Design, Synthesis, Molecular Modeling Study and Biological Evaluation of New N'-arylidene-pyrido[2,3-d]pyrimidine-5-carbohydrazide Derivatives as Anti-HIV-1 Agents

Document Type : Research article

Authors

1 Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

2 Medical Lab Technology Department, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Abstract

In an attempt to identify potential new agents that are active against HIV-1, a series of novel pyridopyrimidine-5-carbohydrazide derivatives featuring a substituted benzylidene fragment were designed and synthesized based on the general pharmacophore of HIV-1 integrase inhibitors. The cytotoxicity profiles of these compounds showed no significant toxicity to human cells and they exhibited anti-HIV-1 activity with EC50 values ranging from 90 to 155 M. Compound 5j bearing 4-methylbenzylidene group was found to be the most active compound with EC50 = 90 M and selectivity index, CC50/EC50 = 6.4. Molecular modeling studies indicated the capacity of compound 5j to interact with two Mg2+ cations and several residues that are important in HIV-1 integrase inhibition. These findings suggested that pyridopyrimidine-5-carbohydrazide scaffold might become a promising template for development of novel anti-HIV-1 agents.

Keywords

Main Subjects


(1) Organization WH. HIV/AIDS. 2017 [cited; Available
from: http://www.who.int/hiv/data/en/.
(2) AIDS H-CCJ. The effect of combined antiretroviral
therapy on the overall mortality of HIV-infected
individuals. AIDS (2010) 24: 123-37.
(3) Cohen MS, Chen YQ, McCauley M, Gamble T,
Hosseinipour MC, Kumarasamy N, Hakim JG,
Kumwenda J, Grinsztejn B and Pilotto JH. Prevention
of HIV-1 infection with early antiretroviral therapy.
N Engl. J. Med. (2011) 365: 493-505.
(4) Sun L, Gao P, Dong G, Zhang X, Cheng X, Ding
X, Wang X, Daelemans D, De Clercq E and
Pannecouque C. 5-Hydroxypyrido [2,3-b] pyrazin6(5H)-one derivatives as novel dual inhibitors of
HIV-1 reverse transcriptase-associated ribonuclease
H and integrase. Eur. J. Med. Chem. (2018) 155:
714-24.
 (5) Zhan P, Pannecouque C, De Clercq E and Liu X.
Anti-HIV drug discovery and development: current
innovations and future trends: miniperspective. J.
Med. Chem. (2015) 59: 2849-78.
(6) Delelis O, Carayon K, Saïb A, Deprez E and
Mouscadet J-F. Integrase and integration: biochemical
activities of HIV-1 integrase. Retrovirology (2008) 5:
114.
(7) Hazuda DJ. HIV integrase as a target for antiretroviral
therapy. Curr. Opin. HIV AIDS. (2012) 7: 383-9.
(8) Lesbats P, Engelman AN and Cherepanov P.
Retroviral DNA integration. Chem. Rev. (2016) 116:
12730-57.
(9) Wang Y, Rong J, Zhang B, Hu L, Wang X and Zeng
C. Design and synthesis of N-methylpyrimidone
derivatives as HIV-1 integrase inhibitors. Bioorg.
Med. Chem. (2015) 23: 735-41.
(10) Hajimahdi Z and Zarghi A. Progress in HIV-1
integrase inhibitors: A review of their chemical
