Synthesis, characterization, crystal structures and biological screening of 4-amino quinazoline sulfonamide derivatives

This is a self-archived version of an original article. This version may differ from the original in pagination and typographic details. Author(s): Title: Year: Version: Copyright: Rights: Rights url: Please cite the original version: CC BY-NC-ND 4.0 https://creativecommons.org/licenses/by-nc-nd/4.0/ Synthesis, characterization, crystal structures and biological screening of 4-amino quinazoline sulfonamide derivatives ©2019 Published by Elsevier B.V. Accepted version (Final draft) Kumar, A. Sunil; Kudva, Jyothi; Lahtinen, Manu; Peuronen, Anssi; Sadashiva, Rajitha; Naral, Damodara Kumar, A. S., Kudva, J., Lahtinen, M., Peuronen, A., Sadashiva, R., & Naral, D. (2019). Synthesis, characterization, crystal structures and biological screening of 4-amino quinazoline sulfonamide derivatives. Journal of Molecular Structure, 1190, 29-36. https://doi.org/10.1016/j.molstruc.2019.04.050 2019 Accepted Manuscript Synthesis, characterization, crystal structures and biological screening of 4-amino quinazoline sulfonamide derivatives A. Sunil Kumar, Jyothi Kudva, Manu Lahtinern, Anssi Peuronen, Rajitha Sadashiva, Damodara Naral PII: S0022-2860(19)30445-4 DOI: https://doi.org/10.1016/j.molstruc.2019.04.050 Reference: MOLSTR 26422 To appear in: Journal of Molecular Structure Received Date: 5 October 2018 Revised Date: 30 March 2019 Accepted Date: 11 April 2019 Please cite this article as: A. Sunil Kumar, J. Kudva, M. Lahtinern, A. Peuronen, R. Sadashiva, D. Naral, Synthesis, characterization, crystal structures and biological screening of 4-amino quinazoline sulfonamide derivatives, Journal of Molecular Structure (2019), doi: https://doi.org/10.1016/ j.molstruc.2019.04.050. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT Synthesis, characterization, crystal structures and biological screening of 4-amino quinazoline sulfonamide derivatives Sunil Kumar A a , Jyothi Kudva a* , Manu Lahtinern b , Anssi Peuronen c , Rajitha Sadashiva d , Damodara Naral e . a,* Department of Chemistry, St Joseph Engineering College, Mangaluru, 575028, India. b Department of Chemistry, University of Jyväskylä. P.O. Box 35, FI-40014 JY, Finland. c Department of Chemistry, University of Turku, FI-20014 Turku, Finland. d Sigma-Aldrich Chemical Pvt. Ltd, Bommasandra, Bengaluru, 560100, India. e Department of Chemistry, Canara Engineering College, Mangaluru, 574219, India. Corresponding author’s email: [email protected]. Graphical Abstract MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 1 Synthesis, characterization, crystal structures and biological screening of 4-amino quinazoline sulfonamide derivatives Sunil Kumar A a , Jyothi Kudva a* , Manu Lahtinern b , Anssi Peuronen c , Rajitha Sadashiva d , Damodara Naral e . a,* Department of Chemistry, St Joseph Engineering College, Mangaluru, 575028, India. b Department of Chemistry, University of Jyväskylä. P.O. Box 35, FI-40014 JY, Finland. c Department of Chemistry, University of Turku, FI-20014 Turku, Finland. d Sigma-Aldrich Chemical Pvt. Ltd, Bommasandra, Bengaluru, 560100, India. e Department of Chemistry, Canara Engineering College, Mangaluru, 574219, India. Corresponding author’s email: [email protected]. Abstract Three quinazolin-4-ylamino derivatives containing phenylbenzenesulfonamides (7a-7c) were synthesized by reacting (E)-N'-(2-cyanophenyl)-N,N-dimethyl formamidine (6) with different 4amino-N-(phenyl)benzenesulfonamides (4a-4c) and characterized by different techniques such as HRMS, IR, 1 H NMR and 13 C NMR spectroscopy. The structural properties were further examined by single crystal X-ray diffraction method. The X-ray data shows that compounds 7a and 7c contain two molecules and 7b contains one molecule in the asymmetric unit. Comparison of conformation