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List of Chronobiotics



Name SMILES FDA Status Effects Targets Mechanisms Articles
CC(=O)C1CCC2C1(CCC3C2CCC4=CC(=O)CCC34C)C Approved Progesterone regulates the expression of clock genes like PER1, which is crucial for circadian timing. CLOCK-BMAL1 , Arntl (gene) , BMAL1 expression (induction) , Progesterone receptor , Estrogen receptor alpha Bmal1, BMAL1 expression modulation, BMAL1 expression modulation, Progesterone receptor, Estrogen receptor alpha, Mineralocorticoid receptor, Steroid 17-alpha-hydroxylase/17,20 lyase Kappa-typ 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.
CN1C=NC2=C1C(=O)N(C(=O)N2C)C Approved as food (400 mg per day) delaying melatonin secretion, particularly when consumed in the evening, and potentially disrupting sleep patterns. It can shift the CCGs rhtyhms Adenosine A1, A2A, A2B, and A3 Receptors Activation of Adenosine Receptors, Adenosine Monophosphate-Activated Protein Kinase (AMPK), adenosine receptor binding Burke, T.M., Markwald, R.R., McHill, A.W., Chinoy, E.D., Snider, J.A., Bessman, S.C., Jung, C.M., O’Neill, J.S. and Wright Jr, K.P., 2015. Effects of caffeine on the human circadian clock in vivo and in vitro. Science translational medicine, 7(305), pp.305ra146-305ra146.
CC(C)/C=C/CCCCC(=O)NCC1=CC(=C(C=C1)O)OC Approved restores normal circadian rhythms TRPV1 TRPV1 capsaicin site binding Liu, L. and Tian, Y., 2023. Capsaicin changes the pattern of brain rhythms in sleeping rats. Molecules, 28(12), p.4736.
C[C@@H](CC1=CC=CC=C1)NC Approved Ultradian oscillations induction in Per1/2/3knockout mice, exposure induces atime-varying circadian rhythm, induced a very long free-running period (~27 h) in heterozygous Gsk3β mutant mice in DD SLC6A2 methamphetamine-sensitive circadian oscillator (MASCO), Monoamine transporter inhibitor, increase dopamine signalling, Non-canonical circadian genes Barnes, S.J., Alanazi, M., Yamazaki, S. and Stefanovska, A., 2025. Methamphetamine alters the circadian oscillator and its couplings on multiple scales in Per1/2/3 knockout mice. PNAS nexus, 4(4), p.pgaf070. , Mohawk, J.A., Baer, M.L. and Menaker, M., 2009. The methamphetamine-sensitive circadian oscillator does not employ canonical clock genes. Proceedings of the National Academy of Sciences, 106(9), pp.3519-3524. , Genetics and functional significance of the understudied methamphetamine sensitive circadian oscillator (MASCO)
CCC1=NN(C(=O)N1CCOC2=CC=CC=C2)CCCN3CCN(CC3)C4=CC(=CC=C4)Cl.Cl Approved Nefazodone decreased both sleep latency and stage 1 sleep and increased sleep efficiency. CLOCK-BMAL1 , Arntl (gene) , BMAL1 expression (induction) de-repressing BMAL1, BMAL1 expression modulation, BMAL1 expression modulation 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(CNC(=O)C)C1=CNC2=CC(=C(C=C21)OC)Cl Not approved efficacy in readjusting phase shifts in all physiological systems. Reduces sleep latancy. Melatonin receptor , MT1 , MT2 Melatonin receptor binding, MT1 receptor binding, MT2 receptor ligand Hardeland, R., 2016. Melatonin and synthetic melatoninergic agonists in psychiatric and age-associated disorders: successful and unsuccessful approaches. Current Pharmaceutical Design, 22(8), pp.1086–1101. , Szabadi, E., 2015. Neuronal networks regulating sleep and arousal: effect of drugs. In: Guglietta, A. (ed.) Drug Treatment of Sleep Disorders. Milestones in Drug Therapy. Springer, Cham, pp.25–70.
