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List of Chronobiotics



Name SMILES FDA Status Effects Targets Mechanisms Articles
CC1=CC2=C(C=C1Cl)N=C(S2)NC(=O)CC3=CC=CC=C3 Not approved Period lengthening in human cells (U2OS) CK1δ Inhibits casein kinase 1 delta (CKIδ) activity Lee, J.W., Hirota, T., Peters, E.C., Garcia, M., Gonzalez, R., Cho, C.Y., Wu, X., Schultz, P.G. and Kay, S.A., 2011. A small molecule modulates circadian rhythms through phosphorylation of the period protein. Angewandte Chemie (International ed. in English), 50(45), p.10608. , Ray, S., Lach, R., Heesom, K.J., Valekunja, U.K., Encheva, V., Snijders, A.P. and Reddy, A.B., 2019. Phenotypic proteomic profiling identifies a landscape of targets for circadian clock–modulating compounds. Life Science Alliance, 2(6).
[2H]C([2H])([2H])C(=O)NCCC1=CC=CC2=C1C=C(C=C2)OC Approved Phase shifting in humans (via MT1/MT2 receptor activation) Melatonin receptor Melatonin receptor binding Russak, E.M. and Bednarczyk, E.M., 2019. Impact of deuterium substitution on the pharmacokinetics of pharmaceuticals. Annals of Pharmacotherapy, 53(2), pp.211–216. , Audinot, V., Mailliet, F., Lahaye-Brasseur, C., Bonnaud, A., Le Gall, A., Amossé, C., Dromaint, S., Rodriguez, M., Nagel, N., Galizzi, J.P., Malpaux, B., Guillaumet, G., Lesieur, D., Lefoulon, F., Renard, P., Delagrange, P. and Boutin, J.A., 2003. New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn-Schmiedeberg's Archives of Pharmacology, 367(6), pp.553–561.
C1=CC(=O)C2=NC=CN=C2C1=O Not approved Transcriptional inhibition of BMAL1–CLOCK complex in human cells CLOCK-BMAL1 Targets BMAL1–CLOCK DNA-binding activity Hosoya, Y., Nojo, W., Kii, I., Suzuki, T., Imanishi, M. and Ohkanda, J., 2020. Identification of synthetic inhibitors for the DNA binding of intrinsically disordered circadian clock transcription factors. Chemical Communications, 56(76), pp.11203-11206.
C1=CC(=CC=C1C(=O)NC2=CC=C(C=C2)C(C(F)(F)F)(C(F)(F)F)O)C(F)(F)F Not approved It affects circadian rhythms by activating RORα/γ, which in turn regulates the transcription of target genes, including the core clock component BMAL1 RORα ROR Wang, Y., Kumar, N., Nuhant, P., Cameron, M.D., Istrate, M.A., Roush, W.R., Griffin, P.R. and Burris, T.P., 2010. Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORα and RORγ. ACS chemical biology, 5(11), pp.1029-1034. , Wang, Y., Kumar, N., Nuhant, P., Cameron, M. D., Istrate, M. A., Roush, W. R., Griffin, P. R., & Burris, T. P. (2010). Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORα and RORγ. ACS Chemical Biology, 5(11), 1029–1034
CC1=CN=C(N1)C2=CN=C(N=C2C3=C(C=C(C=C3)Cl)Cl)NCCNC4=NC=C(C=C4)C# N none disrupts glioblastoma clock, Per2 disruption affected both GBM migration and cell cycle progression. GSK-3α/β Highly selective, ATP-competitive inhibition of GSK-3 (both α and β isoforms), GSK‑3 Inhibition, Selective GSK-3β Inhibition:, inhibits glycogen synthase kinase-3β (GSK-3β) Wagner, P.M., Fornasier, S.J. and Guido, M.E., 2024. Pharmacological modulation of the cytosolic oscillator affects glioblastoma cell biology. Cellular and Molecular Neurobiology, 44(1), p.51.
