-hydrazinoisatin derivatives as carbonic anhydrase inhibitors.

A new series of isatin-linked benzenesulfonamide derivatives (9a-w) were synthesized using the tail approach and assayed for their inhibitory potency against four different human carbonic anhydrase (hCA) isoforms, hCA I, II, IX, and XII. Most of these synthesized compounds exhibited interesting inhibition potency against isoforms hCA I, IX, and XII in the nanomolar range and by taking the standard drug acetazolamide. The most potent compounds in the case of hCA I were 9c (435.8 nM) and 9s (956.4 nM), for hCA IX, 9a (60.5 nM), 9d (95.6 nM), 9g (92.1 nM), and 9k (75.4 nM), and for hCA XII, 9p (84.5 nM). However, these compounds showed more selectivity toward hCA IX over hCA I, II, and XII. Thus, these compounds can be further developed as potential lead molecules for the development of isoform-selective hCA IX inhibitors with further structural modifications.

Development of Novel Indole-3-sulfonamide-heteroaryl Hybrids as Carbonic Anhydrase Inhibitors: Design, Synthesis and in-vitro Screening.

BACKGROUND: Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton. Inhibition of isoforms IX and XII has induced potent anticancer effects. OBJECTIVE: A series of indole-3-sulfonamide-heteroaryl hybrid (6a-y) was synthesized and screened for the inhibition of human (h) hCA isoforms I, II, IX, and XII. METHODS: The synthesis of target compounds (6a-y) was carried out in multistep starting from 5-nitro indole as starting material by using classical reported reaction conditions. The steps involved are N-Alkylation Chlorosulfonation, amination, reduction, and finally amidation reaction. RESULTS: Amongst all the compounds (6a-y) synthesized and screened, 6l was found to be active against all the screened hCA isoforms, with Ki ranging 8.03 µM, 4.15 µM, 7.09 µM, and 4.06 µM respectively. On the other hand, 6i, 6j, 6q, 6s, and 6t were highly selective against tumor-associated hCA IX, and 6u was selective against both hCA II and hCA IX with moderate inhibitory activities under the range of 100 µM. These compounds showed good activity against the tumor-associated hCA IX and might be developed as future drug leads for anticancer drug discovery. CONCLUSION: These compounds may be useful as starting points for the design and development of more selective and potent hCA IX and XII inhibitors.

Design, Synthesis and Biological Assessment of Rhodanine-Linked Benzenesulfonamide Derivatives as Selective and Potent Human Carbonic Anhydrase Inhibitors.

A novel series of twenty-five rhodamine-linked benzenesulfonamide derivatives (7a-u and 9a-d) were synthesized and screened for their inhibitory action against four physiologically relevant human (h) carbonic anhydrase (CA) isoforms, namely hCA I, hCA II, hCA IX, and hCA XII. All the synthesized molecules showed good to excellent inhibition against all the tested isoforms in the nanomolar range due to the presence of the sulfonamide as a zinc binding group. The target compounds were developed from indol-3-ylchalcone-linked benzenesulfonamide where the indol-3-ylchalcone moiety was replaced with rhodanine-linked aldehydes or isatins to improve the inhibition. Interestingly, the molecules were slightly more selective towards hCA IX and XII compared to hCA I and II. The most potent and efficient ones against hCA I were 7h (KI 22.4 nM) and 9d (KI 35.8 nM) compared to the standard drug AAZ (KI 250.0 nM), whereas in case of hCA II inhibition, the derivatives containing the isatin nucleus as a tail were preferred. Collectively, all compounds were endowed with better inhibition against hCA IX compared to AAZ (KI 25.8 nM) as well as strong potency against hCA XII. Finally, these newly synthesized molecules could be taken as potential leads for the development of isoform selective hCA IX and XII inhibitors.

Synthesis of a new series of quinoline/pyridine indole-3-sulfonamide hybrids as selective carbonic anhydrase IX inhibitors.

