Abstract
Synthesis, characterization and biological studies of Schiff base-derived sulfonamides and their Co (II), Cu (II), Ni (II) and Zn (II) complexes have been reported and screened for in-vitro antibacterial activity against six Gram-negative; E. coli, K. pneumoniae, P. aeruginosa, P. mirabilis, S. typhi and S. dysenteriae and four Gram-positive; B. cereus, C. diphtheriae, S. aureus and S. pyogenes bacterial strains and for in-vitro antifungal activity against T. longifusus, C. albicans, A. flavus, M. canis, F. solani, and C. glaberata. All compounds showed moderate to significant antibacterial activity, however, the zinc (II) complexes were found to be more active. Some of the compounds also showed significant antifungal activity against various fungal strains. Only compounds (6) and (10) displayed potent cytotoxic activity with LD50 = 4.644 × 10− 4 and 4.106 × 10− 4 moles/mL respectively, against Artemia salina. The X-ray structure of 4-[(2-hydroxybenzylidene)amino]benzenesulfonamide is also reported.
Introduction
A number of sulfonamides and their derived compounds have been reported for their antibacterial Citation1-3, antitumor [Citation4], anti-carbonic anhydrase Citation5-10, diuretic [Citation11], hypoglycaemic [Citation12], antithyroid [Citation13] and protease inhibitory activity [Citation14,Citation15]. Due to their significant pharmacology applications and widespread use in medicine, these compounds have gained attention in bio-inorganic and metal-based drug chemistry. Metal-based pharmacological properties of sulfonamides were surprisingly observed when they were administered as metal chelates initially coming to light when the silver (I) complex of sulfanilamide was prepared [Citation16] and tested for biological activity. Then other metal complexes of substituted sulfanilamides were subsequently synthesized and investigated for enhanced biological activities in detail [Citation17].
The growing interest in metal-sulfonamides drug chemistry also attracted the attention of the author and forced to commence a program Citation18-28 in meticulously designing and exploring this potential area of research. With this idea, a series of such metal-based sulfonamides and sulphonamide-derived compounds having potential therapeutic properties have been previasly reported. In this context, some now sulfonamides and their metal-based compounds have been reported with their potential bactericidal and fungicidal agents against various bacterial and fungal resistant species, whose increasing incidence is emerging globally as a major problem in drug therapy.
Materials and methods
The solvents used were of analytical grade; all metal (II) were used as chloride salts. IR, NMR, UV-Visible spectra, C, H and N analyses, Conductance and Magnetic measurements were carried out on solid compounds using the respective instruments. In-vitro antibacterial, antifungal and cytotoxic properties were determined at HEJ Research Institute of Chemistry, International Center for Chemical Sciences, University of Karachi, Pakistan.
Preparation of Schiff's bases (L1–L5 )
To an ethanolic (25 mL) solution of the respective sulfonamide (0.007 moles), an ethanol solution of the relevant aldehyde (0.007 moles) was added with stirring. The solution was refluxed for 3 h. After cooling to room temperature, the obtained solution was filtered and left overnight at room temperature, which led to the formation of a crystalline product.
This crystalline product was filtered and recrystallized from hot ethanol to give the orange-red desired product. Purification was checked by TLC, which indicated a single spot. All other Schiff's bases (L 1–L 5) were prepared following the same method.
Preparation of metal complexes (1)–(12)
To a hot ethanol (25 mL) solution of the respective sulfonamide (0.02 moles), an ethanol solution of the corresponding metal (II) salt (0.01 moles) was added. The reactant mixture was refluxed for 2 h and the reaction was monitored through TLC. After completion of the reaction, precipitates appeared on cooling in an ice-bath, which were filtered and recrystallized from aqueous-ethanol (1: 3) affording TLC-pure products in good yield.
Only one compound, 4-[(2-hydroxybenzylidene) amino] benzenesulfonamide produced sufficiently good crystals for X-ray structural determination. All other compounds were either amorphous powders or tiny crystals which were unsuitable for X-ray studies.
4-[(4-Hydroxy-3-methoxybenzylidene)amino]benzenesulfonamide (L1)
Yield 77%; m.p. 199 oC; IR (KBr, cm− 1): 3455 (NH2), 3325 (OH), 1590 (HC = N), 1315, 1110 (S = O), 960, 845; 1H NMR (DMSO-d6, δ, ppm): 2.54 (s, 3H, methoxy), 7.35–7.54 (m, 4H, benzene), 7.68–7.77 (m, 3H, benzylidene), 7.85 (br s, 2H, SO2NH2), 7.96 (s, 1H, CH = N), 10.85 (s, 1H, OH); Anal. Calcd. for C14H14N2O4S (306.33): C, 54.89; H, 4.61; N, 9.14. Found: C, 55.12; H, 4.95; N, 9.01%. 1H NMR of Zn (II) complex (DMSO-d6, δ, ppm): 3.11 (s, 3H, methoxy), 7.73–7.85 (m, 4H, benzene), 7.91–7.98 (m, 3H, benzylidene), 8.37 (br s, 2H, SO2NH2), 8.64 (s, 1H, CH = N), 10.97 (s, 1H, OH).