CN1C2CCC1C(C(C2)OC(=O)C3=CC=CC=C3)C(=O)OC Not approved inhibition of photic phase shifts in mice (SCN-dependent) SEROTONIN TRANSPORTER , PPAR gamma , D2R (dopamine receptor) Core clock modulation, Unknown, Dopamine receptor binding Prosser, R.A., Stowie, A., Amicarelli, M., Nackenoff, A.G., Blakely, R.D. and Glass, J.D., 2014. Cocaine modulates mammalian circadian clock timing by decreasing serotonin transport in the SCN. Neuroscience, 275, pp.184–193 , Wang, D.Q., Wang, X.L., Wang, C.Y., Wang, Y., Li, S.X. and Liu, K.Z., 2019. Effects of chronic cocaine exposure on the circadian rhythmic expression of the clock genes in reward-related brain areas in rats. Behavioural Brain Research, 363, pp.61–69.
CCOC(CC1=CC(=CC=C1)C(=NOCC2=CC=C(C=C2)Br)C)C(=O)O Not approved CRY1/2 inhibition, decreased the amplitude of circadian rhythm significantly while having no effect on the period CRY1-PER2 complex , CRY1 , CRY2 Binds CRY1 FAD-binding, CRY1/2 inhibitor, Activation of CLOCK/Bmal1 mediated transcription Chun, S.K., Jang, J., Chung, S., Yun, H., Kim, N.J., Jung, J.W., Son, G.H., Suh, Y.G. and Kim, K., 2014. Identification and validation of cryptochrome inhibitors that modulate the molecular circadian clock. ACS chemical biology, 9(3), pp.703-710. , 전승국, 2014. Development of circadian clock modulator and its application (Doctoral dissertation, 서울대학교 대학원). , Jang, J., Chung, S., Choi, Y., Lim, H.Y., Son, Y., Chun, S.K., Son, G.H., Kim, K., Suh, Y.G. and Jung, J.W., 2018. The cryptochrome inhibitor KS15 enhances E-box-mediated transcription by disrupting the feedback action of a circadian transcription-repressor complex. Life sciences, 200, pp.49-55. , Solovev, I.A., Shaposhnikov, M.V. and Moskalev, A.A., 2021. Chronobiotics KL001 and KS15 extend lifespan and modify circadian rhythms of Drosophila melanogaster. Clocks & Sleep, 3(3), pp.429-441.
CC12CCC3C(C1CCC2=O)CC=C4C3(CCC(C4)O)C Approved Recent reports, however, have shown that high doses of DHEA (e.g., 100 μM) lengthen circadian period and decrease amplitude NMDA receptor modulation of nuclear receptor signaling pathways Tamai, T.K., Nakane, Y., Ota, W., Kobayashi, A., Ishiguro, M., Kadofusa, N., Ikegami, K., Yagita, K., Shigeyoshi, Y., Sudo, M. and Nishiwaki‐Ohkawa, T., 2018. Identification of circadian clock modulators from existing drugs. EMBO molecular medicine, 10(5), p.e8724. , Rey, G., Valekunja, U.K., Feeney, K.A., Wulund, L., Milev, N.B., Stangherlin, A., Ansel-Bollepalli, L., Velagapudi, V., O’Neill, J.S. and Reddy, A.B., 2016. The pentose phosphate pathway regulates the circadian clock. Cell metabolism, 24(3), pp.462-473. , Putker, M., Crosby, P., Feeney, K.A., Hoyle, N.P., Costa, A.S., Gaude, E., Frezza, C. and O'Neill, J.S., 2018. Mammalian circadian period, but not phase and amplitude, is robust against redox and metabolic perturbations. Antioxidants & Redox Signaling, 28(7), pp.507-520. , Tamai, T. K., Nakane, Y., Ota, W., Kobayashi, A., Ishiguro, M., Kadofusa, N., Ikegami, K., Yagita, K., Shigeyoshi, Y., Sudo, M., Nishiwaki-Ohkawa, T., Sato, A., & Yoshimura, T. (2018). Identification of circadian clock modulators from existing drugs. EMBO Molecular Medicine, 10(5), e8724.
