Synthesis and Biological Evaluation of Carbonic Anhydrase III and IX Inhibitors using Gas Chromatography with Modified pH Sensitive Pellets
DOI:
https://doi.org/10.35516/jjps.v16i2.1470Keywords:
Carbonic anhydrase III, Carbonic anhydrase IX, inhibitors, amides, hydroxamic acids, imines, zinc chelationAbstract
Fifteen compounds were synthesized and tested as potential carbonic anhydrase III (CAIII) and carbonic anhydrase IX (CAIX) inhibitors, six of which are novel. Amides (a1-4), hydroxamic acids (b1-2), and imines (c1-9) derivatives were evaluated for their inhibitory activity against CAII and CAIX using gas chromatography with modified pH-sensitive pellets. The derivatives showed inhibition percentages between 12-56% for CAIII and 44-59% for CAIX, compared to 49% and 63% for captopril (the positive control), respectively. Imines showed the best inhibition of CAIII, while all derivatives showed comparable activity against CAIX. It is hypothesized that the nitrogen atom in imine, amide, or hydroxamic acid moieties in the vicinity of an ionizable group is in coordination with the zinc ion in the active site. Furthermore, the candidates were tested for their antimicrobial and antifungal activity. Generally, they showed low to zero activity against some gram-positive and negative bacteria. This supports the theory of their ability to bind to human carbonic anhydrase but not to bacterial one. These compounds could serve as useful scaffolds to develop more potent and selective carbonic anhydrase inhibitors as anti-obesity and anticancer candidates.
References
(1) Andrea Petrenia VDL, C. Andrea Scalonic, et al.Anion inhibition studies of the Zn (II)-bound i-carbonic anhydrase from the Gram-negative bacterium Burkholderia territorii. J Enzyme Inhib Med Chem. 2021;36(1):372-6.
(2) Hamadneh L, Hikmat S, Al-Samad LA, et al. Synthesis, Characterization and Antimicrobial Activity of Novel Symmetrical and Unsymmetrical Thiadiazole Derivatives as Potential Carbonic Anhydrase Inhibitor in E. Coli. Journal of Global Pharma Technology. 2009;11(02):171-80.
(3) Nocentini A, Donald WA, Supuran CT. Human carbonic anhydrases: tissue distribution, physiological role, and druggability. Carbonic Anhydrases. Academic press; 2019. p. 151-85.
(4) Alzweiri M. Inhibitory binding of angiotensin converting enzyme inhibitors with carbonic anhydrase III. Chromatographia. 2020;83(12):1517-24.
(5) Supuran CT, Capasso C. Antibacterial carbonic anhydrase inhibitors: an update on the recent literature. Expert Opin Ther Targets. 2020;30(12):963-82.
(6) Supuran CT. Inhibition of bacterial carbonic anhydrases and zinc proteases: from orphan targets to innovative new antibiotic drugs. Curr Med Chem. 2012;19(6):831-44.
(7) Rasti B, Mazraedoost S, Panahi H, et al.New insights into the selective inhibition of the β-carbonic anhydrases of pathogenic bacteria Burkholderia pseudomallei and Francisella tularensis: a proteochemometrics study. Mol Divers 2019;23(2):263-73.
(8) Murray AB, Aggarwal M, Pinard M, et al. Patrauchan M, Supuran CT, et al. Structural Mapping of Anion Inhibitors to β‐Carbonic Anhydrase psCA3 from Pseudomonas aeruginosa. ChemMedChem. 2018;13(19):2024-9.
(9) Plosker GL, Croom KF. Sulfasalazine. Drugs. 2005;65(13):1825-49.
(10) Alzweiri M, Al‐Hiari Y. Evaluation of vanillic acid as inhibitor of carbonic anhydrase isozyme III by using a modified Hummel–Dreyer method: approach for drug discovery. Biomed Chromatogr. 2013;27(9):1157-61.
(11) Angeli A, Donald WA, Parkkila S, et al. Activation studies with amines and amino acids of the β-carbonic anhydrase from the pathogenic protozoan Leishmania donovani chagasi. Bioorganic Chemistry. 2018;78:406-10.
(12) Chiaramonte N, Bua S, Ferraroni M, et al. 2-Benzylpiperazine: A new scaffold for potent human carbonic anhydrase inhibitors. Synthesis, enzyme inhibition, enantioselectivity, computational and crystallographic studies and in vivo activity for a new class of intraocular pressure lowering agents. Eur J Med Chem. 2018;151:363-75.
(13) Harju AK, Bootorabi F, Kuuslahti M, et al. Carbonic anhydrase III: A neglected isozyme is stepping into the limelight. J Enzyme Inhib Med Chem. 2013;28(2):231-9.