4-{2-[(4-Hydroxy-3-methoxybenzylidene)amino]ethyl}benzenesulfonamide (L2 )
Yield 73%; m.p. 157 oC; IR (KBr, cm− 1): 3455 (NH2), 3325 (OH), 1590 (HC = N), 1315, 1110 (S = O), 960, 845; 1H NMR (DMSO-d6, δ, ppm): 2.54 (s, 3H, methoxy), 5.46–5.71(t, 2H, CH2), 6.42 (t, 2H, NCH2), 7.31–7.53 (m, 4H, benzene), 7.68–7.77 (m, 3H, benzylidene), 7.85 (br s, 2H, SO2NH2), 7.96 (s, 1H, CH = N), 10.85 (s, 1H, OH); Anal. Calcd. for C16H18N2O4S (334.39): C, 57.47; H, 5.43; N, 8.38. Found: C, 57.12; H, 5.65; N, 8.64%. 1H NMR of Zn (II) complex (DMSO-d6, δ, ppm): 3.13 (s, 3H, methoxy), 6.18–6.27 (t, 2H, CH2), 6.84 (t, 2H, NCH2), 7.74–7.81 (m, 4H, benzene), 7.92–7.99 (m, 3H, benzylidene), 8.35 (br s, 2H, SO2NH2), 8.64 (s, 1H, CH = N), 10.98 (s, 1H, OH).
4-[(2-Hydroxybenzylidene)amino]benzenesulfonamide (L3 )
Yield 76%; m.p. 208°C; IR (KBr, cm− 1): 3455 (NH2), 3325 (OH), 1590 (HC = N), 1315, 1110 (S = O), 1385 (C–O), 960, 845; 1H NMR (DMSO-d6, δ, ppm): 7.35–7.54 (m, 4H, benzene), 7.68–7.77 (m, 4H, benzylidene), 7.85 (br s, 2H, SO2NH2), 7.96 (s, 1H, CH = N), 10.85 (s, 1H, OH); Anal. Calcd. for C13H12N2O3S (276.31): C, 56.51; H, 4.38; N, 10.14. Found: C, 56.82; H, 4.75; N, 10.37%. 1H NMR of Zn (II) complex (DMSO-d6, δ, ppm): 7.74–7.82 (m, 4H, benzene), 7.92–7.98 (m, 4H, benzylidene), 8.37 (br s, 2H, SO2NH2), 8.65 (s, 1H, CH = N).
4-{[(2-Hydroxybenzylidene)amino]methyl}benzenesulfonamide (L4 )
Yield 66%; m.p. 209 oC; IR (KBr, cm− 1): 3455 (NH2), 3325 (OH), 1590 (HC = N), 1315, 1110 (S = O), 1385 (C–O), 960, 845; 1H NMR (DMSO-d6, δ, ppm): 6.42 (t, 2H, NCH2), 7.31–7.53 (m, 4H, benzene), 7.68–7.77 (m, 4H, benzylidene), 7.85 (br s, 2H, SO2NH2), 7.96 (s, 1H, CH = N), 10.85 (s, 1H, OH); Anal. Calcd. for C14H14N2O3S (290.33): C, 57.92; H, 4.86; N, 9.65. Found: C, 58.22; H, 4.58; N, 9.82%. 1H NMR of Zn (II) complex (DMSO-d6, δ, ppm): 7.38 (t, 2H, NCH2), 7.74–7.83 (m, 4H, benzene), 7.92–7.97 (m, 4H, benzylidene), 8.36 (br s, 2H, SO2NH2), 8.65 (s, 1H, CH = N).
4-{2-[(2-Hydroxybenzylidene)amino]ethyl}benzenesulfonamide (L5 )
Yield 81%; m.p. 137°C; IR (KBr, cm− 1): 3455 (NH2), 3325 (OH), 1590 (HC = N), 1315, 1110 (S = O), 1385 (C–O), 960, 845; 1H NMR (DMSO-d6, δ, ppm): 5.46–5.71 (t, 2H, CH2), 6.42 (t, 2H, NCH2), 7.31–7.53 (m, 4H, benzene), 7.68–7.77 (m, 3H, benzylidene), 7.85 (br s, 2H, SO2NH2), 7.96 (s, 1H, CH = N), 10.85 (s, 1H, OH); Anal. Calcd. for C15H16N2O3S (304.36): C, 59.19; H, 5.30; N, 9.20. Found: C, 59.38; H, 5.42; N, 9.48%. 1H NMR of Zn (II) complex (DMSO-d6, δ, ppm): 6.17–6.27 (t, 2H, CH2), 6.85 (t, 2H, NCH2), 7.74–7.81 (m, 4H, benzene), 7.92–7.98 (m, 3H, benzylidene), 8.35 (br s, 2H, SO2NH2), 8.64 (s, 1H, CH = N).
