Synthesis, Cytotoxicity, Antimicrobial and Docking Simulation of Novel Pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[3,4-c] pyrimidine Derivatives

Author(s): Hamdi M. Hassaneen* , Fatma M. Saleh , Tayseer A. Abdallah , Magda F. Mohamed , Yasmin Sh. Mohamed , Enas M. Awad , Ismail A. Abdelhamid* .

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 19 , Issue 8 , 2019

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Abstract:

Background: Isobutyrohydrazonoyl bromide 1 was used as a precursor for the synthesis of 4-imino-3-isopropyl-1-(4-nitrophenyl)-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-amine 4, which was converted into hydrazino derivative 5 by heating with hydrazine hydrate at reflux. Hydrazino, as well as imino-amino derivatives, underwent condensation and cyclization reactions to give pyrazolo[ 3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[3,4-c]pyrimidine derivatives, respectively.

Method: Antimicrobial studies are performed using two-gram positive bacteria and two-gram negative bacteria.

Results: Data revealed that compound 9a is the most promising antibacterial agent with high efficiency (low MIC value (48 μg/ml)). The cytotoxic assay was investigated for in vitro antitumor screening against Caucasian breast adenocarcinoma MCF7, hepatocellular carcinoma HepG2 and colon carcinoma HCT-116 cell lines.

Conclusion: The results are compared with doxorubicin standard anticancer drugs as well as normal cell lines like MCF10 and MCF12. Molecular docking was carried out for the highest potent compound 8c with the binding site of dihydrofolate reductase enzyme DHFR PDB:ID (1DLS).

Keywords: Modeling simulation, DHFR, cytotoxicity, imino-amino, hydrazine hydrate, hydrazones, antibacterial activity.