of two distinct molecules, “A” and “B”, in the asymmetric unit of 7a and 7c were studied with the aid of reported literature. The in vitro antiproliferative activity of the compounds was tested against two breast cancer cell lines (MDA-MB-231 and MCF7). Compound 7b observed as a highest potent candidate against MDA-MB-231with IC 50 of 5.44 µg/mL. Antimicrobial activity was also screened against bacterial and fungal strains. Compound 7a with chloro substitution was observed as the most potent candidate against the Gram-negative bacterial strains, whereas the compounds showed no significant activity against the fungal strain. Keywords: X-ray-diffraction, quinazoline-sulfonamide, crystal structure, antimicrobial, antiproliferative activity. MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 2 1. Introduction The biological activity of a variety of quinazoline derivatives depends on the nature and the position of the substituent group in their framework. Out of the broadly identified substitution pattern, 4-aminoquinazolines and their N-anilino derivatives were found to be effective especially as anticancer agents [1, 2]. The literature reports also have explained the broad range biological potential of quinazolinone and quinazoline derivatives in antitubercular [3], antimicrobial [4, 5], antimalarial [6], anticonvulsant [7], antiviral [8], anti-inflammatory [9], antidiabetic [10] and many other biological activities. Therefore, the synthesis of 4aminoquinazolines has attracted broad attention in recent years [11]. On the other hand, sulfonamides and their different derivatives are broadly used in medicine due to their pharmacological properties such as antibacterial activity [12, 13]. Sulfonamides act as inhibitors of folic acid synthesis in the living system which assists in the flourishing condition of bacteria [14]. The existence of donor and acceptor atoms in sulfonamide derivatives helps them to participate in the arrangement of different hydrogen bond networks. Earlier studies show that this property enables them to form different polymorphic [15, 16] as well as co-crystal structures [17, 18]. Therefore, the sulfonamide derivatives have more significance not only in the field of studying their biological application but also their crystal features as well. Our previous work explained the crystal structure, hydrogen bonding and molecular contacts of quinazoline scaffold containing oxazole and fluorophenyl sulfonamide derivatives [19, 20]. This work focused on the quinazoline scaffold containing phenyl sulfonamide derivatives. The synthesized derivatives were characterized by the HRMS, IR, 1 H NMR, 13 C NMR and elemental analysis. The lattice parameters, bond angles, bond lengths, dihedral angles, torsion angles, hydrogen bonding (HB) and intermolecular interactions of the grown crystals were obtained by single crystal X-ray diffraction (XRD). Antiproliferative, antibacterial and antifungal activities were also screened to verify the potency of the compounds. 2. Experimental 2.1 Materials and Methods The melting points (uncorrected) of targeted quinazoline sulfonamide derivatives were determined with DIGITAL MELTING POINT APPARATUS EQ 730 (EQUIPTRONICS) using an open capillary tube with the heating rate of 10 °C/min. HRMS (High-resolution mass spectra) MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 3 were recorded on an Agilent 6520 (QTOF) ESI-HRMS instrument. Infrared spectra were recorded in a Shimadzu FT-IR spectrometer using KBr pellets. 1 H (400 MHz) and 13 C (100 MHz) NMR spectra were recorded on a Bruker Avance (AC 80) instrument in DMSO-d 6 using tetramethylsilane (TMS) as an internal standard. The chemical shift values (δ) were recorded in parts per million (ppm). All synthesis reactions were monitored by thin layer chromatography (TLC) using aluminium TLC plate, silica gel coated with fluorescent indicator F 254 (Merck). The C, H, N and S elemental analysis was performed using Thermo Finnigan Elemental Micro Analyser. 