In this manuscript, design, rational, synthesisand carbonic anhydrases (CAs) inhibitory profile of the quinoline/pyridine linked indole-3-sulfonamide derivatives were reported. The library of 29newly quinoline/pyridine indole-3-sulfonamide derivatives have been generated and examined against the panel of four physiological relevant human CA isoforms, namely, the cytosolic isoforms hCA I and hCA II and the transmembrane tumor associated isoforms hCA IX and hCA XII. Pyridine indole-3-sulfonamide hybrids are selective inhibit transmembrane tumor associated isoforms hCA IX and hCA XII. However, all synthesized quinoline indole-3-sulfonamide hybrids have inhibitory effect on hCA IX isoforms, whereas few have shown inhibitory activity against hCA II and hCA XII as well. However, among all synthesized compound 6q and6p having good inhibitory activity against hCA IX with Ki 1.47 µM and 1.57 µM respectively.These quinoline/pyridine indole-3-sulfonamide conjugatesmay be regarded as potential leads for hCA IXselective inhibitors as anti-cancer agents.

Exploration of 2-phenylquinoline-4-carboxamide linked benzene sulfonamide derivatives as isoform selective inhibitors of transmembrane human carbonic anhydrases.

A novel series of 32 sulfonamide containing quinolines (5a-j, 7a-k and 9a-k) were synthesized using tail approach and assayed for their carbonic anhydrase inhibitory potency against four human (h) carbonic anhydrase (CA) isoforms hCA I, II, IX and XII. Most of these newly synthesized compounds exhibited interesting inhibition potency against hCA I, II, IX and XII, in the nanomolar range with some derivatives being more potent than the standard drug acetazolamide (AAZ). The most effective ones on hCA I were 9b (91.8 nM), on hCA II: 5b (7.1 nM), 9c (9.6 nM) and on hCA IX: 5b (6.5 nM), 5g (21.4 nM), 5i (9.1 nM), 9a (22.8 nM), 9b (9.7 nM). Compounds 5h (8.8 nM), 7a (9.6 nM), 9d (6.9 nM), 9e (6.7 nM) were found highly effective against hCA XII. These 4-functionalized benzenesulfonamides (5a-5j, 9a-9k) were found to be more potent than the corresponding 3-functionalized derivatives (7a-k). These compounds may emerge as potential leads for the development of isoform selective hCA IX and XII inhibitors.

Efficient One-pot Synthesis of 3,3-di(indolyl)indolin-2-ones from Isatin and Indole Catalyzed by VOSO4 as Non-Sulfonamide Carbonic Anhydrase Inhibitors.

BACKGROUND: A high yielding green protocol has been developed and delineated for the synthesis of 3,3- di(indolyl)indolin-2-ones, potentially bioactive compounds, involving one pot aqueous medium condensation of isatin with indole in the presence of VOSO4. The synthesized compounds were screened for their carbonic anhydrase inhibitory activity against human (h) isoforms hCA I, hCA II, hCA IX, and hCA XII. These non-sulfonamide derivatives selectively inhibited hCA II in the micromolar range. OBJECTIVE: To develop a high yielding green protocol to synthesize 3,3-diindolyl oxindole derivatives using water as solvent media and screening the synthesized molecules for their carbonic anhydrase inhibitory activity. METHODS: The target compound is obtained by taking isatin, indole, VOSO4, and H2O in one-pot at 70oC. RESULTS: The designed molecules were synthesized by using the new method. The molecules were screened for their CA inhibitory activity, which shows selective inhibition toward hCA II.The result showed an excellent yield without any loss or decrease in catalytic activity, proving the catalyst's performance and recyclability. CONCLUSION: An efficient, simple, and green protocol was established that provides a facile and straightforward approach for the preparation of 3,3-diindolyl oxindole derivatives (3a-r) from Isatin and Indole by using 10 mol% VOSO4 in high yields in a short period of time by a one-pot coupling reaction. Furthermore, the catalyst can also be recovered and reused for three consecutive catalytic cycles without any loss of its efficiency, which was confirmed by performing the experiment with 3a. The newly synthesized molecules (3a-r) were screened for their carbonic anhydrase inhibition potency against four isoforms, hCA I, II, IX, and XII and most of the compounds were found potent against hCA II with potency low to submicromolar range.