[1]
Hassaneen, H.M.; Shetta, A.; Shawali, A.S. Hydrazidoyl halides in synthesis of Δ2-1,3,4-Selenadiazolin-5-ones. J. Heterocycl. Chem., 1980, 17(6), 1185-1187.
[2]
Shawali, A.S.; Hassaneen, H.M.; Shetta, A.F.; Osman, A.; Abdel-Galil, F. regioselectivity of reactions of 2-Furoyl-N-Aryl nitrile imine with some dipolarophiles. Heterocycles, 1982, 19, 57-66.
[3]
Awad, E.M.; Elwan, N.M.; Hassaneen, H.M.; Linden, A.; Heimgartner, H. New routes to fused isoquinolines. Helv. Chim. Acta, 2002, 85(1), 320-332.
[4]
Elwan, N.M.; Awad, E.M.; Hassaneen, H.M.; Linden, A.; Heimgartner, H. Synthesis of 1,2,4-Triazolo[4,3-a]Pyrimidine derivatives by cyclocondensation of a 2-Thioxopyrimidin-4(3H)-One with hydrazonoyl halides. Helv. Chim. Acta, 2003, 86(3), 739-749.
[5]
Hassaneen, H.M.; Hassaneen, H.M.E.; Mohammed, Y.S.; Pagni, R.M. Synthesis, reactions and antibacterial activity of 3-Acetyl[1,2,4]Triazolo[3,4-a]Isoquinoline derivatives using chitosan as heterogeneous catalyst under microwave irradiation. Zeitschrift für. Naturforsch. B, 2011, 66(3), 299-310.
[6]
Hassaneen, H.M.; Saleh, F.M.; Mohammed, Y.S.; Awad, E.M. A convenient regioselective synthesis of novel 1,4-phenylene-methylene-6,6′-bis-([1,2,4-triazolo]-[4,3-b][1,2,4]-triazin-7(1H)-ones). J. Heterocycl. Chem., 2017, 54(6), 3015-3022.
[7]
Hassaneen, H.M.; Wardakhan, W.W.; Mohammed, Y.S. Synthesis and reactions of pyrido[2,1-a]Isoquinolin-4-yl formimidate derivatives and antimicrobial activities of isolated products. J. Heterocycl. Chem., 2017, 54(5), 2850-2858.
[8]
Hassaneen, H.M.; Shawali, A.S.; Saleh, F.M. A Convenient synthesis of novel 1,3-phenylene bridged bis-heterocyclic compounds. J. Sulfur Chem., 2016, 37(3), 241-250.
[9]
Abdelhamid, A.O.; Hassaneen, H.M.; Shawali, A.S.; Párkányi, C. Reactions of α-Ketohydrazidoyl halides with some heterocyclic amines. Facile synthesis of arylazo derivatives of fused heterocycles with a bridgehead nitrogen atom. J. Heterocycl. Chem., 1983, 20(3), 639-643.
[10]
Abdelhamid, A.O.; Hassaneen, H.M.; Shawali, A.S. Synthesis of Pyrazolo[3,2-c]-1,2,4-Triazines from N-(5-Pyrazolyl)-α-Ketohydrazidoyl halides. J. Heterocycl. Chem., 1985, 22(2), 453-455.
[11]
Hassaneen, H.M.; Mousa, H.A.H.; Shawali, A.S. Chemistry of C-heteroarylnitrilimines. Synthesis and cycloaddition reactions of N-Phenyl-C-(2-Thienyl)Nitrilimine. J. Heterocycl. Chem., 1987, 24(6), 1665-1668.
[12]
Hassaneen, H.M.; Ead, H.A.; Elwan, N.M.; Shawali, A.S. A one step synthesis of 4-Cyanopyrazoles. Heterocycles, 1988, 27(12), 2857-2862.
[13]
Hassaneen, H.M.; Mousa, H.A.H.; Shawali, A.S. Selsctivity in cycloadditions of N-Aryl-C-(2-Thienyl) Nitrilimines to α, β- Disubstituted acrylonitriles. Sulfur Lett., 1988, 8, 217-227.
[14]
Hassaneen, H.M.; Shawali, A.S.; Elwan, N.M. Synthesis and cycloaddition reaction of N-Phenyl-C-Styrylmethanohydrazonyl bromide. Heterocycles, 1990, 31(2), 247-253.
[15]
Elwan, N.M.; Abdelhadi, H.A.; Abdallah, T.A.; Hassaneen, H.M. Synthesis of [1,2,4]Triazolo[3,4-a]Isoquinolines and Pyrrolo[2,1-a]Isoquinolines using α-Keto hydrazonoyl halides. Tetrahedron, 1996, 52(10), 3451-3456.
[16]
Hassaneen, H.M.; Abdelhadi, H.A.; Abdallah, T.A. Novel synthesis of 1,2,4-triazolo[4,3- a]pyrimidin-5-one derivatives. Tetrahedron, 2001, 57(51), 10133-10138.
[17]