2 ii iii H 2 N O SH N O 4a-4c iv + S Cl O O H 3 C-CO-HN 3a-3c 56 HN O O S H N 7a-7c + v CN NH 2 S Cl O O H 3 C-CO-HN H 3 C-CO-HN 12 i R H 2 NR H 2 N O SH N O 4a-4c R N N R N N N 6 N N N 7a: R= Cl 7b: R= F 7c: R= CH 3 Scheme 1. Synthesis of compounds 7a-7c. Reagents and conditions: i) ClSO 3 H/CHCl 3 , RT, 12 h; ii) Pyridine/CHCl 3 , RT, 8 h; iii) HCl/Ethanol, 7580 °C, 4 h; iv) DMF-DMA/DMF, 90 °C, 3-4 h; v) Acetic acid, 100 °C, 3-4 h. 2.1.1 Structural determination by single crystal X-ray diffraction studies Single crystal structure data of 7a, 7b and 7c were collected by Agilent/Rigaku SuperNova diffractometer, equipped with Eos detector, using multilayer optics monochromated Mo K α ( λ = 0.71073 Å) radiation and processed with CrysAlisPro(v. 1.171.38.43c) [21]. The structures were solved (direct methods) and refined within Olex 2 (v. 1.2.10) [22] program package using MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 4 SHELXS [23] and SHELXL [24] programs. All non-hydrogen atoms were anisotropically refined. C–H hydrogen atoms were calculated to their ideal positions and refined using a riding model with U iso parameters 1.2-1.5 times larger to their respective host atoms. O–H and N–H hydrogen atoms were located from the difference density map and refined without any restraints. The crystal lattices of structures of compounds 7a and 7c contain spherical voids that contribute to ca. 1 % of the unit cell volume (calculated using Mercury [25] contact surface with 1.2 Å probe radius and 0.7 Å grid spacing). These voids did not, however, show any residual electron density and thus were not considered to include any solvent molecules. 2.1.2 Antiproliferative studies The compounds (7a-7c) were tested for their in vitro antiproliferative activity against two breast cancer cell lines MDA-MB-231 and MCF7 by MTT assay [26]. Compounds screened at seven different concentrations (1.0, 6.25, 12.5, 25, 50, 100 and 500 µ g/mL) along with Cisplatin, used as a reference standard. The concentration required for 50 % inhibition of cell viability (IC 50 ) was calculated. 2.1.3 Antimicrobial studies The compounds 7a-7c were also screened for their in vitro antibacterial activity against two representative Gram-positive bacterial strains Bacillus subtilis and Staphylococcus aureus ; two Gram-negative bacterial species Escherichia coli and Pseudomonas aeruginosa and a fungal strain Aspergillus niger by broth dilution method [27]. Ciprofloxacin and Fluconazole were used as reference drugs in terms of minimum inhibitory concentration (MIC). 2.2 Synthesis The synthetic routes are shown in Scheme 1 and the molecules were synthesized based on available procedures. 2.2.1 Synthesis of 4-(acetylamino)benzene-1-sulfonyl chloride(2)from acetanilide (1) Acetanilide (1) (10 g, 0.074 moles) was stirred in a minimum quantity of chloroform and cooled to 0 °C. Excess of chlorosulfonic acid (50 mL, 0.74 moles) was added to the cooled solution under stirring. The reaction temperature was maintained between 0-5 °C during the addition. After the completion of the reaction, mixture was slowly added to crushed ice to neutralize the excess of acid and the solid was collected by filtration and dried [28]. MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 5 2.2.2 Synthesis of sulfonamide intermediates (4a-4c) Synthesis of the precursor sulfonamides 4a4c was achieved by treating 0.01 mol of substituted aromatic amines (3a-3c) with 0.015 mol of 4-(acetylamino)benzene sulfonylchloride (2) in 0.03 mol of pyridine at room temperature (RT) for 8 h. Reaction progress was monitored by TLC (with hexane: EtOAc (1:1) mixture as eluent. Excess pyridine was neutralized with diluted HCl solution and the product was isolated by filtration. The hydrolysis of the above product was carried out by refluxing it with concentrated HCl in ethanol for 4 h. The clear solution was cooled and neutralized by ammonium hydroxide solution. The solid precipitated was filtered and dried at 50-55 °C (Scheme 1). 