Development of adamantane scaffold containing 1,3,4-thiadiazole derivatives: Design, synthesis, anti-proliferative activity and molecular docking study targeting EGFR

https://doi.org/10.1016/j.bioorg.2021.104794Get rights and content

Highlights

  • New 1,3,4-Thiadiazolo-adamantane derivatives containing were synthetized.

  • In vitro anti-proliferative screening activity and SAR study were discussed.

  • Mitochondrial apoptosis pathway BAX and Bcl-2 proteins were evaluated.

  • Wide, mutant EGFR inhibitions, apoptosis and cell cycle analysis were determined.

  • Molecular docking and some physicochemical properties were performed.

Abstract

A new series of 1,3,4-thiadiazolo-adamantane derivatives were synthesized through molecular hybridization approach, then used as starting material to synthesize chloro and cyano acetamide-thiadiazole derivatives 2, 3. The newly designed compounds 13 were treated with different reagents to design 5-adamantyl thiadiazole derivatives 417 and evaluate their in vitro anti-proliferative activity against three cancer cell lines (MCF-7, HepG-2 and A549). Doxorubicin was used as a positive control. The most promising compounds 5, 6, 10a, 10b, 14b, 14c, and 17 showed up-regulation for BAX and down-regulation of Bcl-2, these findings proved their role as hopeful apoptotic inducers. In addition, the inhibitory activity against both wild EGFRWT and mutant EGFRL858R-TK for these derivatives revealed that compounds 5, 14c, and 17 have IC50 value ranging from 85 nM to 71.5 nM against wild EGFRWT and 37.85–41.19 nM against the mutant type, Lapatinib was used as a reference standard with IC50 values of 31.8 nM and 39.53 nM, respectively. The most potent derivatives were subjected to further evaluation against double mutant EGFR L858R/T790M and showed good IC50 values between (0.27–0.78 nM) compared to Lapatinib (0.18 nM) and Erlotinib (0.21 nM). Among them, thiazolo-thiadiazole adamantane derivative 17 exhibited the strongest inhibitory activity to the EGFR. Molecular docking studies were performed inside the active site of EGFR (1M17), and binding energy scores ranged between (−19.19 to –22.07 Kcal/mol) compared to Erlotinib (−19.10 Kcal/mol). Furthermore, oral bioavailability beside some pharmacokinetics properties of these derivatives were also investigated in this research work.

Graphical abstract

Plausible targets and the obtained results for the most promising three adamantane derivatives 5, 14c and 17 and Erlotinib.

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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.

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