COC1=CC(=C(C=C1Cl)S(=O)(=O)N2CCCCC2)Cl Not approved AA41612 alters the body's response to light, potentially influencing the timing and duration of circadian rhythms, such as sleep-wake cycles, Melanopsin (Opn4) Photoreception inhibition, Competitive binding at melanopsin’s retinal-binding site Jones, K.A., Hatori, M., Mure, L.S., Bramley, J.R., Artymyshyn, R., Hong, S.P., Marzabadi, M., Zhong, H., Sprouse, J., Zhu, Q. and Hartwick, A.T., 2013. Small-molecule antagonists of melanopsin-mediated phototransduction. Nature chemical biology, 9(10), pp.630-635.
COC1=C(C(=CC=C1)OCCCN)C2=CC(=NN2)NC3=NC=C(N=C3)C#N Approved CKI delta CHK1 inhibitor crosstalk with caseine kinase 1, CK1 Inhibition, Chk1/2 inhibition, PER2 phosphorylation Collis SJ, Boulton SJ. Emerging links between the biological clock and the DNA damage response. Chromosoma (2007) 116:331–9. doi: 10.1007/s00412-007-0108-6
CC1=C2[C@H](C(=O)[C@@]3([C@H](C[C@@H]4[C@]([C@H]3[C@@H]([C@@](C2(C)C)(C[C@@H]1OC(=O)[C@@H]([C@H](C5=CC=CC=C5)NC(=O)C6=CC=CC=C6)O)O)OC(=O)C7=CC=CC=C7)(CO4)OC(=O)C)O)C)OC(=O)C Approved CLOCK-BMAL1 , Arntl (gene) , BMAL1 expression (induction) Bmal1, de-repressing BMAL1, BMAL1 expression modulation, BMAL1 expression modulation Sullivan, K.A., Grant, C.V., Jordan, K.R., Obrietan, K. and Pyter, L.M., 2022. Paclitaxel chemotherapy disrupts behavioral and molecular circadian clocks in mice. Brain, behavior, and immunity, 99, pp.106-118.
C1CC(C1)C(=O)NCCC2=CC=CC3=CC=CC=C32 Not approved Melatonin receptor antagonist of melatonin receptors Masson-Pévet, M., Recio, J., Guerrero, H.Y., Mocaer, E., Delagrange, P., Guardiola-Lemaitre, B. and Pévet, P., 1998. Effects of two melatonin analogues, S-20098 and S-20928, on melatonin receptors in the pars tuberalis of the rat. Journal of Pineal Research, 25(3), pp.172–176. , Willis, G.L. and Robertson, A.D., 2005. Recovery from experimental Parkinson's disease in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride treated marmoset with the melatonin analogue ML-23. Pharmacology Biochemistry and Behavior, 80(1), pp.9–26.
CC(=O)NCCC1=CNC2=C1C=C(C=C2)OCCO none possesses very different efficacies at the two melatonin receptors, beha full melatonin receptor agonist mt1, as an antagonist MT2 effect not studied MT1 , MT2 MT2 receptor antagonist, MT1 receptor binding, MT2 receptor ligand Nonno, R., Lucini, V., Spadoni, G., Pannacci, M., Croce, A., Esposti, D., Balsamini, C., Tarzia, G., Fraschini, F. and Stankov, B.M., 2000. A new melatonin receptor ligand with mt1‐agonist and MT2‐antagonist properties. Journal of pineal research, 29(4), pp.234-240.