X-ray crystallography
X-ray structure and atom labeling scheme of the novel 4-[(2-hydroxybenzene)- amino]benzenesulfonamide (L 3) is presented in , and crystal and refinement data of a yellow needle crystal of C13H12N2O3S having approximate dimensions of 0.20 × 0.20 × 0.20 mm are presented in Tables VI and VII.
Figure 1 ORTEP diagram of a single molecule found in the asymmetric unit.
Antibacterial bioassay (in-vitro)
All the synthesized compounds (L 1)–(L 5) and metal (II) complexes (1)–(12) were screened in-vitro for their antibacterial activity against six Gram-negative (E. coli, K. pneumonia, P. aeruginosa, P. mirabilis, S. typhi and S. dysenteriae) and four Gram-positive (B. cereus, C. diphtheriae, S. aureus and S. pyogenes) bacterial strains by the agar-well diffusion method [Citation29,Citation30]. The wells (6 mm in diameter) were dug in the media with the help of a sterile metallic borer with centers at least 24 mm apart. Two to eight h old bacterial inocula containing approximately 104–106 colony-forming units (CFU/mL) were spread on the surface of the nutrient agar with the help of a sterile cotton swab. The recommended concentration of the test sample (1 mg/mL in DMSO) was introduced in the respective wells. Other wells supplemented with DMSO and reference antibacterial drug, imipenum, served as negative and positive controls, respectively.
The plates were incubated immediately at 37°C for 24 h. Activity was determined by measuring the diameter of zones showing complete inhibition (mm). In order to clarify any participating role of DMSO in the biological screening, separate studies were carried out with the solutions alone of DMSO and they showed no activity against any bacterial strains.
Antifungal Activity (in-vitro)
Antifungal activities of all compounds were studied against six fungal cultures. Sabouraud dextrose agar (oxoid, Hampshire, England) was seeded with 105 (cfu) mL− 1 fungal spore suspensions and transferred to petri plates. Discs soaked in 20 ml (200 μg/mL in DMSO) of all compounds were placed at different positions on the agar surface. The plates were incubated at 32°C for seven days. The results were recorded [Citation31] as % inhibition and compared with standard drugs miconazole and amphotericin B.
Minimum inhibitory concentration (MIC)
Compounds showing high antibacterial activity (over 80%) were selected for minimum inhibitory concentration (MIC) studies. The minimum inhibitory concentration was determined using the disc diffusion technique by preparing discs containing 10, 25, 50 and 100 μg/mL of the compounds and applying the protocol [Citation32].
Cytotoxicity (in-vitro)
Brine shrimp (Artemia salina leach) eggs were hatched in a shallow rectangular plastic dish (22 × 32 cm), filled with artificial seawater, which was prepared with commercial salt mixture and double distilled water. An unequal partition was made in the plastic dish with the help of a perforated device. Approximately 50 mg of eggs were sprinkled into the large compartment, which was darkened while the minor compartment was opened to ordinary light. After two days nauplii were collected by a pipette from the lighted side. A sample of the test compound was prepared by dissolving 20 mg of each compound in 2 mL of DMF. From this stock solutions 500, 50 and 5 μg/mL were transferred to 9 vials (three for each dilution were used for each test sample and LD50 is the mean of three values) and one vial was kept as control having 2 mL of DMF only. The solvent was allowed to evaporate overnight. After two days, when the shrimp larvae were ready, 1 mL of sea water and 10 shrimps were added to each vial (30 shrimps/dilution) and the volume was adjusted with sea water to 5 mL per vial. After 24 h the number of survivors was counted. Data were analyzed by a Finney computer program to determine the LD50 values [Citation33,Citation34].
Result and discussion
Chemistry, composition and characterization of the ligands
The sulfonamide derived ligands (L 1)–(L 5) were prepared as shown in Scheme . All ligands were only soluble in hot ethanol, DMF and DMSO. The composition of the ligands is consistent with their microanalytical data.
Scheme 1 Preparation of Ligands.
Chemistry, composition and characterization of the metal (II) complexes
The metal (II) complexes (1)–(12) of the ligands (L 3)–(L 5) were prepared according to the following equations:
The ligands (L 1) and (L 2) however, could not form metal complexes because of the presence of the (OH) group at a position which is not able to donate its lone pair towards the metal atom to form a coordination compound. Some physical properties such as melting points and % yields are given in . The proposed structure of the compexes is shown in .