Design and development of novel series of indole-3-sulfonamide ureido derivatives as selective carbonic anhydrase II inhibitors.

Indole is a privileged moiety with a wide range of bioactivities, making it a popular scaffold in drug design and development studies as well as in synthetic chemistry. Here, novel urea derivatives of indole, containing sulfonamide at position-3 of indole, were synthesized using a well-known tail approach, as carbonic anhydrases (CAs; EC 4.2.1.1) inhibitors. All the newly synthesized molecules were screened for their CA-inhibitory activity against four clinically relevant isoforms of human-origin carbonic anhydrase (hCA), that is, hCA I, hCA II, hCA IX, and hCA XII. These compounds were specifically active against hCA II, more than against hCA I, hCA IX, and hCA XII. Derivative 6l was found to be most active, with a Ki value of 7.7 µM against hCA II.

Ureidosulfocoumarin Derivatives As Selective and Potent Carbonic Anhydrase IX and XII Inhibitors.

Owing to severe allergic reactions (anaphylaxis) and resistance exhibited by sulfonamide-based carbonic anhydrase (CA) inhibitors, non-classical or non-sulfonamide CA inhibitors are gaining increased attention by medicinal chemists. In this context, we report the design and synthesis of 30 new non-sulfonamide sulfocoumarin derivatives as CA inhibitors. They were investigated against hCA I and II (cytosolic isozymes) as well as hCA IX and XII (transmembrane, tumor-associated enzymes). All compounds showed prominent selectivity for the tumor-associated isoenzymes hCA IX and XII over the cytosolic isoenzymes hCA I and II. Among all synthesized compounds, 1-(2,2-dioxidobenzo[e][1,2]oxathiin-6-yl)-3-(o-tolyl)urea(5 j)and1-(3-fluorophenyl)-3-(8-methoxy-2,2-dioxidobenzo[e][1,2]oxathiin-6-yl)urea(5 q)were found to be more potent and to have better inhibition constant values against hCA IX than the standard acetazolamide (AAZ), with Ki values of 23.6 and 23.3 nM, respectively. All other compounds were found to be active under Ki =920 nM against hCA IX and XII.This study provides a new perspective for the future development of non-sulfonamide derivatives as selective CA inhibitors.

Synthesis and Biological Evaluation of Coumarin-Linked 4-Anilinomethyl-1,2,3-Triazoles as Potent Inhibitors of Carbonic Anhydrases IX and XIII Involved in Tumorigenesis.

A series of coumarin-linked 4-anilinomethyl-1,2,3-triazoles (6a-t) was synthesized via a molecular hybridization approach, through carbon C-6 of the coumarin moiety. The synthesized compounds were evaluated for their inhibition of carbonic anhydrase (CA) isoforms I, II, IX and XIII. CAs IX and XIII were selectively inhibited over the off-target isoforms I and II. The best inhibitory profiles against CA IX were shown by compounds 6a, 6e and 6f (Ki < 50 nM), with compound 6e displaying the best inhibition with a Ki value of 36.3 nM. Compounds 6a, 6b, 6j, 6o and 6q exhibited the best inhibitory profiles against CA XIII (Ki < 100 nM). These compounds can be further explored for the discovery of potent and effective CA IX and CA XIII inhibitors.

Design and synthesis of benzenesulfonamide-linked imidazo[2,1-b][1,3,4]thiadiazole derivatives as carbonic anhydrase I and II inhibitors.

