Development of adamantane scaffold containing 1,3,4-thiadiazole derivatives: Design, synthesis, anti-proliferative activity and molecular docking study targeting EGFR
Graphical abstract
Plausible targets and the obtained results for the most promising three adamantane derivatives 5, 14c and 17 and Erlotinib.
Introduction
Cancer is emerging as one of the fastest-growing diseases in the world and a leading cause of death following cardiovascular diseases [1], [2], [3]. Cancer is the world's second-largest cause of death, accounting for 9.6 million deaths in 2018, with approximately one in nine deaths due to cancer [4], [5]. Current cancer care approaches include surgery, radiotherapy, and chemotherapy either alone or in combination, however, metastasis (spread of disease to other areas in the body) is still representing a challenge [6]. DNA-damaging agents, such as radiation and chemotherapeutic drugs, can induce programmed cell death (apoptosis) [7]. Many studies have shown a close association between increased anticancer drug resistance and decreased apoptosis capacity [8], [9], [10], [11], [12], [13]. Hence, inhibition of apoptosis will play a major role in cancer progression during carcinogenesis. There are different types of molecular pathways used by the cancer cells to inhibit apoptosis [12]. BAX and Bcl-2 are respectively apoptotic and anti-apoptotic proteins, and the ratio of those two proteins determines the frequency in apoptosis in cells [14], [15], [16], [17]. An important determinant of cell survival is the relationship between the apoptotic and anti-apoptotic levels [18]. EGFR belongs to a family of four related receptor tyrosine kinases including EGFR (HER1/ErbB1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4) that act as a key mediator in cell signaling pathways involving cell proliferation, apoptosis, angiogenesis, and metastatic spread [19], [20]. Although each member of the EGFR family is the potent mediator of normal cell growth and development, overexpression of EGFR appears in various human tumors [21], [22]. The advantage of the adamantyl group confers additional potency in drugs in which it was present. The property underlined was the lipophilicity of adamantane which increases the ease with, which the compound reaches the activity site as well as the bulkiness property that indicates a steric factor is also necessary at the activity site for the interactions[23]. Adamantane derivatives have several enticing pharmacological activities, such as antibacterial [24], [25], antifungal [26], antiviral [27], [28], [29], antidiabetic [30], carbonic anhydrase inhibitors [31], and anticancer effects [32], [33], [34], [35]. Amantadine and many similar compounds with three-dimensional ‘box-like’ adamantane structure are employed in the treatment of certain neurological disorders [36]. It was found that N-1-adamantylcitraconimide (ACI) (I), N-1-adamantylmaleimide (AMI) (II) and dimethyl adamantyl maleimide (DMAMI) (III) exhibited modest growth-inhibitory activity against four cancer cell lines (Colo 205, HepG-2, SK-BR-3 and Molt-4). Also, AMI was also successful in inhibiting the growth of both in vitro and in vivo human gastric cancer cells and induced in vitro apoptosis [37]. Dimethyl adamantyl maleimide (DMAMI), the AMI derivative, induces apoptosis and inhibits the development of human colon cancer Colo 205 in SCID mice [38]. In addition, 1,3,4-thiadiazoles are heterocyclic scaffolds found in several compounds that have various pharmacological activities as such as fungicidal [39], insecticidal [40], anticonvulsant [41], anti-tuberculosis [42], anticancer [43], [44], antiviral [45], antibacterial [46]. The wide range of pharmaceutically suitable biological activities is due to the existence of the NCS group, a hydrogen-binding domain with two-electron donor systems, as well as sulfur atom that enhances the liposolubility of the molecule [47], [48], [49]. The broad and wide biological activities of 1,3,4-thiadiazole derivatives are due to the aromaticity of the ring, which also provides great in vivo stability to this five-membered ring system and low toxicity for higher vertebrates, including human beings [50], [51] (Fig. 1).
Molecular hybridization has become an appealing technique for the rational design of anticancer agents with improved affinity and efficacy in comparison with parent drugs and increased activity [52]. The hybrid drug is a new term in development which involves combining two or more pharmaceutical cores to produce a new hybrid drug which can interact with multiple targets or minimize side effects using single-target agents [53], [54]. Based on the previous findings and our ongoing efforts to develop a new heterocyclic compound with biological activity [55], [56], [57], [58], [59]. It was conceived that binding more than one pharmacophores as adamantane and thiadiazole moieties to design one scaffold using drug design strategy would be of great interest developing potent anticancer agents as described previously [60], [61]. Nowadays, the creation of hybrid molecules is a phenomenon that aims to combine multiple pharmacophore fragments in the same molecule with different biological potentials [62], [63], [64], [65], [66], [67], [68], [84], [85]. Our study's rationale came up from the great importance and synthetic accessibility of adamantly-thiadiazole hybrids incorporating some amide, azomethane, amine, pyridine derivatives, and some new fused ring with thiadiazole as imidazo and pyrimidino derivatives. The synthesized derivatives were evaluated as anti-proliferative activity against three cell lines, mitochondrial apoptosis by regulating BAX and Bcl-2 proteins' expression, and EGFR inhibition. Besides, study cell cycle, apoptosis assay, and finally, some physicochemical and pharmacokinetic properties as well as molecular docking study for the most active derivatives were determined hoping to generate potential anticancer molecules.