Table I. Physical, Spectral and Analytical Data of the Metal (II) Complexes.
Figure 2 Proposed structure of the metal complex.
Conductance and magnetic susceptibility measurements
The molar conductance values (in DMF) for complexes (1)–(12) fall within the range 86–92 Ω− 1 cm2 mol− 1, showing their non-electrolytic nature[Citation35].
The room temperature magnetic moment values of the complexes are given in . The observed magnetic moment (4.76–4.88 B.M.) is consistent with half-spin octahedral cobalt (II) complexes. The magnetic moment values (1.67–1.81 B.M.) measured for the copper (II) complexes lie in the range expected for a d9- system, which contain one unpaired electron with octahedral geometry [Citation36]. The measured values (3.25–3.30 B.M.) for the nickel (II) complexes suggest [Citation37] octahedral geometry for these complexes. The zinc (II) complexes were found to be diamagnetic as expected.
IR spectra
The important IR spectral bands of the ligands and their metal complexes are given in the Experimental and in . All ligands contain four potential donor sites: the benzylidene hydroxyl oxygen, the azomethine nitrogen, the sulfonamide oxygen and the sulfonamide nitrogen. In the IR spectra of the ligands a broad band observed at 3325 cm− 1 and a sharp band at 1590 cm− 1 are assigned [Citation38] to the ν(OH) and (C = N) modes respectively. Evidence of the nitrogen bonding of the azomethine (C = N) group to the central metal atom stems from the shift of the ν(C = N) frequency to lower frequency by 15–25 cm− 1 (1565–1575 cm− 1) in all of its metal complexes. This is further supported by the appearance of the new bands at 425–440 cm− 1 due to the ν(M–N) band [Citation39].
The coordination through the hydroxyl oxygen is revealed only in ligands (L 3)–(L 5) by disappearance of the mode at 3325 cm− 1 and appearance of a new band at 1385 cm− 1 due to the C–O mode. This is further confirmed by the appearance of the new band at 510–545 cm− 1 due to ν(M–O) in the metal complexes of ligands (L 3)–(L 5). The disappearance of a band assigned to the hydroxyl group in ligands (L 1) and (L 2) was not observed indicating that the hydroxyl group of these ligands does not participate in coordination. This is due to the fact that the hydroxyl group in ligands (L 1) and (L 2) can not involve in participation with the metal atom whereas in the case of ligands (L 3)–(L 5), the hydroxyl group readily involves itself in the coordination process. The bands in the ligand due to νasymm(SO2) and νsymm(SO2) appear at 1315 and 1140 cm− 1, respectively [Citation40]. These bands remain almost unchanged in the complexes, indicating that this group is not participating in coordination. This is supported by the unchanged ν(S–N) and ν(C–S) modes appearing at 960 and 845 cm− 1, respectively [Citation41,Citation42], in the ligands after complexation.
1H NMR spectra
1H NMR spectra of the free ligands and their diamagnetic zinc (II) complexes were recorded in DMSO-d6. The 1H NMR spectral data along with the possible assignments is recorded in the Experimental. All the protons due to heteroaromatic/aromatic groups were found to be in their expected region [Citation43]. The conclusions drawn from these studies lend further support to the mode of bonding discussed in their IR spectra. The coordination of the azomethine nitrogen is inferred by the downfield shift of the –CH = N- proton signal from 7.96 ppm in the ligand to 8.52–8.68 ppm in the complexes. The hydroxyl proton at 10.85 ppm in the spectra of Zn (II) complexes of ligands (L 3)–(L 5) disappeared indicating deprotonation and coordination of the oxygen with the metal ion whereas this hydroxyl proton in the spectra of Zn (II) complexes of ligands (L 1) and (L 2) did not disappear suggesting their non-coordination. All other protons underwent a downfield shift by 0.3–0.6 ppm due to the increased conjugation [Citation44] and coordination with the metal atom.
Electronic spectra
The Co(II) complexes exhibited well-resolved, low-energy bands at 7,285–7,470 cm− 1, 17,360–17,510 cm− 1 and a strong high-energy band at 20,455–20,670 cm− 1 () which are assigned [Citation36] to the transitions 4T1g(F) → 4T2g(F), 4T1g(F) → 4A2g(F) and 4T1g(F) → 4T2g(P) in an octahedral geometry [Citation37]. A high intensity band at 29,290–29,385 cm− 1 was assigned to the metal to ligand charge transfer. The magnetic susceptibility measurements for the solid Co (II) complexes are also indicative of three unpaired electrons per Co (II) ion suggesting [Citation45] consistency with their octahedral environment.
