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List of Chronobiotics



Name SMILES FDA Status Effects Targets Mechanisms Articles
C1=NC(=C2C(=N1)N(C=N2)[C@H]3[C@@H]([C@@H]([C@H](O3)CO)O)O)N Approved Phase shift modulation and period regulation via adenosine receptor signaling (in mice and mammals) Adenosine A1, A2A, A2B, and A3 Receptors Activation of Adenosine Receptors Jagannath, A., Varga, N., Dallmann, R., Rando, G., Gosselin, P., Ebrahimjee, F., Taylor, L., Mosneagu, D., Stefaniak, J., Walsh, S. and Palumaa, T., 2021. Adenosine integrates light and sleep signalling for the regulation of circadian timing in mice. Nature communications, 12(1), p.2113.
CCN(C1=CC=CC(=C1)C2=CC=NC3=C(C=NN23)C#N)C(=O)C Approved Affects melatonin synthsis, increases melatonin synthesis GABAA receptors GABA A receptor binding, GABAergic system influence Morera, A.L., Abreu-Gonzalez, P. and Henry, M., 2009. Zaleplon increases nocturnal melatonin secretion in humans. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 33(6), pp.1013-1016.
C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)O)C)C)[C@@H]2[C@H]1C)C)C(=O)O Not approved Modulation of clock gene expression and metabolic rhythm regulation in liver (in mammals) ROR gamma PTEN, ROCK, p53 Kojetin, D.J. and Burris, T.P., 2014. REV-ERB and ROR nuclear receptors as drug targets. Nature reviews Drug discovery, 13(3), pp.197-216. , Kwon, E.Y., Shin, S.K. and Choi, M.S., 2018. Ursolic acid attenuates hepatic steatosis, fibrosis, and insulin resistance by modulating the circadian rhythm pathway in diet-induced obese mice. Nutrients, 10(11), p.1719. , Zahran, E.M., Mohamad, S.A., Elsayed, M.M., Hisham, M., Maher, S.A., Abdelmohsen, U.R., Elrehany, M., Desoukey, S.Y. and Kamel, M.S., 2024. Ursolic acid inhibits NF-κB signaling and attenuates MMP-9/TIMP-1 in progressive osteoarthritis: a network pharmacology-based analysis. RSC advances, 14(26), pp.18296-18310.
CC1=CC(=NO1)NS(=O)(=O)C2=CC=C(C=C2)N Approved Circadian phase shift and dysrhythmia in eclosion rhythm in Drosophila melanogaster mPer2 , mPer1 , CRY1-PER2 complex , CRY1 , CLOCK-BMAL1 Core clock suppression Yu, Z., Shen, J., Li, Z., Yao, J., Li, W., Xue, L., Vandenberg, L.N. and Yin, D., 2020. Obesogenic effect of sulfamethoxazole on Drosophila melanogaster with simultaneous disturbances on eclosion rhythm, glucolipid metabolism, and microbiota. Environmental Science & Technology, 54(9), pp.5667-5675.
CCCC1CC(N(C1)C)C(=O)NC(C2C(C(C(C(O2)SC)O)O)O)C(C)O not approved alone caused a long circadian period. However, the degree of lengthening was less than with Fe deficiency alone Fe deficiency Unknown Chen, Y.Y., Wang, Y., Shin, L.J., Wu, J.F., Shanmugam, V., Tsednee, M., Lo, J.C., Chen, C.C., Wu, S.H. and Yeh, K.C., 2013. Iron is involved in the maintenance of circadian period length in Arabidopsis. Plant physiology, 161(3), pp.1409-1420.