CC1=C(C(CCC1)(C)C)/C=C/C(=C/C=C/C(=C/C(=O)O)/C)/C Approved Circadian modulation in human U2OS cells CLOCK-BMAL1 , Arntl (gene) , BMAL1 expression (induction) Bmal1, de-repressing BMAL1, BMAL1 expression modulation, BMAL1 expression modulation, Retinoic acid receptor RXR-alpha, beta, gamma binding, Binding retinoic acid receptor alpha Tamai, T.K., Nakane, Y., Ota, W., Kobayashi, A., Ishiguro, M., Kadofusa, N., Ikegami, K., Yagita, K., Shigeyoshi, Y., Sudo, M. and Nishiwaki‐Ohkawa, T., 2018. Identification of circadian clock modulators from existing drugs. EMBO molecular medicine, 10(5), p.e8724.
CC1=C(C=C(C=C1)NC2=NC=CC(=N2)N(C)C3=CC4=NN(C(=C4C=C3)C)C)S(=O)(=O)N.Cl Approved Circadian modulation in human U2OS cells CLOCK-BMAL1 , Arntl (gene) , BMAL1 expression (induction) Bmal1, de-repressing BMAL1, BMAL1 expression modulation, BMAL1 expression modulation, Vascular endothelial growth factor receptor 1, 2, 3, Platelet-derived growth factor receptor alpha, beta, Mast/stem cell growth factor receptor Kit, Fibroblast growth factor receptor 3, Tyrosine-protein kinase ITK/TSK, Fibroblast growth factor 1, SH2B adapter protein 3 Tamai, T.K., Nakane, Y., Ota, W., Kobayashi, A., Ishiguro, M., Kadofusa, N., Ikegami, K., Yagita, K., Shigeyoshi, Y., Sudo, M. and Nishiwaki‐Ohkawa, T., 2018. Identification of circadian clock modulators from existing drugs. EMBO molecular medicine, 10(5), p.e8724.
C1=CC=C(C=C1)S(=O)(=O)N(CC(F)(F)F)C2=CC=C(C=C2)C(C(F)(F)F)(C(F)(F)F)O Not approved Circadian modulation via nuclear receptor pathways (LXRα/β) in mammalian cells Liver X receptors LXRα, LXRβ Ribeiro, R.F., Cavadas, C. and Silva, M.M.C., 2021. Small-molecule modulators of the circadian clock: Pharmacological potentials in circadian-related diseases. Drug Discovery Today, 26(7), pp.1620-1641. , Gbaguidi, G.F. and Agellon, L.B., 2004. The inhibition of the human cholesterol 7α‐hydroxylase gene (CYP7A1) promoter by fibrates in cultured cells is mediated via the liver x receptor α and peroxisome proliferator‐activated receptor α heterodimer. Nucleic acids research, 32(3), pp.1113-1121. , Feillet, C., Guérin, S., Lonchampt, M., Dacquet, C., Gustafsson, J.Å., Delaunay, F. and Teboul, M., 2016. Sexual Dimorphism in Circadian Physiology Is Altered in LXR α Deficient Mice. PLoS One, 11(3), p.e0150665. , Ribeiro, R. F. N., Cavadas, C., & Silva, M. M. C. (2021). Small-molecule modulators of the circadian clock: Pharmacological potentials in circadian-related diseases. Drug Discovery Today, 26(7), 1620–1641.
CN1C2=C(C(=O)N(C1=O)C)NC=N2.CN1C2=C(C(=O)N(C1=O)C)NC=N2.C(CN)N Approved Period lengthening in fungi Adenosine A1, A2A, A2B, and A3 Receptors cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A Inhibitor, Adenosine receptor A1Antagonist, cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A, Adenosine receptor A3Antagonist Olivares-Yañez, C., Alessandri, M.P., Salas, L. and Larrondo, L.F., 2023. Methylxanthines modulate circadian period length independently of the action of phosphodiesterase. Microbiology Spectrum, 11(4), pp.e03727-22. , Manrui, L., Xu, Y., Liu, J., Zhang, X., Yuan, R., Sun, Y., Sun, Y., Yang, Q., Liao, M., Lv, M. and Hu, X., 2025. Aminophylline targets miR-128-3p/Slc7a11 axis to attenuate neuronal ferroptosis after traumatic brain injury. Cellular and Molecular Life Sciences, 82(1), pp.1-23.