The electronic spectra of the Cu (II) complexes () showed two low-energy weak bands at 14,725–15,155 cm− 1 and 19,140–19,315 cm− 1 and a strong high-energy band at 30,335–30,380 cm− 1 which may be assigned to 2B1 g → 2A1 g and 2B1 g → 2Eg transitions, respectively [Citation46]. The strong high-energy band, in turn, is assigned to a metal → ligand charge transfer. Also, the magnetic moment values for the copper (II) are indicative of anti-ferromagnetic spin-spin interaction through molecular association indicative of their octahedral geometry [Citation37].
The electronic spectra of the Ni (II) complexes showed d-d bands in the region 10,355–10,485, 15,610–15,865 and 26,325–26,675 cm− 1. These are assigned [Citation47] to the transitions 3A2g(F) → 3T2g(F), 3A2g(F) → 3T1g(F) and 3A2g(F) → 3T2g(P), respectively, consistent with their well-defined octahedral configuration. The band at 29,850–30,225 cm− 1 was assigned to metal → ligand charge transfer. The magnetic measurements showed two unpaired electrons per Ni (II) ion suggesting [Citation46] also an octahedral geometry for the Ni (II) complexes. The electronic spectra of the Zn (II) complexes exhibited only a high-intensity band at 28,540–29,140 cm− 1 and are assigned [Citation47] to a ligand-metal charge transfer.
Biological activity
Antibacterial bioassay (in-vitro)
All compounds were tested against six Gram-negative (E. coli, K. pneumoniae, P. mirabilis, P. aeruginosa, S. typhi and S. dysenteriae) and four Gram-positive (B. cereus, C. diphtheriae, S. aureus and S. pyogenes) bacterial strains () according to literature protocol [Citation29,Citation30].
Table II. Results of Antibacterial Bioassay (concentration used 1 mg/mL of DMSO).
The results were compared with those of the standard drug imipenum (). All ligands showed moderate to significant activity against all Gram-negative and Gram-positive bacterial strains except the activity of all compounds against strain (b) where moderate to significant activity was not observed. Compounds (2)–(12) exhibited overall a significant activity (above 80%) against (a). The Zinc (II) complexes of all the ligands were observed to be the most active against all species. It was interesting to note that methyl and ethyl carbon chains in the ligands and their respective metal chelates had an impact on the bactericidal activity. As the carbon chain increased from methylene to ethylene in compounds (5)–(12) the bactericidal activity was increased as compared to the other compounds of the series (9)–(11) where this chain was absent.
Figure 3 Comparison of Antibacterial Activity.
Antifungal bioassay (in-vitro)
The antifungal screening of all compounds was carried out against T. longifusus, C. albican, A. flavus, M. canis, F. solani and C. glaberate fungal strains according to the literature protocol [Citation31]. The inhibition results were compared with those for the standard drugs miconazole and amphotericin B and individual synthesized compounds (; ).
Figure 4 Comparison of Antifungal Activity.
Table III. Results of Antifungal Bioassay (concentration used 200 μg/mL).
Minimum inhibitory concentration (MIC) for antibacterial activity
The preliminary antibacterial screening showed that compounds (4),(6),(7),(8),(9),(10),(11) and (12) were the most active ones (above 80%). These compounds were therefore, selected for minimum inhibitory concentration (MIC) studies ().
Table IV. Results of Minimum Inhibitory Concentration (MIC) of Selected Compounds (4), (6), (7), (8), (9), (10), (11), and (12) against Selected Bacteria.
Cytotoxic bioassay (in-vitro)
All the synthesized compounds were screened for their cytotoxicity (brine shrimp bioassay) using the protocol of Meyer et al. [Citation33]. From the data recorded in , it is evident that only two compounds, (6) and (10) displayed potent cytotoxic activity against Artemia salina, while the other compounds were almost inactive in this assay. Compound (6) showed activity (LD50 = 4.644 × 10− 4 moles/mL) in the present series of compounds whereas the other active compound (10) of the series demonstrated activity, LD50 = 4.106 × 10− 4 moles/mL. It was interesting to note that only copper complexes showed potent cytotoxicity whereas the other metal complexes did not. This activity relationship may help to serve as a basis for future direction towards the development of certain cytotoxic agents for clinical applications.
Table V. Brine Shrimp Bioassay Data of the Ligands (L1)–(L5) and their Metal (II) Complexes (1)–(12).
The enhancement of antibacterial/antifungal activity in ligands (L 3)–(L 5) upon chelation may be rationalized on the basis of their structures. It has been suggested that chelation/coordination reduces the polarity of the metal ion Citation48-53 because of the partial sharing of its positive charge with the donor groups and possibly the π-electron delocalisation within the whole chelate ring system thus formed during coordination. This process of chelation thus increases the lipophilic nature of the central metal atom, which in turn favours Citation54-57 its permeation through the lipoid layer of the membrane. It has also been observed that some moieties such as azomethine linkage or heteroaromatic system introduced into such compounds exhibit Citation57-61 extensive biological activities that may be responsible for increasing the hydrophobic character and liposolubility of the molecules in crossing cell membrane of the micro-organism and hence enhance the biological utilization ratio and activity of the compounds.