C1=CC=C(C=C1)C(C2=CC=CC=C2)C(=O)N[C@H](CCCN=C(N)N)C(=O)NCC3=CC=C(C=C3)CNC(=O)N.C(=O)(C(F)(F)F)O none Phase shift via Y1 receptor antagonism in rodents Neuropeptide Y Y1 receptor Neuropeptide Y1 receptor binding Cohen, S., Vainer, E., Matar, M.A., Kozlovsky, N., Kaplan, Z., Zohar, J., Mathé, A.A. and Cohen, H., 2015. Diurnal fluctuations in HPA and neuropeptide Y-ergic systems underlie differences in vulnerability to traumatic stress responses at different zeitgeber times. Neuropsychopharmacology, 40(3), pp.774-790.
CC1=C(C(=CC=C1)C(C)C2=CN=CN2)C Approved Altered expression of clock genes in mice mPer2 , mPer1 , CRY1-PER2 complex Core clock modulation Huang, X., Lin, D., Sun, Y., Wu, A. and Wei, C., 2021. Effect of dexmedetomidine on postoperative sleep quality: a systematic review. Drug design, development and therapy, pp.2161-2170.
CC1C=CC=C(C(=O)NC2=C(C3=C(C4=C(C(=C3O)C)OC(C4=O)(OC=CC(C(C(C(C(C(C1O)C)O)C)OC(=O)C)C)OC)C)C5=C2N6C=CC(=CC6=N5)C)O)C Approved protective effects against cognitive impairment caused by circadian rhythm disruption Microbiota protect Meng, D., Yang, M., Hu, L., Liu, T., Zhang, H., Sun, X., Wang, X., Chen, Y.U., Jin, Y.U. and Liu, R., 2022. Rifaximin protects against circadian rhythm disruption–induced cognitive impairment through preventing gut barrier damage and neuroinflammation. Journal of neurochemistry, 163(5), pp.406-418.
CCOC(=O)N1CCC(C1)CN(CC2=CC=C(C=C2)Cl)CC3=CC=C(S3)[N+](=O)[O-] not approved Phase stabilization and circadian gene modulation in mice mPer2 , REV-ERBα , Per2 expression Agonist REV-ERB alpha Solt, L.A., et al, 2012. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature, 485(7396), pp.62-68. , Yang, M.Y., Lin, H.Y.H., Chen, Y.Y.M., Hu, M.L., Chen, I.Y. and Yang, C.H., 2025. Chronic low-dose REV-ERBs agonist SR9009 mitigates constant light-induced weight gain and insulin resistance via adipogenesis modulation. Biomedical Journal, p.100830.
C1CCC2(C1)CC(=O)N(C(=O)C2)CCCCN3CCN(CC3)C4=NC=CC=N4 Approved Phase advance and reduced amplitude in mice and hamsters 5-HT1A Serotoninergic signaling Smith, V.M., Iannatonne, S., Achal, S., Jeffers, R.T. and Antle, M.C., 2014. The serotonergic anxiolytic buspirone attenuates circadian responses to light. European Journal of Neuroscience, 40(10), pp.3512-3525.
C1=CC=C2C(=C1)C3=C4C2=CC5=CC=CC6=C5C4=C(C=C6)C=C3 none Circadian rhythm disruption in mammals CLOCK-BMAL1 Disruption of circadian clock, aryl hydrocarbon receptor (AhR) binding Koh, Y.C. and Pan, M.H., 2024. Food-Borne Polycyclic Aromatic Hydrocarbons and Circadian Disruption. ACS omega, 9(29), pp.31298-31312.
CN1CCN(CC1)CCCN2C3=CC=CC=C3SC4=C2C=C(C=C4)C(F)(F)F Approved Phase shift in fungi (Neurospora) Calmodulin Calmodulin binding (Neurospora) Suzuki, S., Katagiri, S. and Nakashima, H., 1996. Mutants with altered sensitivity to a calmodulin antagonist affect the circadian clock in Neurospora crassa. Genetics, 143(3), pp.1175-1180.