(14) Mahon BP, McKenna R. Carbonic Anhydrases as Biocatalysts. Chapter 5: Carbonic Anhydrase III, pages: 91-108: Elsevier; 2015.
(15) Mitterberger MC, Kim G, Rostek U, et al. Carbonic anhydrase III regulates peroxisome proliferator-activated receptor-γ2. Exp Cell Res. 2012;318(8):877-86.
(16) Mohammad HK, Alzweiri MH, Khanfar MA, et al.6-Substituted nicotinic acid analogues, potent inhibitors of CAIII, used as therapeutic candidates in hyperlipidemia and cancer. Med Chem Res. 2017;26(7):1397-404.
(17) Alzweiri M, Al-Balas Q, Al-Hiari Y. Chromatographic evaluation and QSAR optimization for benzoic acid analogues against carbonic anhydrase III. J Enzyme Inhib Med Chem. 2015;30(3):420-9.
(18) Supuran CT, Winum JY. Carbonic anhydrase IX inhibitors in cancer therapy: an update. Future Med Chem. 2015;7(11):1407-14.
(19) Mahon BP, Pinard MA, McKenna R. Targeting carbonic anhydrase IX activity and expression. Molecules. 2015;20(2):2323-48.
(20) McDonald PC, Winum J-Y, Supuran CT, et al. Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget. 2012;3(1):84.
(21) Rasti B, Mazraedoost, S., Panahi, H., et al.New insights into the selective inhibition of the β-carbonic anhydrases of pathogenic bacteria Burkholderia pseudomallei and Francisella tularensis: a proteochemometrics study. Mol Divers 2018;23:263–73.
(22) Capasso C, Supuran CT. Bacterial, fungal and protozoan carbonic anhydrases as drug targets. Expert Opin Ther Targets. 2015;19(12):1689-704.
(23) Köhler S, Ouahrani-Bettache, S., Winum, J.V. Brucella suis carbonic anhydrases and their inhibitors: Towards alternative antibiotics? J Enzyme Inhib Med Chem. 2017;32(1):683-7.
(24) Apaydın S, Török M. Sulfonamide derivatives as multi-target agents for complex diseases. Bioorg Med Chem Lett. 2019;29(16):2042-50.
(25) Supuran CT. Carbon-versus sulphur-based zinc binding groups for carbonic anhydrase inhibitors? J Enzyme Inhib Med Chem. 2018;33(1):485-95.
(26) Zhang L, Zhang J, Jiang Q.et al. Zinc binding groups for histone deacetylase inhibitors. J Enzyme Inhib Med Chem. 2018;33(1):714-21.
(27) Kusamoto H, Shiba A, Tsunehiro M. et al. A simple method for determining the ligand affinity toward a zinc-enzyme model by using a TAMRA/TAMRA interaction. Dalton Trans. 2018;47(6):1841-8.
(28) Liu Z-Q, Ng YM, Tiong PJ, et al. Five-coordinate zinc (II) complex: synthesis, characterization, molecular structure, and antibacterial activities of bis-[(E)-2-hydroxy-N′-1-(4-methoxyphenyl) ethylidenebenzohydrazido] dimethylsulfoxidezinc (II) complex. International Journal of Inorganic Chemistry. 2017;2017.
(29) Takahashi T, Miyazawa M. Synthesis and structure–activity relationships of serotonin derivatives effect on α-glucosidase inhibition. Med Chem Res. 2012;21(8):1762-70.
(30) Stachulski AV, Santoro MG, Piacentini S, et al. Second-generation nitazoxanide derivatives: thiazolides are effective inhibitors of the influenza A virus. Future Med Chem. 2018;10(8):851-62.
(31) Stachulski AV, Pidathala C, Row EC, et al. Thiazolides as novel antiviral agents. 1. Inhibition of hepatitis B virus replication. J Med Chem. 2011;54(12):4119-32.
(32) Trujillo-Ferrara J, Vazquez I, Espinosa J, et al.Reversible and irreversible inhibitory activity of succinic and maleic acid derivatives on acetylcholinesterase. Eur J Pharm Sci. 2003;18(5):313-22.
(33) Ameduri B, Boutevin B, Malek F. Synthesis and characterization of styrenic polymers with pendant pyrazole groups. II. J Polym Sci Part A Polym Chem. 1994;32(4):729-40.
(34) Bayer T, Chakrabarti A, Lancelot J, et al. Synthesis, crystallization studies, and in vitro characterization of cinnamic acid derivatives as SmHDAC8 Inhibitors for the treatment of schistosomiasis. ChemMedChem. 2018;13(15):1517-29.
(35) Ai T, Xu Y, Qiu L, et al. Hydroxamic acids block replication of hepatitis C virus. J Med Chem. 2015;58(2):785-800.