CC[C@@]1(C[C@H]2C[C@@](C3=C(CCN(C2)C1)C4=CC=CC=C4N3)(C5=C(C=C6C(=C5)[C@]78CCN9[C@H]7[C@@](C=CC9)([C@H]([C@@]([C@@H]8N6C)(C(=O)OC)O)OC(=O)C)CC)OC)C(=O)OC)O.OS(=O)(=O)O Approved Circadian modulation via Bmal1 activation (U2OS cells) CLOCK-BMAL1 , Arntl (gene) , BMAL1 expression (induction) Bmal1, BMAL1 expression modulation, BMAL1 expression modulation, Tubulin alpha-1A, beta, delta, gamma-1, epsilon chain Transcription factor AP-1 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(NCCC1=C2C=C(OC)C=CC2=CC=C1)=O.O=C(O)[C@H](O)[C@@H](O)C(O)=O Not approved Circadian phase modulation via MT1/MT2 agonism Melatonin receptor Melatonin receptor binding 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. , Millan, M.J., Gobert, A., Lejeune, F., Dekeyne, A., Newman-Tancredi, A., Pasteau, V., Rivet, J.M. and Cussac, D., 2003. The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. Journal of Pharmacology and Experimental Therapeutics, 306(3), pp.954–964. , Aguiar, C.C., Almeida, A.B., Araújo, P.V., Vasconcelos, G.S., Chaves, E.M., do Vale, O.C., Macêdo, D.S., Leal, L.K., de Barros Viana, G.S. and Vasconcelos, S.M., 2013. Effects of agomelatine on oxidative stress in the brain of mice after chemically induced seizures. Cellular and Molecular Neurobiology, 33(6), pp.825–835.
CC(=O)NCCC1=C(NC2=C1C=C(C=C2)OC)CN3CCC4=CC=CC=C43 none suggests it could potentially interact with the circadian system, which involves processes like sleep-wake cycles and hormone production MT2 MT2 receptor antagonist Zlotos, D.P., Attia, M.I., Julius, J., Sethi, S. and Witt-Enderby, P.A., 2009. 2-[(2, 3-Dihydro-1 H-indol-1-yl) methyl] melatonin Analogues: A Novel Class of MT2-Selective Melatonin Receptor Antagonists. Journal of medicinal chemistry, 52(3), pp.826-833.
CC1=CC2=C(C=C1C)N(C3=NC(=O)NC(=O)C3=N2)C[C@@H]([C@@H]([C@@H](CO)O)O)O Approved restored the circadian oscillations of differentiation-related genes and core clock genes that were reduced by D-galactose PER2 gene expression Restores oscillations of circadian genes Lee, S., Sim, Y., Lee, M., Choi, Y., Lim, J.Y., Lee, J.H. and Kim, E., 2025. Riboflavin as a circadian modulator mitigates D-galactose-induced muscle senescence via oxidative stress and mitochondrial regulation in C2C12 cells. Journal of Functional Foods, 130, p.106924.
CC(C1CC1)N2C=NC3=C(N=C(N=C32)NCCN(C)C)NCC4=CC(=CC=C4)C(F)(F)F Not approved showed stronger period effects (0.32 μM for 5 h period lengthening) in a cell-based circadian assay CKI delta Inhibits casein kinase 1 delta (CKIδ) activity, Inhibits CKIδ Lee, J.W., Hirota, T., Ono, D., Honma, S., Honma, K.I., Park, K. and Kay, S.A., 2019. Chemical control of mammalian circadian behavior through dual inhibition of casein kinase Iα and δ. Journal of medicinal chemistry, 62(4), pp.1989-1998.
O=C1NC2=C(C=CC=C2)/C1=C\C3=C(OC)C=C(OC)C=C3OC None can induce a phase delay in circadian rhythms CK1 epsilon Targets CK1 epsilon Cheong, J.K., Hung, N.T., Wang, H., Tan, P., Voorhoeve, P.M., Lee, S.H. and Virshup, D.M., 2011. IC261 induces cell cycle arrest and apoptosis of human cancer cells via CK1δ/ɛ and Wnt/β-catenin independent inhibition of mitotic spindle formation. Oncogene, 30(22), pp.2558-2569.
CC1=CC2=C(C=C1C(=C)C3=CC=C(C=C3)C(=O)O)C(CCC2(C)C)(C)C Approved Circadian modulation detected in Bmal1-reporter assay CLOCK-BMAL1 , BMAL1 expression (induction) Bmal1, de-repressing BMAL1, BMAL1 expression modulation, BMAL1 expression modulation 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)NCCN1C2=CC(=C(C=C2N=C1OC)Cl)OC not approved Melatonin receptor agonism Melatonin receptor Melatonin receptor binding 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.