Shawali, A.S.; Párkanyi, C. Hydrazidoyl halides in the synthesis of heterocycles. J. Heterocycl. Chem., 1980, 17(5), 833-854.
[18]
Shawali, A.S. Reactions of hydrazidoyl halides with sulfer compounds. Heterocycles, 1983, 20(11), 2239-2285.
[19]
Ghozlan, S.A.S.; Abdelhamid, I.A.; Elnagdi, M.H.; Gaber, H.M. Studies on enaminonitriles: A new synthesis of 1,3-Substituted Pyrazole-4-Carbonitrile. J. Heterocycl. Chem., 2005, 42(6), 1185-1189.
[20]
Wolkoff, P. A new method of preparing hydrazonyl halides. Can. J. Chem., 1975, 53(9), 1333-1335.
[21]
Abdelhamid, A.O.; Rateb, N.M.; Dawood, K.M. Reactions with hydrazonoyl halides XXX: Synthesis of some 2,3-Dihydro-1,3,4-Thiadiazoles and unsymmetrical azines containing benzothiazole moiety. Phosphorus Sulfur Silicon Relat. Elem., 2000, 167(1), 251-258.
[22]
Abdelhamid, A.O.; Abdelall, E.K.A.; Zaki, Y.H. Reactions with hydrazonoyl halides 62: Synthesis and antimicrobial evaluation of some new Imidazo[1,2‐a]Pyrimidine, Imidazo [1,2‐a]Pyridine, Imdazo[1,2‐b]Pyrazole, and quinoxaline derivatives. J. Heterocycl. Chem., 2010, 47(2), 477-482.
[23]
Shawali, A.S. Reactions of heterocyclic compounds with nitrilimines and their precursors. Chem. Rev., 1993, 93(8), 2731-2777.
[24]
Shawali, A.S.; Abdallah, M.A. The chemistry of heterocyclic hydrazonoyl halides. Adv. Heterocycl. Chem., 1995, 63, 277-338.
[25]
Shawali, A.S.; Mosselhi, M.A.N. Hydrazonoyl halides: Useful Building blocks for the synthesis of arylazoheterocycles. J. Heterocycl. Chem., 2003, 40(4), 725-746.
[26]
Shawali, A.S.; Edrees, M.M. Reactions of Nitrilimines with heterocyclic amines and enamines. Convenient methodology for synthesis and annulation of heterocycles. Gen. Pap. Ark., 2006, ix, 292-365.
[27]
Shawali, A.S.; Samy, N.A. Hydrazonoyl halides: Their versatile biological activities. Open Bioactive Compd. J., 2009, 2(1), 8-16.
[28]
Huisgen, R. 1,3-Dipolar cycloadditions. Past and future. Angew. Chem. Int. Ed. Engl., 1963, 2(10), 565-598.
[29]
Heusgen, R. Mechanism of 1,3-Dipolar cycloadditions. Reply. J. Org. Chem., 1968, 33(6), 2291-2297.
[30]
Huisgen, R. Kinetics and mechanism of 1,3-Dipolr cycloadditions. Angew. Chem. Int. Ed. Engl., 1963, 2(11), 633-645.
[31]
Hegarty, A.F.; Cashman, M.P.; Scott, F.L. Synthesis of aliphatic hydrazonyl bromides and kinetics of their conversion into hydrazides. J. Chem. Soc., Perkin Trans. 2, 1972, 10, 1381-1385.
[32]
Shawali, A.S.; Hassaneen, H.M. Chemistry of aliphatic hydrazonyl bromides. Part II– Reactions with carbanions of active methylene compounds. Indian J. Chem., 1976, 14b, 549-550.
[33]
Yamini, L.; Vijjulatha, M. Inhibitors of human dihydrofolate reductase: A computational design and docking studies using glide. E-J. Chem., 2008, 5(2), 263-270.
[34]
Banjanac, M.; Tatic, I.; Ivezic, Z.; Tomic, S.; Dumic, J. Pyrimido- pyrimidines : A novel class of dihydrofolate reductase inhibitors. Food Technol. Biotechnol., 2009, 47, 236-245.
[35]
Ghozlan, S.A.S.; Mohamed, M.F.; Ahmed, A.G.; Shouman, S.A.; Attia, Y.M.; Abdelhamid, I.A. Cytotoxic and antimicrobial evaluations of novel apoptotic and anti-angiogenic spiro cyclic 2-Oxindole derivatives of 2-Amino-Tetrahydroquinolin-5-One. Arch. Pharm. (Weinheim), 2015, 348(2), 113-124.
[36]