CCOC(=O)C1CC2=CC=CC=C2CN1C(=O)C3=CC=C(S3)SC Not approved Amplitude enhancement and phase shift in human cells CLOCK-BMAL1 Antagonist of Rev-Erb nuclear receptors, de-repressing BMAL1 Kojetin, D., Wang, Y., Kamenecka, T.M. and Burris, T.P., 2011. Identification of SR8278, a synthetic antagonist of the nuclear heme receptor REV-ERB. ACS chemical biology, 6(2), pp.131-134. , Anabtawi, N., Cvammen, W. and Kemp, M.G., 2021. Pharmacological inhibition of cryptochrome and REV-ERB promotes DNA repair and cell cycle arrest in cisplatin-treated human cells. Scientific Reports, 11(1), p.17997.
C1=CC2=C3C(=C1)C4=CC=CC5=C4C6=C(C=C5)C=CC(=C36)C=C2 None Circadian rhythm disruption in mammals mPer2 , mPer1 , CRY1-PER2 complex , CLOCK-BMAL1 Disruption of circadian clock, Interferes with CLOCK–BMAL1, aryl hydrocarbon receptor (AhR) binding Koh, Y.C. and Pan, M.H., 2024. Food-Borne Polycyclic Aromatic Hydrocarbons and Circadian Disruption. ACS omega, 9(29), pp.31298-31312.
CN(C)CCCN1C2=CC=CC=C2SC3=CC=CC=C31 Approved Circadian rhythm disruption in humans D2R (dopamine receptor) Hypnotic effect, Sleep promotion Nagayama, H., Takagi, A., Sakurai, Y., Nishiwaki, K. and Takahashi, R., 1978. Chronopharmacological study of neuroleptics: II. Circadian susceptibility rhythm to chlorpromazine. Psychopharmacology, 58, pp.49-53.
CC1=C(OC2=C1C3=C(C=C2)OC(CC3=O)(C)C4=CC=C(C=C4)Cl)C(=O)N5CCC6=CC=CC=C65 Not approved Period lengthening in human cells (U2OS) CRY1 Binds CRY1 FAD-binding Gul, S., Akyel, Y.K., Gul, Z.M., Isin, S., Ozcan, O., Korkmaz, T., Selvi, S., Danis, I., Ipek, O.S., Aygenli, F. and Taskin, A.C., 2022. Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice. Nature Communications, 13(1), p.6742.
C1=CC=C2C(=C1)C=CC3=CC4=C(C=CC5=CC=CC=C54)C=C32 none Circadian disruption via core clock interference (in mammals) mPer2 , mPer1 , CRY1-PER2 complex , CLOCK-BMAL1 Disruption of circadian clock, Bmal1, Interferes with CLOCK–BMAL1, aryl hydrocarbon receptor (AhR) binding Koh, Y.C. and Pan, M.H., 2024. Food-Borne Polycyclic Aromatic Hydrocarbons and Circadian Disruption. ACS omega, 9(29), pp.31298-31312.
C1CN(CCC1N2C3=CC=CC=C3NC2=O)CCCC(C4=CC=C(C=C4)F)C5=CC=C(C=C5)F Approved Phase-dependent modulation of activity amplitude and onset (in rodents) D2R (dopamine receptor) Dopamine receptor binding Davies, J.A., 1979. The Influence of Dopaminergic Mechanism on 24-Hour Temperature and Activity Rhythms in Rodents. In Neuro-Psychopharmacology (pp. 611-620). Pergamon.
C1CCC(CC1)N2C=NC(=C2C3=NC(=NC=C3)N)C4=CC=C(C=C4)F.Cl.Cl Not approved Period lengthening and phase delay in rodents and SCN slices CK1δ Inhibits CK1δ Meng, Q.J., Maywood, E.S., Bechtold, D.A., Lu, W.Q., Li, J., Gibbs, J.E., Dupré, S.M., Chesham, J.E., Rajamohan, F., Knafels, J. and Sneed, B., 2010. Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes. Proceedings of the National Academy of Sciences, 107(34), pp.15240-15245.