A novel series of imidazothiadiazole-linked benzenesulfonamide derivatives (5a-t) was synthesized and subjected for screening against the four physiologically and pharmacologically relevant human carbonic anhydrase (hCA) isoforms: hCA I, II, VA, and IX. The compounds selectively inhibited hCA I and II over hCA VA and IX. Furthermore, among the two cytosolic isoforms, hCA II was more effectively inhibited as compared with hCA I. The most active compounds were 5o with K i = 0.246 µM and 5p with K i = 0.376 µM against hCA II, whereas compound 5f showed good inhibition against both hCA I and II with K i = 0.493 and 0.4 µM, respectively. This class of underexplored sulfonamides may be used to design isoform-selective CA inhibitors targeting enzymes of medicinal chemistry interest.

Discovery of a novel series of indolylchalcone-benzenesulfonamide hybrids acting as selective carbonic anhydrase II inhibitors.

The primary sulfonamide group is one of the most efficient zinc binding group (ZBG) for designing carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. In the present study primary sulfonamide linked with indolylchalcone were designed. The newly synthesized molecules (5a-r) were examined against four human (h) CA isoforms (hCA I, hCA II, hCA IX and hCA XIII). These sulfonamides showed good inhibition activity against isoforms hCA I, hCA II and hCA XIII. Compound 5i (2.3 nM), 5m (2.4 nM), 5o (3.6 nM) and 5q (7.0 nM) were more potent than standard drug AAZ (12.1 nM) against isoform hCA II, respectively. Most of the other compounds in the present series inhibited hCA XIII and hCA IX in the range of 50 nM - 100 nM.

3-Functionalised benzenesulphonamide based 1,3,4-oxadiazoles as selective carbonic anhydrase XIII inhibitors: Design, synthesis and biological evaluation.

A new series of benzenesulphonamide linked-1,3,4-oxadiazole hybrids (6a-s) has been synthesized and tested for their carbonic anhydrase inhibition against human (h) carbonic anhydrase (CA) isoforms hCA I, II, IX, and XIII. Fluorescence properties of some of the synthesized molecules were studied. Most of the molecules exhibited significant inhibitory power, comparable or better than the standard drug acetazolamide (AAZ) on hCA XIII. Out of 19 tested molecules, compound 6e (75.8 nM) was 3 times more potent than AAZ (250.0 nM) against hCA I, whereas compound 6e (15.4 nM), 6g (16.2 nM), 6h (16.4 nM) and 6i (17.0 nM) were found to be more potent than AAZ (17.0 nM) against isoform hCA XIII. It is anticipated that these compounds could be taken as the potential leads for the development of selective hCA XIII isoform inhibitors with improved potency.

New coumarin/sulfocoumarin linked phenylacrylamides as selective transmembrane carbonic anhydrase inhibitors: Synthesis and in-vitro biological evaluation.

Two novel series of phenylacrylamide linked coumarins and sulfocoumarins (6a-p, 8a-i, and 14a-g) were synthesized and evaluated against four physiologically relevant human carbonic anhydrases (hCAs, EC 4.2.1.1), isoforms hCA I, hCA II, hCA IX and hCA XII for their inhibitory action. All new compounds when screened for carbonic anhydrase inhibitory activity have shown selective inhibition towards the tumor associated isoforms hCA IX and XII over CA I and II, with inhibition constants in the submicromolar to low nanomolar range. Compound 6b and 14g exhibited significant inhibition with low nanomolar potency against hCA IX, whereas 6k was effective against hCA XII. Compounds 6b, 14g and 6k may be considered as lead molecules for future development of cancer therapeutics based on a novel mechanism of action.

Synthesis and carbonic anhydrase inhibition studies of sulfonamide based indole-1,2,3-triazole chalcone hybrids.