CC1=C(C=C(C=C1)C(=O)NC2=CC(=CC(=C2)C(F)(F)F)N3C=C(N=C3)C)NC4=NC=CC(=N4)C5=CN=CC=C5 Approved Circadian gene expression modulation in human cells (U2OS) CLOCK-BMAL1 , Arntl (gene) , BMAL1 expression (induction) , Tyrosine proteine kinase ABL1 Bmal1, de-repressing BMAL1, BMAL1 expression modulation, BMAL1 expression modulation, "Tyrosine-protein kinase ABL1 Mast/stem cell growth factor receptor binding Tamai, T.K., Nakane, Y., Ota, W., Kobayashi, A., Ishiguro, M., Kadofusa, N., Ikegami, K., Yagita, K., Shigeyoshi, Y., Sudo, M. and Nishiwaki‐Ohkawa, T., 2018. Identification of circadian clock modulators from existing drugs. EMBO molecular medicine, 10(5), p.e8724.
CC(=O)NCCC1=C(NC2=CC=CC=C21)CC3=CC=CC=C3 not approved Phase shift disruption in animals Melatonin receptor Melatonin receptor binding, antagonist of melatonin receptors Dubocovich, M.L., 1988. Luzindole (N-0774): a novel melatonin receptor antagonist. Journal of Pharmacology and Experimental Therapeutics, 246(3), pp.902–910. , Estarás, M., Ameur, F.Z., Roncero, V., Fernández-Bermejo, M., Blanco, G., López, D., Mateos, J.M., Salido, G.M. and González, A., 2019. The melatonin receptor antagonist luzindole induces Ca²⁺ mobilization, reactive oxygen species generation and impairs trypsin secretion in mouse pancreatic acinar cells. Biochimica et Biophysica Acta (BBA) - General Subjects, 1863(11), p.129407.
CCCCCCC(C)(C)C1=CC(=C2C3CC(=O)CCC3C(OC2=C1)(C)C)O Approved Sleep improvement; potential indirect circadian stabilization via CB1 activation Cannabinoid receptor Cannabinoid receptor stimulation Peball, M., Heim, B., Carbone, F., Schorr, O., Werkmann, M., Ellmerer, P., Marini, K., Krismer, F., Knaus, H.G., Poewe, W., Djamshidian, A. and Seppi, K., 2024. Long-term safety and efficacy of open-label nabilone on sleep and pain in Parkinson’s disease. NPJ Parkinson’s Disease, 10(1), p.61.
CCC(=O)NCCC1CCC2=C1C3=C(C=C2)OCC3 Approved Phase advance in humans, 5-h phase advance in the sleep-wake cycle Melatonin receptor Melatonin receptor binding Richardson, G.S., Zee, P.C., Wang-Weigand, S., Rodriguez, L. and Peng, X., 2008. Circadian phase-shifting effects of repeated ramelteon administration in healthy adults. Journal of Clinical Sleep Medicine, 4(5), pp.456–461. , Takeshima, M., Shimizu, T., Ishikawa, H. and Kanbayashi, T., 2020. Ramelteon for delayed sleep-wake phase disorder: a case report. Clinical Psychopharmacology and Neuroscience, 18(1), pp.167–169. , Zammit, G.K., 2007. Ramelteon: a novel hypnotic indicated for the treatment of insomnia. Psychiatry (Edgmont), 4(9), pp.36–42.
CC(=O)N1CCCC(C1)C2=CNC3=C2C=C(C=C3)OC Not approved Circadian disruption via melatonin receptor antagonism Melatonin receptor Melatonin receptor antagonist Teh, M.T. and Sugden, D., 1999. The putative melatonin receptor antagonist GR128107 is a partial agonist on Xenopus laevis melanophores. British Journal of Pharmacology, 126(5), pp.1237–1245. , Teh, M.T. and Sugden, D., 1999. The putative melatonin receptor antagonist GR128107 is a partial agonist on Xenopus laevis melanophores. British Journal of Pharmacology, 126(5), pp.1237–1245.