structure diversity. Iran. J. Pharm. Res. (2016) 15:
595-628.
(11) Boros EE, Edwards CE, Foster SA, Fuji M,
Fujiwara T, Garvey EP, Golden PL, Hazen RJ,
Jeffrey JL and Johns BA. Synthesis and Antiviral
Activity of 7-Benzyl-4-hydroxy-1,5-naphthyridin2(1H)-one HIV Integrase Inhibitors. J. Med. Chem.
(2009) 52: 2754-61.
(12) Johnson TW, Tanis SP, Butler SL, Dalvie D,
DeLisle DM, Dress KR, Flahive EJ, Hu Q, Kuehler
JE and Kuki A. Design and synthesis of novel
N-hydroxy-dihydronaphthyridinones as potent and
orally bioavailable HIV-1 integrase inhibitors. J.
Med. Chem. (2011) 54: 3393-417.
(13) Pace P, Di Francesco ME, Gardelli C, Harper
S, Muraglia E, Nizi E, Orvieto F, Petrocchi A,
Poma M and Rowley M. Dihydroxypyrimidine-4-
carboxamides as novel potent and selective HIV
integrase inhibitors. J. Med. Chem. (2007) 50:
2225-39.
(14) Cocohoba J and Dong BJ. Raltegravir: the first HIV
integrase inhibitor. Clin. Ther. (2008) 30: 1747-65.
(15) Kawasuji T, Johns BA, Yoshida H, Taishi T, Taoda
Y, Murai H, Kiyama R, Fuji M, Yoshinaga T and
Seki T. Carbamoyl pyridone HIV-1 integrase
inhibitors. 1. Molecular design and establishment
of an advanced two-metal binding pharmacophore.
J. Med. Chem. (2012) 55: 8735-44.
(16) Kawasuji T, Johns BA, Yoshida H, Weatherhead
JG, Akiyama T, Taishi T, Taoda Y, MikamiyamaIwata M, Murai H, Kiyama R, Fuji M, Tanimoto
N, Yoshinaga T, Seki T, Kobayashi M, Sato A,
Garvey EP and Fujiwara T. Carbamoyl Pyridone
HIV-1 Integrase Inhibitors. 2. Bi- and Tricyclic
Derivatives Result in Superior Antiviral and
Pharmacokinetic Profiles. J. Med. Chem. (2013)
56: 1124-35.
(17) Shimura K and Kodama EN. Elvitegravir: a new
HIV integrase inhibitor. Antivir. Chem. Chemother.
(2009) 20: 79-85.
 (18) Hare S, Maertens GN and Cherepanov P. 3′‐
Processing and strand transfer catalysed by
retroviral integrase in crystallo. EMBO J. (2012)
31: 3020-8.
(19) Hare S, Gupta SS, Valkov E, Engelman A and
Cherepanov P. Retroviral intasome assembly and
inhibition of DNA strand transfer. Nature (2010)
464: 232-236.
(20) Krapf MK, Gallus J, Vahdati S and Wiese M.
New Inhibitors of Breast Cancer Resistance
Protein (ABCG2) Containing a 2,4-Disubstituted
Pyridopyrimidine Scaffold. J. Med. Chem. (2018)
61: 3389-408.
247
N'-Arylidene-pyrido[2,3-d]pyrimidine-5-carbohydrazide Derivatives as Anti-HIV-1 Agents
(21) Hou J, Wan S, Wang G, Zhang T, Li Z, Tian Y, Yu
Y, Wu X and Zhang J. Design, synthesis, anti-tumor
activity, and molecular modeling of quinazoline
and pyrido[2,3-d]pyrimidine derivatives targeting
epidermal growth factor receptor. Eur. J. Med.
Chem. (2016) 118: 276-89.
(22) Chan J, Burke BJ, Baucom K, Hansen K, Bio
MM, DiVirgilio E, Faul M and Murry J. Practical
Syntheses of a CXCR3 Antagonist. J. Org. Chem.
(2011) 76: 1767-74.
(23) Satasia SP, Kalaria PN and Raval DK. Catalytic
regioselective synthesis of pyrazole based
pyrido[2,3-d]pyrimidine-diones and their