Sulfonamide is one of the most promising classes of classical carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. A novel series of indolylchalcones incorporating benzenesulfonamide-1,2,3-triazole (6a-q) has been synthesized by click chemistry reaction and investigated for hCA inhibitory activity against a panel of human carbonic anhydrases (hCAs). Most of these newly synthesized compounds exhibited interesting inhibition constants, in the nanomolar range, with some derivatives being more potent than the standard drug acetazolamide (AAZ) on hCA I isoform. Among the tested compounds, the compounds 6d (18.8 nM), 6q (38.3 nM) and 6e (50.4 nM) were 13, 6 and 5 times more potent than AAZ against hCA I isoform, respectively. Compounds 6o, 6m and 6f efficiently inhibited isoform hCA XII, with KIs in the range of 10-41.9 nM. Several compounds were also active against isoforms hCA II and hCA IX, with KIs under 100 nM. These indolylchalcone-benzenesulfonamide-1,2,3-triazole hybrids may be considered as potential leads for hCA I-selective inhibitors.

Synthesis and exploration of 2-morpholino-4-phenylthiazol-5-yl acrylamide derivatives for their effects against carbonic anhydrase I, II, IX and XII isoforms as a non-sulfonamide class of inhibitors.

Novel series of 2-morpholino-4-phenylthiazol-5-yl acrylamide derivatives (8a-s) have been synthesized and explored as a non-sulfonamide class of carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The newly synthesized molecules were evaluated for their CA inhibitory potency against four isoforms: the cytosolic isozyme hCA I, II as well as trans-membrane tumor associated isoform hCA IX and hCA XII taking acetazolamide (AAZ) as standard drug. The results revealed that most of the compounds showed good activity against hCA II, IX, and XII whereas none of them were active against hCA I (Ki >100 µM). It is observed that the physiologically most important cytosolic isoform hCA II was inhibited by these molecules in the range of Ki 9.3-77.7 µM. It is also found the both the transmembrane isoforms hCA IX and XII were also inhibited with Kis ranging between 54.7-96.7 µM and 4.6-8.8 µM, respectively. The binding modes of the active compounds within the catalytic pockets of hCA II, IX and XII were evaluated by docking studies. This new non-sulfonamide class of selective inhibitors of hCA II, IX and XII over the hCA I isoform may be used for further understanding the physiological roles of some of these isoforms in various pathologies.

Synthesis of a new series of 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides as carbonic anhydrase I, II, IV and IX inhibitors.

The synthesis of a novel series of 3-functionalised benzenesulfonamides incorporating phenyl-1,2,3-triazole with an amide linker was achieved by using the "click-tail" approach. The new compounds, including the intermediates, were assayed as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isoforms) and also for hCA IV and IX (transmembrane isoforms) taking acetazolamide as standard drug. Most of these compounds exhibited excellent activity against all these isoforms. hCA I was inhibited with Kis in the range of 50.8-966.8 nM, while the glaucoma associated hCA II was inhibited with Kis in the range of 6.5-760.0 nM. Isoform hCA IV was inhibited with Kis in the range of 65.3-957.5 nM, whereas the tumor associated hypoxia induced hCA IX was inhibited with Kis in the range of 30.8-815.9 nM. The structure activity relationship study for the 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides against these isoforms was also inferred from the results.

Vanadium-Catalyzed Oxidative C(CO)-C(CO) Bond Cleavage for C-N Bond Formation: One-Pot Domino Transformation of 1,2-Diketones and Amidines into Imides and Amides.

A novel vanadium-catalyzed one-pot domino reaction of 1,2-diketones with amidines has been identified that enables their transformation into imides and amides. The reaction proceeds by dual acylation of amidines via oxidative C(CO)-C(CO) bond cleavage of 1,2-diketones to afford N,N'-diaroyl-N-arylbenzamidine intermediates. In the reaction, these intermediates are easily hydrolyzed into imides and amides through vanadium catalysis. This method provides a practical, simple, and mild synthetic approach to access a variety of imides as well as amides in high yields. Moreover, one-step construction of imide and amide bonds with a long-chain alkyl group is an attractive feature of this protocol.