2.2.3 Synthesis of N,N -dimethylformamidine intermediate (6) The N,N -dimethylformamidine intermediate (6) was obtained by heating 0.01 mol of 2aminobenzonitrile (5) with 0.015 mol of dimethylformamide-dimethylacetal (DMF-DMA) at 90 °C in DMF solvent [29]. The product was precipitated by diluting with water and isolated by filtration. 2.2.4 Synthesis of 4-amino quinazoline derivatives (7a-7c) The target quinazoline derivatives (7a-7c) were obtained by refluxing 0.01 mol of intermediate 6 with 0.011 mol of synthesized sulfonamides (4a-4c) in acetic acid. The products were isolated by filtration [19]. N-(4-Chlorophenyl)-4-[(quinazolin-4-yl)amino]benzene-1-sulfonamide (7a) Yield 74 %; mp: 243-245 o C; IR (KBr, cm -1 ): 3378 (N-H), 1621 (C=N), 1322 (SO 2 asym), 1150 (SO 2 sym); 1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.32 (s, 1H, SO 2 N-H), 9.99 (s, 1H, N-H), 8.63 (s, 1H, Ar), 8.48-8.50 (d, J=8.4Hz, 1H, Ar), 8.05-8.07 (d, 2H, Ar), 7.81-7.84 (t, 1H, Ar), 7.767.78 (d, J=8.4Hz, 1H, Ar), 7.71-7.73 (d, 2H, Ar), 7.59-7.62 (t, 1H, Ar), 7.23-7.25 (d, 2H, Ar), 7.07-7.09 ppm (d, 2H, Ar); 13 C NMR (100 MHz, DMSO): δ = 157.3, 154.0, 149.8, 143.5, 136.8, 133.3, 132.7, 129.0, 127.9, 127.9, 127.5, 126.5, 123.0, 121.4, 121.2, 115.2 ppm; HRMS (ESI) m/z calcd: 411.0683 [M+H] + , found 411.0681; Anal. calcd for C 20 H 15 N 4 SO 2 Cl (%): C 58.46; H 3.68; N 13.64; S 7.80, found: C 58.38; H 3.58; N 13.69; S 7.74. MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 6 N -(4-Fluorophenyl)-4-[(quinazolin-4-yl)amino]benzene-1-sulfonamide (7b) Yield 94 %; mp: 276-278 o C; IR (KBr, cm -1 ): 3386 (N-H), 1622 (C=N), 1330 (SO 2 asym), 1153 (SO 2 sym); 1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.45 (s, 1H, SO 2 N-H), 10.06 (s, 1H, N-H), 8.69 (s, 1H, Ar), 8.55-8.57 (d, 1H, Ar), 8.13-8.15 (d, 2H, Ar), 7.87-7.91 (t, 1H, Ar), 7.82-7.84 (d, 1H, J= 8 Hz, Ar), 7.77-7.79 (d, 2H, Ar), 7.65-7.67 (t, 1H, Ar), 7.29-7.31 (d,1H, Ar), 7.24-7.27 (t, 1H, Ar), 7.09-7.13 ppm (m,1H, Ar); 13 C NMR (100 MHz, DMSO): δ = 157.2, 153.9, 152.4, 149.6, 144.2, 137.0, 133.3, 129.2, 128.2, 127.9, 126.5, 121.2, 121.0, 119.2, 116.4, 115.7 ppm; HRMS (ESI) m/z calcd: 395.0972 [M+H] + , found 395.0968; Anal. calcd for C 20 H 15 N 4 SO 2 F (%): C 60.90, H 3.83, N 14.20, S 8.13, found: C 60.78, H 3.72, N 14.13, S 8.18. N-(4-Methylphenyl)-4-[(quinazolin-4-yl)amino]benzene-1-sulfonamide (7c) Yield 91 %; mp: 243-245 o C; IR (KBr, cm -1 ): 3361 (NH), 1624 (C=N), 1313 (SO 2 asym), 1150 (SO 2 sym); 1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.07 (s, 1H, SO 2 N-H), 10.02 (s, 1H, N-H), 8.68 (s. 1H, Ar), 8.54-8.56 (d, 1H, Ar), 8.09-8.11 (d, 2H, Ar), 7.81-7.87 (m, 2H, Ar), 7.76-7.78 (d, 2H, Ar), 7.64-7.67 (t, 1H, Ar), 7.03 (s, 4H, Ar), 2.17 ppm (s, 3H, -CH 3 ); 13 C NMR (100 MHz, DMSO): δ = 157.3, 154.0, 149.7, 143.2, 135.2, 133.2, 133.2, 133.1, 129.5, 127.8, 126.5, 122.99, 121.1, 120.4, 115.2, 20.25 ppm; HRMS (ESI) m/z calcd: 391.1223 [M+H] + , found 391.1228; Anal. calcd for C 21 H 18 N 4 SO 2 (%): C 64.60, H 4.65, N 14.35, S 8.21, found: C 64.64, H 4.58, N 14.42, S 8.10. 