C1=CC=C2C(=C1)C=CC3=C2C=CC4=CC=CC=C43 none Circadian disruption via core clock targeting in mammals mPer2 , mPer1 , CRY1-PER2 complex , CRY1 , CLOCK-BMAL1 Disruption of circadian clock, Bmal1, modulation of nuclear receptor signaling pathways, Interferes with CLOCK–BMAL1, Targets BMAL1–CLOCK DNA-binding activity Koh, Y.C. and Pan, M.H., 2024. Food-Borne Polycyclic Aromatic Hydrocarbons and Circadian Disruption. ACS omega, 9(29), pp.31298-31312.
C1CCC(C(C1)CN2CCN(CC2)C3=NSC4=CC=CC=C43)CN5C(=O)C6C7CCC(C7)C6C5=O Approved Clock gene normalization and potential phase shift in rats mPer2 , mPer1 , CRY1-PER2 complex , CRY1 , CLOCK-BMAL1 , Arntl (gene) Core clock modulation Calabrese, F., Savino, E., Papp, M., Molteni, R. and Riva, M.A., 2016. Chronic mild stress-induced alterations of clock gene expression in rat prefrontal cortex: modulatory effects of prolonged lurasidone treatment. Pharmacological research, 104, pp.140-150. , Krystal, A.D. and Zammit, G., 2016. The sleep effects of lurasidone: a placebo‐controlled cross‐over study using a 4‐h phase‐advance model of transient insomnia. Human Psychopharmacology: Clinical and Experimental, 31(3), pp.206-216.
C1=CC=C2C=C3C4=CC=CC5=C4C(=CC=C5)C3=CC2=C1 none Circadian disruption via core clock gene targeting in animals (PAH exposure model) mPer2 , mPer1 , CRY1-PER2 complex , CRY1 , CLOCK-BMAL1 Disruption of circadian clock, Bmal1, Interferes with CLOCK–BMAL1, Targets BMAL1–CLOCK DNA-binding activity, aryl hydrocarbon receptor (AhR) binding Koh, Y.C. and Pan, M.H., 2024. Food-Borne Polycyclic Aromatic Hydrocarbons and Circadian Disruption. ACS omega, 9(29), pp.31298-31312.
C1CN(CCN1CCC=C2C3=CC=CC=C3SC4=C2C=C(C=C4)C(F)(F)F)CCO Approved Circadian disruption in humans (rest-activity rhythm disturbance with flupentixol) Unknown Unknown, 5-HT7 binding Dagan, Y. and Borodkin, K., 2005. Behavioral and psychiatric consequences of sleep-wake schedule disorders. Dialogues in clinical neuroscience, 7(4), pp.357-365. , Bad News for Antipsychotics and Circadian Rhythms
CCCCCC1=CC(=C2C(=C1)OC(C3=C2C=C(C=C3)C)(C)C)O Not approved Circadian modulation potential via CB2 in mammals (indirect, immune-related pathways) Cannabinoid receptor , CB2 Disruption of circadian clock, Core clock modulation, Unknown, Cannabinoid receptor stimulation Lafaye G, Desterke C, Marulaz L, Benyamina A. Cannabidiol affects circadian clock core complex and its regulation in microglia cells. Addiction Biology. 2018.
CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC=CC=N3 Approved restores normal circadian rhythms, shifted the phases T58921 Peroxisome proliferator-activated receptor gamma (PPAR-gamma) , BMAL1 expression (induction) , CLOCK gene expression protect Tian, Y., Luan, X. and Yang, K., 2024. Chronotherapy involving rosiglitazone regulates the phenotypic switch of vascular smooth muscle cells by shifting the phase of TNF-α rhythm through triglyceride accumulation in macrophages. Heliyon, 10(10), p.e30708. , Tian, Y., Luan, X. and Yang, K., 2024. Chronotherapy involving rosiglitazone regulates the phenotypic switch of vascular smooth muscle cells by shifting the phase of TNF-α rhythm through triglyceride accumulation in macrophages. Heliyon, 10(10), p.e30708.