biological evaluation. Org. Biomol. Chem. (2014)
12: 1751-8.
(24) Farghaly TA and Hassaneen HME. Synthesis of
pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin5-ones as potential antimicrobial agents. Arch.
Pharmacal Res. (2013) 36: 564-72.
(25) Mohamed NR, El-Saidi MMT, Ali YM and
Elnagdi MH. Utility of 6-amino-2-thiouracil as a
precursor for the synthesis of bioactive pyrimidine
derivatives. Bioorg. Med. Chem. (2007) 15: 6227-
35.
(26) Lazerwith SE, Bahador G, Canales E, Cheng G,
Chong L, Clarke MO, Doerffler E, Eisenberg EJ,
Hayes J, Lu B, Liu Q, Matles M, Mertzman M,
Mitchell ML, Morganelli P, Murray BP, Robinson
M, Strickley RG, Tessler M, Tirunagari N, Wang J,
Wang Y, Zhang JR, Zheng X, Zhong W and Watkins
WJ. Optimization of Pharmacokinetics through
Manipulation of Physicochemical Properties in a
Series of HCV Inhibitors. ACS Med. Chem. Lett.
(2011) 2: 715-9.
(27) Velthuisen EJ, Johns BA, Gerondelis P, Chen
Y, Li M, Mou K, Zhang W, Seal JW, Hightower
KE, Miranda SR, Brown K and Leesnitzer L.
Pyridopyrimidinone inhibitors of HIV-1 RNase H.
Eur. J. Med. Chem. (2014) 83: 609-16.
(28) Donghi M, Kinzel OD and Summa V. 3-Hydroxy4-oxo-4H-pyrido [1,2-a] pyrimidine-2-
carboxylates—A new class of HIV-1 integrase
inhibitors. Bioorg. Med. Chem. Lett. (2009) 19:
1930-4.
(29) Hong H, Neamati N, Wang S, Nicklaus MC,
Mazumder A, Zhao H, Burke TR, Pommier Y
and Milne GWA. Discovery of HIV-1 Integrase
Inhibitors by Pharmacophore Searching. J. Med.
Chem. (1997) 40: 930-6.
(30) Yang L, Wang P, Wu J-F, Yang L-M, Wang R-R,
Pang W, Li Y-G, Shen Y-M, Zheng Y-T and Li
X. Design, synthesis and anti-HIV-1 evaluation
of hydrazide-based peptidomimetics as selective
gelatinase inhibitors. Bioorg. Med. Chem. (2016)
24: 2125-36.
(31) Trott O and Olson AJ. AutoDock Vina: improving
the speed and accuracy of docking with a new
scoring function, efficient optimization, and
multithreading. J. Comput. Chem. (2010) 31: 455-
61.
(32) Morris GM, Goodsell DS, Halliday RS, Huey R,
Hart WE, Belew RK and Olson AJ. Automated
Docking Using a Lamarckian Genetic Algorithm
and and Empirical Binding Free Energy Function.
J. Comput. Chem. (1998) 19: 1639-62.
(33) HyperChem(TM) Professional 8.0, Hypercube,
Inc., 1115 NW 4th Street, Gainesville, Florida
32601, USA.
(34) Hajimahdi Z, Ranjbar A, Suratgar AA and Zarghi
A. QSAR Study on anti-HIV-1 activity of 4-oxo1,4-dihydroquinoline and 4-oxo-4H-pyrido[1,2-a]
pyrimidine derivatives using SW-MLR, artificial
neural network and filtering methods. Iran. J.
Pharm. Res. (2015) 14 (Supplement): 69-75.
(35) Hajimahdi Z, Zabihollahi R, Aghasadeghi MR,
Ashtiani SH and Zarghi A. Novel quinolone-3-
carboxylic acid derivatives as anti-HIV-1 agents:
design, synthesis, and biological activities. Med.
Chem. Res. (2016) 25: 1861–76.
(36) Hajimahdi Z, Zabihollahi R, Aghasadeghi MR and
Zarghi A. Design, synthesis and docking studies