3 Results and discussion 3.1 Synthesis In the present work, we have synthesized three N -(quinazolin-4-yl)sulfonamide derivatives by condensing different aryl sulfonamides with ( E )- N '-(2-cyanophenyl)- N,N -dimethylformamidine. It is assumed that the synthesized aromatic amine first attacks on the carbon of the N,N - dimethylamine following an ejection of N,N -dimethylamine [29]. The intermediate aromatic amidine then undergoes cyclization into a quinazoline frame in which the endocyclic and exocyclic nitrogen atoms interchange their place via Dimroth rearrangement to obtain the expected 4-anilinoquinazoline (Scheme 1). The attack of an amine into the cyano group is impossible in practice without a probable catalytic action of an acid [30]. MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 13 Fig. 4. a) Illustration of the asymmetric unit of structure of 7bwith atomic labels shown (ellipsoids presented at 30 % probability level). b) and c) Examples of the different intermolecular N–H···N and N–H···O=S hydrogen bond networks found in the crystal lattice of 7b. d) Comparison between the H···O=S hydrogen bond networks observed in 7a and 7b. 3.4 Biological evaluation 3.4.1 Antiproliferative activity The synthesized compounds (7a-7c) were tested for their in vitro antiproliferative activity against two cancer cell lines (MDA-MB-231 and MCF7) and the results were summarized in Table 3. The tested compounds exhibited a remarkable cytotoxicity against MDA-MB-231 cell line. MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 14 Among these compounds, electronegative fluoro substituted compound 7b has shown the most potent activity with IC 50 of 5.44 µg/mL and the activity observed was more than the standard drug Cisplatin (IC 50 = 5.61µg/mL). Chloro (7a) and methyl (7c) derivatives exhibited moderate inhibitory activities with IC 50 of 17.83 and 19.56 µg/mL respectively. The tested compounds have not shown any significant cytotoxicity against MCF7 cell line even at higher concentrations (IC 50 > 500 µg/mL). The structural evaluation of similar compounds from the literature revealed that the fluoro substituted quinazoline derivatives have been reported to possess an excellent range of antiproliferative activities. It was observed from the reports that, the fluorophenyl substitution at 4-aminoquinazoline ring can enhance the anticancer activity [40, 41]. Table 3. In vitro antiproliferative activity studies of compound 7a-7c Comp. No. R Antiproliferative activity (IC 50 in µg/mL) MDA-MB-231 MCF7 7a 4 - Cl 17.83 >500 7b 4 - F 5.44 >500 7c 4 - CH 3 19.56 >500 Cisplatin - 5.61 6.78 3.4.2 Antimicrobial activity The in vitro antibacterial activity was tested against two Gram-positive (B. subtilis and S. aureus) and two Gram-negative (E. coli and P. aeruginosa) bacterial strains by broth dilution method. The results are displayed in Table 4. The compounds showed toxic effects against all the tested bacterial strains and the toxicity is more pronounced against Gram-negative bacterial strains than Gram-positive bacterial species. Compound 7c with methyl substitution showed less toxicity profile against all the tested bacterial strains. The replacement of the methyl group with halo substitutions enhanced the activity. Compounds 7a and 7b showed a moderate to good activity against the Gram-negative bacterial strains (E. coli and P. aeruginosa). It is significant that 4-chloro derivative 7a was found to be more active against Gram-negative bacteria than Ciprofloxacin, which is a known antimicrobial drug. The compound 7a also showed moderate activity against the tested Gram-positive bacteria. Therefore, compound 7a can be considered as a potent antibacterial candidate against the Gram-negative bacteria. The antibacterial activity of compounds is mainly due to the presence of sulfonamide moiety and the synthesized phenylsulfonamide derivatives were observed as less active compared to heterocyclic sulfa drugs MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 15 [42, 43]. The compounds were also tested against a fungal strain A. niger, but did not show any remarkable activity. They were active only at higher concentration (MIC 50 µg/mL) compared to the standard drug Fluconazole. Table 4. Antimicrobial activity studies of compound 7a-7c. Comp. No. Antimicrobial activity, MIC in µg/mL Gram-positive Bacteria Gram-negative bacteria Fungal strain B. S a S. A b E. C c P. A d A. N e 7a 12.5 6.25 1.6 3.12 50 7b 50 12.5 6.25 3.12 50 7c 25 6.25 50 50 50 Cisplatin NT NT NT NT NT Ciprofloxacin 2.0 2.0 4.0 2.0 NT Fluconazole NT NT NT NT 4.0 ‘NT’ Indicates not tested; a, B. subtilis, b. S. aureus, c, E. coli, d, P. aeruginosa, e. A. niger. 