Section snippets
Chemistry
The synthetic procedures adopted to obtain the target compounds are depicted in Scheme 1, Scheme 2, Scheme 3. The starting compound, 5-(adamantan-1-yl)-1,3,4-thiadiazol-2-amine (1) was prepared according to the previously reported procedure [69]. Thus, 2-aminothiadiazole derivative 1 was subjected to chloroacetylation through its reaction with chloroacetyl chloride in the presence of trimethylamine as a catalyst to afford the corresponding 2-chloro acetamide derivative 2. Structure of the
Conclusion
A novel series of twenty-one 1,3,4-thiadiazolo-adamantane derivatives were designed and synthetized starting from 5-(adamantan-1-yl)-1,3,4-thiadiazol-2-amine (1). The newly synthetized derivatives 2 to 17 were evaluated in vitro for their anti-proliferative activity against the selected three cancer cell lines. The structure of the new designed compounds was established and confirmed based on its elemental analysis and spectral data. Cytotoxic values showed a broad spectrum of the designed
Chemistry
Uncorrected melting points were recorded on digital Gallen Kamp MFB-595 instrument. The IR spectra (KBr) (cm−1) were measured on a Shimadzu 440 spectrophotometer.1H NMR spectra (δ, ppm) were obtained in deuterated dimethyl sulfoxide (DMSO–d6) and 13C NMR at 101 MHz, spectra were obtained on a Bruker spectrometer (400 MHz) spectrometer, using TMS as an internal standard; chemical shifts are reported as δ ppm units. The data were presented as follows: chemical shift, multiplicity (s = singlet,
CRediT authorship contribution statement
Mohammed M.S. Wassel: Conceptualization, Methodology, Investigation, Resources, Writing - original draft. Yousry A. Ammar: Conceptualization, Methodology, Software, Formal analysis, Writing - original draft, Writing - review & editing, Supervision, Project administration. Gameel A.M. Elhag Ali: Conceptualization, Methodology, Investigation, Resources, Writing - original draft, Supervision. Amany Belal: Methodology (Biology) and participation in the revise of manuscript. Ahmed B.M. Mehany:
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
Dr. Mohammed M. S. Wassel wants to thank Dr. Ahmed Ragab, lecturer of Organic Chemistry, Faculty of Science (Boys), Al-Azhar University, for his real sharing, valuable creative thoughts, honest advice, helpful supervision, sincere encouragement, and continual help throughout the development of this work. Besides, all authors thank Dr. Amany Belal and Dr. Ahmed B. M. Mehany for their efforts in the biological part (methodology) as well as their participation in revise of the manuscript.
References (85)
- et al.
Synthesis, theoretical, spectroscopic and electrochemical DNA binding investigations of 1, 3, 4-thiadiazole derivatives of ibuprofen and ciprofloxacin: cancer cell line studies
J. Photochem. Photobiol. B Biol.
(2018) - et al.
Structure-guided design of antibacterials that allosterically inhibit DNA gyrase
Bioorg. Med. Chem. Lett.
(2019) - et al.
Inhibiting the inhibitors: targeting anti-apoptotic proteins in cancer and therapy resistance
Drug Resist. Updat.
(2020) - et al.
Broad targeting of resistance to apoptosis in cancer, in
Semin. Cancer Biol.
(2015) - et al.
Expression and regulation of Bcl-2, Bcl-xl, and Bax correlate With p53 status and sensitivity to apoptosis in childhood acute lymphoblastic leukemia
Blood
(1997) - et al.
In vitro cytotoxic activity of thiazole-indenoquinoxaline hybrids as apoptotic agents, design, synthesis, physicochemical and pharmacokinetic studies
Bioorg. Chem.
(2020) - et al.
Design, synthesis, molecular docking and biological activity evaluation of some novel indole derivatives as potent anticancer active agents and apoptosis inducers
Bioorg. Chem.
(2019) - et al.
Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death
Cell
(1993) - et al.
A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy
Bioorg. Chem.
(2020) - et al.
5-Adamantan thiadiazole-based thiazolidinones as antimicrobial agents. Design, synthesis, molecular docking and evaluation
Bioorg. Med. Chem.
(2018)
Synthesis and antimicrobial activity of new adamantane derivatives
Farm.
Synthesis and antiviral activity evaluation of some new 6-substituted 3-(1-adamantyl)-1, 2, 4-triazolo [3, 4-b][1, 3, 4] thiadiazoles
Farm.