Supplementary material
Crystallographic data for the structural analysis has been deposited with the Cambridge Crystallographic Data Centre, CCDC No. 606492 for compound C13H12 N2O3S1. Copies of this information may be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. (fax: +44-1223-336-033, [email protected] or www:http://www.ccdc.cam.ac.uk)
Table VI. Selected Bond lengths [A] and Bond angles [deg] for (L3).
Table VII. Crystal data for 4-[(2-hydroxybenzene)- amino]benzenesulfonamide (L3).
Acknowledgements
The author (ZHC) wishes to thank the Higher Education Commission (HEC), Government of Pakistan for the financial assistance to carry out this research Project No. 20–16/Acad(R&D)/2nd Phase/03/211. Dr. David Vicic of University of Arkansas, Fayetteville, U.S.A. is acknowledged for his help in the X-ray structure determination. Finally, HEJ Research Institute of Chemistry, University of Karachi is also acknowledged for help in undertaking the NMR and biological assays.
References
- Domagk G. Chemotherapy of bacterial infections. Deut Med Wochensch 1935; 61: 250
- Mandell GL, Petri WA. Pharmacological basis of therapeutics9th ed, JG Hardman, LE Limbird, PB Molinoff, RW Ruddon, AG Gilman. McGraw-Hill, New York 1966; 1057–1072
- Maren TH. Relations between structure and biological activity of sulfonamides. Annu Rev Pharmacol Toxicol 1976; 16: 309–327
- Owa T, Nagasu T. Novel sulfonamide derivatives for the treatment of cancer. Exp Opin Ther Pat 2000; 10: 1725–1740
- Supuran CT, Scozzafava A. Carbonic anhydrase and their therapeutic potentials. Exp Opin Ther Pat 2000; 10: 575–600
- Supuran CT, Scozzafava A. Carbonic anhydrase inhibitors. Curr Med Chem-Imm, Endoc Metab Agents 2001; 1: 61–97
- Popescu A, Simion A, Scozzafava A, Briganti F, Supuran CT. Carbonic anhydrase inhibitors. Schiff bases of some aromatic sulfonamides and their metal complexes: Towards more selective inhibitors of carbonic anhydrase isozyme IV. J Enz Inhib 1999; 14: 407–423
- Supuran CT, Scozzafava A. Novel aromatic/heterocyclic sulfonamides and their metal complexes as inhibitors of carbonic anhydrase isozymes I, II and IV. J Enz Inhib 1997; 12: 37–51
- Supuran CT, Scozzafava A, Mincione F, Menabuoni L, Briganti F, Mincione G, Jitianu M. Carbonic anhydrase inhibitors. Part 60(#). The topical intraocular pressure-lowering properties of metal complexes of a heterocyclic sulfonamide: influence of the metal ion upon biological activity. Eur J Med Chem 1999; 34: 585–595
- Supuran CT, Scozzafava A, Menabuoni L, Mincione F, Briganti F, Mincione G. Carbonic anhydrase inhibitors. Part 71. Synthesis and ocular pharmacology of a new class of water-soluble, topically effective intraocular pressure lowering sulfonamides incorporating picolinoyl moieties. Eur J Pharm Sci 1999; 8: 317–328
- Boyd AE. Sulfonylurea receptors, ion channels, and fruit flies. Diabetes 1988; 37: 847–850
- Thornber CW. Isosterism and molecular modification in drug design. Chem Soc Rev 1979; 8: 563–580
- Ogden RC, Flexner CW. Protease inhibitors in AIDS therapy. Marcel Dekker, New York, USA 2001
- Supuran CT, Scozzafava A, Mastrolorenzo A. Bacterial proteases: Current theraputic use and future prospects for the development of new antibiotics. Exp Opin Therap Pat 2000; 111: 221–259
- Scozzafava A, Supuran CT. Carbonic anhydrase and matrix metalloproteinase inhibitors: Sulfonylated amino acid hydroxamates with MMP inhibitory properties act as efficient inhibitors of CA isozymes I, II, and IV, and N-hydroxysulfonamides inhibit both these zinc enzymes. J Med Chem 2000; 43: 3677–3687
- Braun CE, Towle JL. N1-Silver derivatives of sulfonamide and some related compounds. J Am Chem Soc 1941; 63: 3523
- Bult A. Metal ions in biological systems, H Sigel, A Sigel, New York 1983; 261–268, and references cited therein; M. Dekker;