of new 4-hydroxyquinoline-3-carbohydrazide
derivatives as anti-HIV-1 agents. Drug Res. (2013)
63: 192–7.
(37) Hajimahdi Z, Zarghi A, Zabihollahi R and
Aghasadeghi MR. Synthesis, biological
evaluation, and molecular modeling studies of new
1,3,4-oxadiazole- and 1,3,4-thiadiazole-substituted
4-oxo-4H-pyrido[1,2-a]pyrimidines as anti-HIV-1
agents. Med. Chem. Res. (2013) 22: 2467–75.
(38) Parizadeh N, Alipour E, Soleymani S, Zabihollahi
R, Aghasadeghi MR, Hajimahdi Z and Zarghi A.
Synthesis of novel 3-(5-(alkyl/arylthio)-1,3,4-
oxadiazol-2-yl)-8-phenylquinolin-4(1H)-one
derivatives as anti-HIV agents. Phosphorus Sulfur
Silicon Relat. Elem. (2018) 193: 225-31.
(39) Safakish M, Hajimahdi Z, Zabihollahi R,
Aghasadeghi MR, Vahabpour R and Zarghi A.
Design, synthesis, and docking studies of new
2-benzoxazolinone derivatives as anti-HIV-1
agent. Med. Chem. Res. (2017) 26: 2718–26.
(40) Livani ZA, Safakish M, Hajimahdi Z, Soleymani
S, Zabihollahi R, Aghasadeghi MR, Alipour E and
Zarghi A. Design, synthesis, molecular modeling,
in silico ADME studies and anti-HIV-1 assay of
new diazocoumarin derivatives. Iran. J. Pharm.
Res. (2018) 17: 65-77.
(41) Lin C-C, Cheng H-Y, Yang C-M and Lin T-C. 
248
Ebrahimzadeh E et al. / IJPR (2019), 18 (Special Issue): 237-248
Antioxidant and antiviral activities of Euphorbia
thymifolia L. J. Biomed. Sci. (2002) 9: 656–64.
(42) Scudiero DA, Shoemaker RH, Paull KD, Monks
A, Tierney S, Nofziger TH, Currens MJ, Seniff D
and Boyd MR. Evaluation of a soluble tetrazolium/
formazan assay for cell growth and drug sensitivity
in culture using human and other tumor cell lines.
Cancer Res. (1988) 48: 4827-33.
(43) Scudiero DA, Shoemaker RH, Paull KD, Monks A,
Tierney S, Nofziger TH, Currens MJ, Seniff D and
Boyd MR. Evaluation of a Soluble Tetrazolium/
Formazan Assay for Cell Growth and Drug
Sensitivity in Culture Using Human and Other
Tumor Cell Lines. Cancer Res. (1988) 48: 4827-
33.
(44) Mahboubi Rabbani SMI, Vahabpour R, Hajimahdi
Z and Zarghi A. Design, Synthesis, Molecular
Modeling Studies and Biological Evaluation of
N′-Arylidene-6-(benzyloxy)-4-oxo-1,4-dihydroquinoline-3- carbohydrazide Derivatives as Novel
Anti-HCV Agents. Iran. J. Pharm. Res. (2019) 18:
1790-802.
(45) Valkov E, Gupta SS, Hare S, Helander A, Roversi
P, McClure M and Cherepanov P. Functional and
structural characterization of the integrase from the
prototype foamy virus. Nucleic Acids Res. (2009)
37: 243-55.
(46) Faghihi K, Safakish M, Zebardast T, Hajimahdi
Z and Zarghi A. Molecular Docking and QSAR
Study of 2-Benzoxazolinone, Quinazoline and
Diazocoumarin Derivatives as Anti-HIV-1 Agents.
Iran. J. Pharm. Res. (2019) 18: 1253-63.
(47) Hajimahdi Z, Zabihollahi R, Aghasadeghi MR and
Zarghi A. Design, Synthesis, Docking Studies
and Biological Activities Novel 2,3-Diaryl-4-
Quinazolinone Derivatives as Anti-HIV-1 Agents.
Curr. HIV Res. (2019) 17: 214-22.