CC(=O)NCCC1=CNC2=C1C=C(C=C2)OC Approved restores normal circadian rhythms T58921 Peroxisome proliferator-activated receptor gamma (PPAR-gamma) , Melatonin receptor , MT3 , MT1 , MT2 , RORα , Mel1C , CAND2 , VDR , QR2 , MMP9 , PEPSIN , PP2A , mPTP , PEPT1 , PEPT2 , GLUT1 , HBS , CaM , TUBULIN , Calreticulin SIRT1, Melatonin receptor binding, ROR, RORγ binding, RORyt/RORc inhibitor, Melatonin receptor agonist, Antioxidant Arendt, J. and Skene, D.J., 2005. Melatonin as a chronobiotic. Sleep Medicine Reviews, 9(1), pp.25–39. , Pévet, P., Bothorel, B., Slotten, H. and Saboureau, M., 2002. The chronobiotic properties of melatonin. Cell and Tissue Research, 309, pp.183–191. , Cardinali, D.P., 2024. Melatonin as a chronobiotic/cytoprotective agent in bone. Doses involved. Journal of Pineal Research, 76(1), p.e12931.
C1=CC(=CC=C1/C=C/C2=CC(=CC(=C2)O)O)O Approved Resveratrol can influence the expression of key clock genes like CLOCK, BMAL1, PER, and CRY, which are involved in establishing and maintaining the 24 T60529 , MTOR (Human) , CLOCK-BMAL1 COMPLEX SIRT1, mTOR signaling inhibition, Serine/threonine-protein kinase mTOR, Altering Circadian Metabolism via the SIRT1-AMPK-PP2A Axis, Repression of PER/CRY feedback loops via deacetylation., AMPK-PP2A axis suppresses mTOR, advancing circadian phase in muscle. Sun, L., Wang, Y., Song, Y., Cheng, X.R., Xia, S., Rahman, M.R., Shi, Y. and Le, G., 2015. Resveratrol restores the circadian rhythmic disorder of lipid metabolism induced by high-fat diet in mice. Biochemical and Biophysical Research Communications, 458(1), pp.86–91. , Spaleniak, W. and Cuendet, M., 2023. Resveratrol as a circadian clock modulator: mechanisms of action and therapeutic applications. Molecular Biology Reports, 50, pp.6159–6170. , Avital-Cohen, N., Chapnik, N. and Froy, O., 2024. Resveratrol induces myotube development by altering circadian metabolism via the SIRT1-AMPK-PP2A axis. Cells, 13, p.1069.
CC(=O)NCC1CC2=CC=CC=C2CC3=C1C=C(C=C3)OC not approved Phase shift disruption in mammals Melatonin receptor antagonist of melatonin receptors Spadoni, G., Bedini, A., Diamantini, G., Tarzia, G., Rivara, S., Lorenzi, S., Lodola, A., Mor, M., Lucini, V., Pannacci, M., Caronno, A. and Fraschini, F., 2007. Synthesis, enantiomeric resolution, and structure–activity relationship study of a series of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene MT2 receptor antagonists. ChemMedChem, 2(12), pp.1741–1749. , Lucini, V., Pannacci, M., Scaglione, F., Fraschini, F., Rivara, S., Mor, M., Bordi, F., Plazzi, P.V., Spadoni, G., Bedini, A., Piersanti, G., Diamantini, G. and Tarzia, G., 2004. Tricyclic alkylamides as melatonin receptor ligands with antagonist or inverse agonist activity. Journal of Medicinal Chemistry, 47(17), pp.4202–4212.