CC(=O)N/C=C/C1=C(C=CC2=C1C=C(C=C2)OC)OC none MT1 agonist with poorly described MT1 MT1 receptor binding Morellato, L., Lefas-Le Gall, M., Langlois, M., Caignard, D.H., Renard, P., Delagrange, P. and Mathé-Allainmat, M., 2013. Synthesis of new N-(arylcyclopropyl) acetamides and N-(arylvinyl) acetamides as conformationally-restricted ligands for melatonin receptors. Bioorganic & medicinal chemistry letters, 23(2), pp.430-434.
CC(CC1=CC2=C(C=C1)OCO2)NC Not approved Disrupts sleep, alters the response of the circadian clock to a photic and non-photic stimulus SLC18A2 , HTR2C , SLC6A3 , SLC6A2 , HTR2A , SLC6A4 , HTR2B Synaptic vesicular amine transporter interaction, 5-hydroxytryptamine receptor 2C binding, Sodium-dependent dopamine transporter binding, Sodium-dependent noradrenaline transporter, 5-hydroxytryptamine receptor 2A binding, Sodium-dependent serotonin transporter, 5-hydroxytryptamine receptor 2B binding Koczor, C.A., Ludlow, I., Hight, R.S., Jiao, Z., Fields, E., Ludaway, T., Russ, R., Torres, R.A. and Lewis, W., 2015. Ecstasy (MDMA) alters cardiac gene expression and DNA methylation: implications for circadian rhythm dysfunction in the heart. Toxicological Sciences, 148(1), pp.183-191. , Colbron, S., Jones, M. and Biello, S.M., 2002. MDMA alters the response of the circadian clock to a photic and non-photic stimulus. Brain research, 956(1), pp.45-52. , McCann, U.D. and Ricaurte, G.A., 2007. Effects of (±) 3, 4‐Methylenedioxymethamphetamine (MDMA) on Sleep and Circadian Rhythms. The Scientific World Journal, 7(1), pp.231-238.
C1=CC(=C(C=C1C(=O)O)O)O none reduced reactive oxygen species (ROS) levels and upregulated antioxidant enzymes, promoted skin barrier integrity by increasing structural protein and ceramide-related gene expression, enhanced cellular longevity markers, such as cyclin-dependent kinase inhibitor 1B (CDKN1B) and telomerase reverse transcriptase (TERT) RORA , RORα Core clock modulation, ROR Lee, J., Kim, J.Y., Lee, J.H. and Lee, K.H., 2025. Protocatechuic acid modulates the circadian rhythm of keratinocytes and maintains skin barrier integrity. Molecular Biology Reports, 52(1), p.765.
CCC1=C2C=COC2=C(OCC(F)CO)C=C1 none directly targets BMAL1, impacting its ability to regulate gene expression within the circadian clock and immune system CLOCK-BMAL1 , BMAL1 Bmal1, Interferes with CLOCK–BMAL1, Targets BMAL1–CLOCK DNA-binding activity Zeng, Y., Guo, Z., Wu, M., Chen, F. and Chen, L., 2024. Circadian rhythm regulates the function of immune cells and participates in the development of tumors. Cell death discovery, 10(1), p.199.
CC(=O)N1CCN(CC1)C2=CC=C(C=C2)OC[C@H]3CO[C@](O3)(CN4C=CN=C4)C5=C(C=C(C=C5)Cl)Cl Approved Circadian modulator activity CLOCK-BMAL1 , BMAL1 expression (induction) BMAL1 expression modulation, BMAL1 expression modulation, Binding Androgen receptor, 17-hydroxylase, Steroid 21-hydroxylase, 11-hydroxylase, Cytochrome P450 19A1, Potassium voltage- 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=C2C(=C1)C3=NN(C4=CC=CC(=C43)C2=O)CCO None Period lengthening JNK JNK kinase mediated circadian rhythm modulation Park, W.R., Choi, B., Kim, Y.J., Kim, Y.H., Park, M.J., Kim, D.I., Choi, H.S. and Kim, D.K., 2022. Melatonin regulates iron homeostasis by inducing hepcidin expression in hepatocytes. International Journal of Molecular Sciences, 23(7), p.3593. , Wu, H.M., Shen, Q.Y., Fang, L., Zhang, S.H., Shen, P.T., Liu, Y.J. and Liu, R.Y., 2016. JNK-TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis. Journal of Pineal Research, 60(4), pp.415–423.