4 Conclusion Three novel quinazoline derivatives containing phenylsulfonamide moiety were synthesized and single crystals of each compound were grown by a slow evaporation method in acetone. X-ray single crystal structures were succesfully determined for all three quinazoline derivates. Compounds 7a and 7c showed to be isostructural whereas the fluoro derivative 7b manifested clearly different molecular packing and hydrogen bond network in the crystal lattice. Even though the molecular packing scheme between 7a/7c and 7b proved to be different, the three compounds exhibited only two different types of molecular conformations: two types (A and B) in case of 7a and 7c and type B in case of 7b. The in vitro anticancer activity of the compounds was tested against two breast cancer cell lines (MDA-MB-231 and MCF7). The fluoro derivative 7b displayed excellent activity against MDA-MB-231 with IC 50 value of 5.44 µg/mL, which was more than the standard drug Cisplatin. Compound 7a with chloro substitution revealed the highest antimicrobial activity against the Gram-negative bacterial strain, E. coli out of the three tested compounds, whereas no significant activity was shown against the fungal strain by any of the compounds. MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT 16 Electronic Supplementary Information (ESI) available: NMR data, additional figures and crystallographic data tables. CCDCs 1857204, 1563909 and 1857205 contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures. Acknowledgements The authors are gratefully acknowledge the financial support provided by VGST-K-FIST (L1)/2017, GRD No. 557 and the Academy of Finland (Project No. 277250 and 315911). References [1] S. Poudapally, S. Battu, L. R. Velatooru, M. S. Bethu, V. R. Janapala, S. Sharma, S. Sen, N. Pottabathini, V. B. R. Iska, V. Katangoor, Synthesis and biological evaluation of novel quinazoline-sulfonamides as anti-cancer agents, Bioorg. Med. Chem. Lett. 27 (2017) 19231928. [2] M. L. Barbosa, L. M. Lima, R. Tesch, C. M. Sant'Anna, F. Totzke, M. H. Kubbutat, C. Schächtele, S.A. Laufer, E. J. Barreiro, Novel 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors, Eur. J. Med. Chem. 71 (2014) 1-14. [3] J. Kunes, J. Bazant, M. Pour, K. Waisser, M. 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Khodarahmi, Quinazolinone and quinazoline derivatives: recent structures with potent antimicrobial and cytotoxic activities, Res. Pharm. Sci. 11 (2016) 1–14. ***** MANUS CRIP T ACCEP TED ACCEPTED MANUSCRIPT Synthesis, characterization, crystal structures and biological screening of 4-amino quinazoline sulfonamide derivatives Sunil Kumar A a , Jyothi Kudva a* , Manu Lahtinern b , Anssi Peuronen c , Rajitha Sadashiva d , Damodara Naral e . a,* Department of Chemistry, St Joseph Engineering College, Mangaluru, 575028, India. b Department of Chemistry, University of Jyväskylä. P.O. Box 35, FI-40014 JY, Finland. c Department of Chemistry, University of Turku, FI-20014 Turku, Finland. d Sigma-Aldrich Chemical Pvt. Ltd, Bommasandra, Bengaluru, 560100, India. e Department of Chemistry, Canara Engineering College, Mangaluru, 574219, India. Corresponding author’s email: [email protected]. Highlights • Three quinazolin-4-ylamino derivatives containing phenylbenzenesulfonamides (7a-7c) were synthesized. • Structural properties were examined by single crystal X-ray diffraction. • Two different types (A and B) of molecular conformations of crystals were studied. • In vitro antiproliferative and antimicrobial activity studies were performed.