- Chohan ZH. Synthesis and biological properties of Cu(II) complexes with 1,10-disubstituted ferrocenes. Synth React Inorg Met-Org Chem 2004; 34: 833
- Chohan ZH, Supuran CT, Scozzafava A. Metalloantibiotics: Synthesis and antibacterial activity of cobalt(II), copper(II), nickel(II) and zinc(II) complexes of kefzol. J Enz Inhib Med Chem 2004; 19: 79
- Chohan ZH, Scozzafava A, Supuran CT. Synthesis of biologically active Co(II), Cu(II), Ni(II) and Zn(II) complexes of symmetrically 1,10-disubstituted ferrocene-derived compounds. Synth React Inorg Met-Org Chem 2003; 33: 241
- Hassan MU, Scozzafava A, Chohan ZH, Supuran CT. Carbonic anhydrase inhibitors: Metal complexes of a sulfonamide derived schiff base and their interaction with isozymes I, II and IV. J Enz Inhib Med Chem 2001; 16: 499
- Hassan MU, Chohan ZH, Andrea S, Supuran CT. Carbonic anhydrase inhibitors: Schiff's bases of aromatic and heterocyclic sulfonamides and their metal complexes. J Enz Inhib Med Chem 2004; 19: 263
- Chohan ZH, Shaikh AU, Naseer MM, Supuran CT. In-vitro antibacterial, antifungal and cytotoxic properties of metal-based furanyl derived sulfonamides. J Enzy Inhib Med Chem 2006; 21: 771
- Chohan ZH. Antibacterial copper(II) complexes of 1,1-symmetric ferrocene-derived schiff-base ligands: Studies of the effect of anions on their antibacterial properties. Appl Organomet Chem 2002; 16: 17
- Hassan MU, Chohan ZH, Supuran CT. Antibacterial Zn(II) compounds of schiff bases derived from some benzothiazoles. Main Group Metal Chemistry 2002; 25: 291
- Chohan ZH, Scozzafava A, Supuran CT. Zinc complexes of benzothiazole-derived schiff-bases with antibacterial activity. J Enz Inhib Med Chem 2003; 18: 259
- Chohan ZH, Scozzafava A, Supuran CT. Unsymmetrically 1,10-disubstituted ferrocenes: Synthesis of Co(II), Cu(II), Ni(II) and Zn(II) chelates of ferrocenyl-1-thiadiazolo-10-tetrazole,-1-thiadiazolo-10-triazole and -1-tetrazolo-10-triazole with antimicrobial properties. J Enz Inhib Med Chem 2002; 17: 261
- Puccetti L, Fosolis G, Daniela V, Chohan ZH, Andrea S, Supuran CT. Carbonic anhydrase inhibitors. Inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, IX, and XII with schiff's bases incorporating chromone and aromatic sulfonamide moieties, and their zinc complexes in-vitro antibacterial, antifungal and cytotoxic properties of sulfonamide-derived Schiff's bases and their metal complexes. Bioorg Med Chem Lett 2005; 15: 3096
- Atta-ur-Rahman, Choudhary MI, Thomsen WJ. Bioassay techniques for drug development. Harwood Academic Publishers, The Netherlands 2001; 16
- Chohan ZH. Synthesis of cobalt(II) and nickel(II) complexes of ceclor (cefaclor) and preliminary experiments on their antibacterial character. Chem Pharm Bull 1991; 39: 1578
- Atta-ur-Rahman, Choudhary MI, Thomsen WJ. Bioassay techniques for drug development. Harwood Academic Publishers, The Netherlands 2001; 22
- McLaughlin JL, Chang C-J, Smith DL. Studies in natural products chemistry, “Bentch-Top” bioassays for the discovery of bioactive natural products: An update, structure and chemistry (part-B), Atta-ur-Rahman. Elsevier Science Publishers B.V, The Netherlands 1991; Vol. 9: 383
- Meyer BN, Ferrigni NR, Putnam JE, Jacobsen LB, Nichols DE, McLaughlin JL. Brine shrimp: A convenient general bioassay for active plant constituents. Planta Medica 1982; 45: 31
- Finney DJ. Probit analysis3rd ed. Cambridge University Press, Cambridge 1971
- Geary WJ. Use of conductivity measurements in organic solvents for the characterization of coordination compounds. Coord Chem Rev 1971; 7: 81
- Lever ABP, Lewis J, Nyholm RS. Square-planar bisethylenediamine-metal complexes. J Chem Soc 1963; 59: 2552
- Carlin RL. Transition metal chemistry2nd ed. Marcel Decker, New York 1965
- Bellamy LJ. The infrared spectra of complex molecules. John Wiley, New York 1971
- Ferrero JR. Low-frequency vibrations of inorganic and coordination compounds. John Wiley, New York 1971