Mohamed, M.F.; Darweesh, A.F.; Elwahy, A.H.M.; Abdelhamid, I.A. Synthesis, characterization and antitumor activity of novel tetrapodal 1,4-dihydropyridines: P53 Induction, Cell Cycle arrest and low damage effect on normal cells induced by genotoxic factor H2O2. RSC Advances, 2016, 6(47), 40900-40910.
[37]
Mohamed, M.F.; Mohamed, M.S.; Fathi, M.M.; Shouman, S.A.; Abdelhamid, I.A. Chalcones incorporated pyrazole ring inhibit proliferation, Cell cycle progression, angiogenesis and induce apoptosis of MCF7 cell line. Anticancer. Agents Med. Chem., 2014, 14(9), 1282-1292.
[38]
Mohamed, M.F.; Attia, Y.M.; Shouman, S.A.; Abdelhamid, I.A. Anticancer activities of new N-Hetaryl-2-Cyanoacetamide derivatives incorporating 4,5,6,7-Tetrahydrobenzo[b]Thiophene moiety. Anticancer. Agents Med. Chem., 2017, 17(8), 1084-1092.
[39]
Mohamed, M.F.; Hassaneen, H.M.; Abdelhamid, I.A. Cytotoxicity, molecular modeling, cell cycle arrest, and apoptotic induction induced by novel Tetrahydro-[1,2,4]Triazolo[3,4-a]Isoquinoline Chalcones. Eur. J. Med. Chem., 2018, 143(1), 532-541.
[40]
Salama, S.K.; Mohamed, M.F.; Darweesh, A.F.; Elwahy, A.H.M.; Abdelhamid, I.A. Molecular docking simulation and anticancer assessment on human breast carcinoma cell line using novel Bis(1,4-Dihydropyrano[2,3-c]Pyrazole-5-Carbonitrile) and Bis(1,4-Dihydropyrazolo[4′,3′:5,6]Pyrano[2,3-b]Pyridine-6-Carbonitrile) derivatives. Bioorg. Chem., 2017, 71, 19-29.
[41]
Ibrahim, N.S.; Mohamed, M.F.; Elwahy, A.H.M.; Abdelhamid, I.A. Biological activities and docking studies on novel bis 1,4-dhps linked to arene core via ether or ester linkage. Lett. Drug Des. Discov., 2018, 15, 1036-1045.
[42]
Mohamed, M.F.; Samir, N.; Ali, A.; Ahmed, N.; Ali, Y.; Aref, S.; Hossam, O.; Mohamed, M.S.; Abdelmoniem, A.M.; Abdelhamid, I.A. Apoptotic induction mediated P53 mechanism and Caspase-3 activity by novel promising cyanoacrylamide derivatives in breast carcinoma. Bioorg. Chem., 2017, 73, 43-52.
[43]
Mohamed, M.F.; Abdelmoniem, A.M.; Elwahy, A.H.M.; Abdelhamid, I.A. DNA Fragmentation, Cell cycle arrest, and docking study of novel bis Spiro-Cyclic 2-oxindole of Pyrimido[4,5-b]Quinoline-4,6-Dione derivatives against breast carcinoma. Curr. Cancer Drug Targets, 2018, 18(4), 372-381.
[44]
Abdella, A.M.; Mohamed, M.F.; Mohamed, A.F.; Elwahy, A.H.M.; Abdelhamid, I.A. Novel Bis(Dihydropyrano[3,2-c]Chromenes): Synthesis, antiproliferative effect and molecular docking simulation. J. Heterocycl. Chem., 2018, 55(2), 498-507.
[45]
Bauer, A.W.; Kirby, W.M.; Sherris, J.C.; Turck, M. Antibiotic susceptibility testing by a standardized single disk method. Am. J. Clin. Pathol., 1966, 45(4), 493-496.
[46]
Pfaller, M.A.; Burmeister, L.; Bartlett, M.S.; Rinaldi, M.G. Multicenter evaluation of four methods of yeast inoculum preparation. J. Clin. Microbiol., 1988, 26(8), 1437-1441.
[47]
Nccls. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard, 2nd ed; Serving the World’s Medical Science Community Through Voluntary Consensus, 2002, Vol. 22, .
[48]
Rex, J.H.; Johnson, E.M.; Ghannoum, M.A.; Knapp, C.C.; Alexander, B.D.; Motyl, M.R.; Andes, D.; Ostrosky-Zeichner, L.; Brown, S.D.; Pfaller, M.A. Method for Antifungal Disk Diffusion Susceptibility Testing of Yeasts: Approved Guideline M44-A; , 2009. Vol. 24.
[49]