(36) Aakeröy CB, Sinha AS, Epa KN, et al.versatile and green mechanochemical route for aldehyde–oxime conversions. ChemComm. 2012;48(92):11289-91.
(37) Shukla SN, Gaur P, Bagri SS, et al. Pd (II) complexes with ONN pincer ligand: Tailored synthesis, characterization, DFT, and catalytic activity toward the Suzuki-Miyaura reaction. J Mol Struct. 2021;1225:129071.
(38) Elshaarawy RF, Mustafa FH, Sofy AR, et al. New synthetic antifouling coatings integrated novel aminothiazole-functionalized ionic liquids motifs with enhanced antibacterial performance. Journal of Environmental Chemical Engineering. 2019;7(1):102800.
(39) Prashanthi Y, Kiranmai K. Spectroscopic characterization and biological activity of mixed ligand complexes of Ni (II) with 1, 10-phenanthroline and heterocyclic schiff bases. Bioinorganic Chemistry and Applications. 2012;2012.
(40) Shang X, Li J, Guo K, et al. Development and cytotoxicity of Schiff base derivative as a fluorescence probe for the detection of l-Arginine. J Mol Struct. 2017;1134:369-73.
(41) Petek H, Albayrak Ç, İskeleli NO, et al.Crystallographic and conformational analyses of zwitterionic form of (E)-2-methoxy-6-[(2-morpholinoethylimino) methyl] phenolate. J Chem Crystallogr. 2007;37(4):285-90.
(42) Bhanja A, Moreno-Pineda E, Herchel R, et al. Self-assembled octanuclear [Ni 5 Ln 3](Ln= Dy, Tb and Ho) complexes: synthesis, coordination induced ligand hydrolysis, structure and magnetism. Dalton Trans. 2020;49(23):7968-76.
(43) Reihsig J, Krause H-W. Über organische Katalysatoren, LXXIV. Chelatkatalyse XVII. Journal für Praktische Chemie. 1966;31(3-4):167-78.
(44) Alzweiri M, Sweidan K, Al-Helo T. Synthesis and evaluation of new 2-oxo-1, 2-dihydroquinoline-3-carboxamides as potent inhibitors against acetylcholinesterase enzyme. Med Chem Res. 2022;31(9):1448-60.
(45) Alzweiri M, Al-Helo T. Gas Chromatography with Modified pH-Sensitive Pellets in Evaluating Esterase Activity of Carbonic Anhydrase III Enzyme: Drug Discovery Approach. Chromatographia. 2021;84 (12):1113-20.
(46) Mboge MY, Chen Z, Wolff A, et al. Selective inhibition of carbonic anhydrase IX over carbonic anhydrase XII in breast cancer cells using benzene sulfonamides: Disconnect between activity and growth inhibition. PLoS One. 2018;13(11):e0207417.
(47) Summers JB, Mazdiyasni H, Holms JH, et al. Hydroxamic acid inhibitors of 5-lipoxygenase. J Med Chem. 1987;30(3):574-80.
(48) Pepeljnjak S, Zorc B, Butula I. Antimicrobial activity of some hydroxamic acids. Acta Pharmaceutica. 2005;55(4):401-8.
(49) Yekkour A, Meklat A, Bijani C, et al. A novel hydroxamic acid‐containing antibiotic produced by a Saharan soil‐living Streptomyces strain. Letters in applied microbiology. 2015;60(6):589-96.
(50) Abu Hajleh MN, Alzweiri, M., Bustanji, Y. K.et al. Biodegradable Poly (lactic-co-glycolic acid) Microparticles Controlled Delivery System: A Review. Jordan J Pharm. Sci. 2020;13(3):317-35.
(51) Bayer A, Kirby W, Sherris J, et al.Antibiotic susceptibility testing by a standardized single disc method. Am J Clin Pathol. 1966;45(4):493-6.
(52) Mahmoud IS, Altaif, K. I., Abu Sini, M. K., et al. Determination of Antimicrobial Drug Resistance among Bacterial Isolates in Two Hospitals of Baghdad Jordan J Pharm. Sci. 2020;13(1):1-9.
(53) Wayne P. Clinical and laboratory standards institute: performance standards for antimicrobial disk susceptibility tests. Approved standard M2–A9, Clinical and laboratory standards institute. 2006.
(54) Antonio-Velmonte AJG, M. Local production of low cost quality antibiotic susceptibility disks for the Philippines. Philos J Microb Infect Dis. 1988;17 66-75.
(55) National Committee for Clinical Laboratory Standards Performance standards for antimicrobial susceptibility testing: eleventh informational supplement, National Committee for Clinical Laboratory Standard. PA, USA: Wayne; 2003.