- Burns GR. Metal complexes of thiocarbohydrazide. Inorg Chem 1968; 7: 277
- Maurya RC, Patel P. Synthesis, magnetic and special studies of some novel metal complexes of Cu (II), Ni (II), Co (II), Zn (II), Nd (III), Th (IV), and UO2 (VI) with schiff bases derived from sulfa drugs, viz, sulfanilamide/sulfamerazine and o-vanillin. Spectr Lett 1999; 32: 213
- Nakamoto K. Infrared spectra of inorganic and coordination compounds2nd ed. Wiley Interscience, New York 1970
- Simmons WW. The Sadtler handbook of protonNMRspectra. Sadtler Research Laboratories, Inc. 1978
- Pasto DJ. Organic structure determination. Prentice Hall International, London 1969
- Estes WE, Gavel DP, Hatfield WB, Hodgson DJ. Magnetic and structural characterization of dibromo- and dichlorobis (thiazole) copper (II). Inorg Chem 1978; 17: 1415
- Balhausen CJ. An introduction to ligand field. McGraw Hill, New York 1962
- Lever ABP. Inorganic electronic spectroscopy. Elsevier, Amsterdam 1984
- Chohan ZH, Kausar S. Biologically active complexes of nickel(II), copper(II) and zinc(II) with Schiff-base ligand derived from the reaction of 2-aminopyridine and pyrrol-2-carboxaldehyde–their synthesis and characterisation. Chem Pharm Bull 1992; 40: 2555
- Chohan ZH. Antibacterial and antifungal ferrocene incorporated dithiothione and dithioketone compounds. Appl Organomet Chem 2006; 20: 112
- Chohan ZH, Kausar S. Synthesis, structural and biological studies of nickel(II), copper(II) and zinc(II) chelates with tridentate Schiff bases having NNO and NNS donor systems. Chem Pharm Bull 1993; 41: 951
- Chohan ZH, Shaikh AU, Naseer MM. Metal-based isatin-bearing sulfonamides: Their synthesis. Characterization and biological properties. Appl Organomet Chem 2006; 20: 85
- Chohan ZH, Shaikh AU, Supuran CT. In-vitro antibacterial, antifungal and cytotoxic activity of cobalt (II), copper (II), nickel (II) and zinc (II) complexes with furanylmethyl- and thienylmethyl-dithiolenes: [1, 3-dithiole- 2-one and 1,3-dithiole-2-thione. J Enz Inhib Med Chem 2006; 21: 733
- Chohan ZH, Supuran CT. Metalloantibiotics: Synthesis, characterization and in-vitro antibacterial studies on cobalt (II), copper (II), nickel (II) and zinc (II) complexes with cloxacillin. J Enz Inhib Med Chem 2006; 22: 69
- Chohan ZH, Farooq MA. Mixed ligand biologically active complexes of cobalt(II), copper(II), nickel(II) and zinc(II) with triazine derived NO and NS donor systems. J Chem Soc Pak 1995; 17: 14
- Chohan ZH, Sherazi SKA. Synthesis and spectroscopic studies of biologically active Co(II), Cu(II) and Ni(II) complexes of hydrazine derived Schiff-base ligands. J Chem Soc Pak 1997; 19: 196
- Rehman SU, Chohan ZH, Naz F, Supuran CT. In vitro antibacterial, antifungal and cytotoxic activities of some coumarines and their metal complexes. J Enz Inhib Med Chem 2005; 20: 333
- Chohan ZH, Supuran CT. Organometallic compounds with biologically active molecules: In-vitro antibacterial and antifungal activity of some 1,10-(dicarbohydrazono)ferrocenes and their Co (II), Cu (II), Ni (II) and Zn (II) complexes. Appl Organomet Chem 2005; 19: 1207
- Chohan ZH, Supuran CT. In-vitro antibacterial and cytotoxic activity of cobalt (II), copper (II), nickel (II) and zinc (II) complexes of the antibiotic drug cephalothin (keflin). J Enz Inhib Med Chem 2005; 20: 463
- Chohan ZH, Supuran CT, Scozzafava A. Metal binding and antibacterial activity of ciprofloxacin complexes. J Enz Inhib Med Chem 2005; 20: 303
- Chohan ZH, Praveen M. Ghaffar A.Synthesis, characterisation and biological role of anions (nitrate, sulphate, oxalate and acetate) in Co(II), Cu(II) and Ni(II) metal chelates of some Schiff-base derived amino acids. Synth React Inorg Met-Org Chem 1998; 28: 1673
- Chohan ZH. Antibacterial and antifungal ferrocene incorporated dithiothione and dithioketone compounds. Appl Organomet Chem 2006; 20: 112–116