Jordão, A.K.; Novais, J.; Leal, B.; Escobar, A.C.; dos Santos Júnior, H.M. Castro, H.C.; Ferreira, V.F. Synthesis using microwave irradiation and antibacterial evaluation of new N,O-Acetals and N,S-Acetals derived from 2-Amino-1,4-naphthoquinones. Eur. J. Med. Chem., 2013, 63, 196-201.
[50]
Geng, Z.Z.; Zhang, J.J.; Lin, J.; Huang, M.Y.; An, L.K.; Zhang, H.B.; Sun, P.H.; Ye, W.C.; Chen, W.M. Novel cajaninstilbene acid derivatives as antibacterial agents. Eur. J. Med. Chem., 2015, 100, 235-245.
[51]
Suresh, N.; Nagesh, H.N.; Renuka, J.; Rajput, V.; Sharma, R.; Khan, I.A.; Gowri, C.S.K.V. Synthesis and evaluation of 1-Cyclopropyl-6-Fluoro-1,4-Dihydro-4-Oxo-7-(4-(2-(4-Substitutedpiperazin-1-Yl) Acetyl)Piperazin-1-Yl)Quinoline-3-carboxylic acid derivatives as anti-tubercular and antibacterial agents. Eur. J. Med. Chem., 2014, 71, 324-332.
[52]
Ghose, A.K.; Viswanadhan, V.N.; Wendoloski, J.J. Prediction of hydrophobic (lipophilic) properties of small organic molecules using fragmental methods: An analysis of ALOGP and CLOGP methods. J. Phys. Chem. A, 1998, 102(21), 3762-3772.
[53]
Gibson, A.E.; Arris, C.E.; Bentley, J.; Boyle, F.T.; Curtin, N.J.; Davies, T.G.; Endicott, J.A.; Golding, B.T.; Grant, S.; Griffin, R.J. Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with o6-substituted guanine derivatives. J. Med. Chem., 2002, 45(16), 3381-3393.
[54]
Rashad, A.E.; Heikal, O.A.; El-Nezhawy, A.O.H.; Abdel-Megeid, F.M.E. Synthesis and isomerization of thienotriazolopyrimidine and thienotetrazolopyrimidine derivatives with potential Anti-Inflammatory activity. Heteroatom Chem., 2005, 16(3), 226-234.
[55]
Hosmane, R.S.; Lim, B.B.; Burnett, F.N. Rearrangements in heterocyclic synthesis: A novel translocation of an (N-Amino-N-Methylamino)Methylene group from a heterocyclic N-Amino-N-Methylformamidine side chain to the vinylogous nitrile function. J. Org. Chem., 1988, 53(3), 382-386.
[56]
Rashad, A.E.; Heikal, O.A.; El-Nezhawy, A.O.H.; Abdel-Megeid, F.M.E. Synthesis and isomerization of thienotriazolopyrimidine and thienotetrazolopyrimidine derivatives with potential anti-inflammatory activity. Heteroatom Chem., 2005, 16(3), 226-234.
[57]
Edition, I.; Chemistry, O. Studies on mechanisms of the rearrangement of thieno [3,2e][1,2, 4] Triazolo [4, 3c] Pyrimidines into Thieno [3,2e][1,2,4] Triazolo [1,5c] Pyrimidines. Russ. Chem. Bull., 2006, 55(12), 2247-2255.
[58]
Abdel-Fattah, B.; Kandeel, M.M.; Abdel-Hakeem, M.; Fahmy, Z.M. Synthesis of certain fused thienopyrimidines of biological interest. J. Chin. Chem. Soc., 2006, 53(2), 403-412.
[59]
Chopra, I.; Roberts, M. Tetracycline antibiotics: Mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol. Mol. Biol. Rev., 2001, 65(2), 232-260.
[60]
Hopkins, A.L.; Groom, C.R. The druggable genome. Nat. Rev. Drug Discov., 2002, 1(9), 727-730.
[61]
Kubinyi, H. Opinion: Drug research: Myths, Hype and Reality. Nat. Rev. Drug Discov., 2003, 2(8), 665-668.
[62]
Shier, W. Mammalian cell culture on $5 a Day: A laboratory manual of low cost methods. Los Banos, Univ. Philipp, 1991. 64.


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VOLUME: 19
ISSUE: 8
Year: 2019
Page: [657 - 670]
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DOI: 10.2174/1389557518666181017162459
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