CC(NC([2H])([2H])C([2H])([2H])C1=CNC2=C1C=C(OC)C=C2)=O Approved Phase shift induction in mammals via MT1/MT2 receptor agonism MT1 , MT2 Melatonin receptor binding González, S., Moreno-Delgado, D., Moreno, E., Pérez-Capote, K., Franco, R., Mallol, J., Cortés, A., Casadó, V., Lluís, C., Ortiz, J., Ferré, S., Canela, E. and McCormick, P.J., 2012. Circadian-related heteromerization of adrenergic and dopamine D₄ receptors modulates melatonin synthesis and release in the pineal gland. PLoS Biology, 10(6), p.e1001347.
CC(=O)NCCC1=C(NC2=C1C=C(C=C2)OC)I not approved Phase shift induction in mammals via MT1/MT2 receptor agonism MT1 , MT2 SIRT1, Melatonin receptor binding, MT2 receptor antagonist, MT1 receptor binding Masana, M.I., Benloucif, S. and Dubocovich, M.L., 2000. Circadian rhythm of MT1 melatonin receptor expression in the suprachiasmatic nucleus of the C3H/HeN mouse. Journal of Pineal Research, 28(3), pp.185–192. , Larson-Prior, L.J., Siuciak, J.A. and Dubocovich, M.L., 1996. Localization of 2-[¹²⁵I]iodomelatonin binding sites in visual areas of the turtle brain. European Journal of Pharmacology, 297(1–2), pp.181–185.
CCC(=O)NC1CCC2=C(C1)C(=CC=C2)OC Not approved Phase shift modulation in mammals via selective MT2 receptor agonism MT2 MT2 receptor ligand Mendoza-Vargas, L., Solís-Chagoyán, H., Benítez-King, G. and Fuentes-Pardo, B., 2009. MT2-like melatonin receptor modulates amplitude receptor potential in visual cells of crayfish during a 24-hour cycle. Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 154(4), pp.486–492. , Ambriz-Tututi, M. and Granados-Soto, V., 2007. Oral and spinal melatonin reduces tactile allodynia in rats via activation of MT2 and opioid receptors. Pain, 132(3), pp.273–280.
CC(=O)NCCC1=CC=CC2=C1C=C(C=C2)OC Aapproved Phase shift in humans via MT1/MT2 receptor agonism, Agomelatine has been shown to induce robust circadian phase shifts, can improve sleep continuity and quality, shorten sleep latency (time it takes to fall asleep, advance the timing of sleep onset and other circadian rhythms like core body temperature and heart rate. Melatonin receptor antagonist of melatonin receptors Pandi-Perumal, S.R., Moscovitch, A., Srinivasan, V., Spence, D.W., Cardinali, D.P. and Brown, G.M., 2009. Bidirectional communication between sleep and circadian rhythms and its implications for depression: lessons from agomelatine. Progress in Neurobiology, 88(4), pp.264–271. , Tchekalarova, J., Stoynova, T., Ilieva, K., Mitreva, R. and Atanasova, M., 2018. Agomelatine treatment corrects symptoms of depression and anxiety by restoring the disrupted melatonin circadian rhythms of rats exposed to chronic constant light. Pharmacology Biochemistry and Behavior, 171, pp.1–9. , Souza, L.C., Martynhak, B.J., Bassani, T.B., Turnes, J.D.M., Machado, M.M., Moura, E., Andreatini, R. and Vital, M.A., 2018. Agomelatine's effect on circadian locomotor rhythm alteration and depressive-like behavior in 6-OHDA lesioned rats. Physiology & Behavior, 188, pp.298-310.
CC(NCCN1C2=CC(OC)=C(Cl)C=C2N=C1OC)=O not approved Circadian rhythm entrainment in diet-induced obese rats via MT1/MT2 agonism Melatonin receptor , MT1 , MT2 MT1 receptor binding, MT2 receptor ligand Ferreira, M.A. Jr, Azevedo, H., Mascarello, A., Segretti, N.D., Russo, E., Russo, V. and Guimarães, C.R.W., 2021. Discovery of ACH-000143: a novel potent and peripherally preferred melatonin receptor agonist that reduces liver triglycerides and steatosis in diet-induced obese rats. Journal of Medicinal Chemistry, 64(4), pp.1904–1929.