Synthesis, crystal structure, superoxide scavenging activity, anticancer and docking studies of novel adamantyl nitroxide derivatives
J. Mol. Struct.
Preparation and characterization of doxorubicin functionalized gold nanoparticles
Eur. J. Med. Chem.
Straightforward synthesis of 2-chloro-N-(5-(cyanomethyl)-1, 3, 4-thiadiazol-2-yl) benzamide as a precursor for synthesis of novel heterocyclic compounds with insecticidal activity
Synth. Commun.
Synthesis and biological evaluation of 5-fatty-acylamido-1, 3, 4-thiadiazole-2-thioglycosides
Bioorg. Med. Chem. Lett.
Synthesis and antiproliferative studies of 5-aryl-2-(3-thienylamino)-1, 3, 4-thiadiazoles
Bioorg. Med. Chem. Lett.
1, 3, 4-Oxadiazole, 1, 3, 4-thiadiazole and 1, 2, 4-triazole derivatives as potential antibacterial agents
Arab. J. Chem.
Synthesis and cytotoxicity of 3, 4-disubstituted-5-(3, 4, 5-trimethoxyphenyl)-4H-1, 2, 4-triazoles and novel 5, 6-dihydro-[1, 2, 4] triazolo [3, 4-b][1, 3, 4] thiadiazole derivatives bearing 3, 4, 5-trimethoxyphenyl moiety
Bioorg. Med. Chem. Lett.
Synthesis, characterization and anti cancer activity of some fluorinated 3, 6-diaryl-[1, 2, 4] triazolo [3, 4-b][1, 3, 4] thiadiazoles
Arab. J. Chem.
One-pot synthesis and anticancer studies of 2-arylamino-5-aryl-1, 3, 4-thiadiazoles
Bioorg. Med. Chem. Lett.
Rational approaches, design strategies, structure activity relationship and mechanistic insights for anticancer hybrids
Eur. J. Med. Chem.
Polypharmacology in HIV inhibition: can a drug with simultaneous action against two relevant targets be an alternative to combination therapy?
Eur. J. Med. Chem.
Design, synthesis, in vitro antimicrobial evaluation and molecular docking studies of indol-2-one tagged with morpholinosulfonyl moiety as DNA gyrase inhibitors
Bioorg. Chem.
Design, synthesis, antimicrobial activity and molecular docking studies of some novel di-substituted sulfonylquinoxaline derivatives
Bioorg. Chem.
European Journal of Medicinal Chemistry One-pot synthesis and molecular docking of some new spiropyranindol-2-one derivatives as immunomodulatory agents and in vitro antimicrobial potential with DNA gyrase inhibitor
Eur. J. Med. Chem.
A novel adamantane thiadiazole derivative induces mitochondria-mediated apoptosis in lung carcinoma cell line
Bioorg. Med. Chem.
Antimicrobial evaluation of thiadiazino and thiazolo quinoxaline hybrids as potential DNA gyrase inhibitors; design, synthesis, characterization and morphological studies
Bioorg. Chem.
Synthesis, antimicrobial and anti-inflammatory activities of novel 5-(1-adamantyl)-1, 3, 4-thiadiazole derivatives
Eur. J. Med. Chem.
Cyanoacetanilides intermediates in heterocyclic synthesis. Part 6: Preparation of some hitherto unknown 2-oxopyridine, bipyridine, isoquinoline and chromeno[3,4-c]pyridine containing sulfonamide moiety
Arab. J. Chem.
A new insight into the Pfitzinger reaction. A facile synthesis of 6-sulfamoylquinoline-4-carboxylic acids
Tetrahedron Lett.
Synthesis and anticancer activity of thiourea derivatives bearing a benzodioxole moiety with EGFR inhibitory activity, apoptosis assay and molecular docking study
Eur. J. Med. Chem.
Homogeneous time-resolved fluorescence and its applications for kinase assays in drug discovery
Anal. Biochem.
Novel Structural hybrids of quinolone and thiazole moieties: Synthesis and evaluation of antibacterial and antifungal activities with molecular modeling studies
Bioorganic Chemistry
Nutritional treatment improves the effectiveness of anti-cancer therapy
Nowotwory. J. Oncol.
Antiproliferative benzoindazolequinones as potential cyclooxygenase-2 inhibitors
Molecules
Global cancer statistics, GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
CA. Cancer J. Clin.
Integration of EMT and cellular survival instincts in reprogramming of programmed cell death to anastasis
Cancer Metastasis Rev.
CircRNAs in anticancer drug resistance: recent advances and future potential
Mol. Cancer.
Overcoming drug resistance by enhancing apoptosis of tumor cells
Curr. Cancer Drug Targets
Increased multi-drug resistance and reduced apoptosis in osteosarcoma side population cells are crucial factors for tumor recurrence
Exp. Ther. Med.
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