1. INTRODUCTION:

Severe Acute Respiratory Syndrome Coronavirus 2 is the new coronavirus that is believed to be the source of Coronavirus Disease 2019 (COVID-19) (SARS-CoV-2; formerly called 2019-nCoV).¹ In Wuhan City, Hubei Province, China, on December 31, 2019, the WHO China Country Office received information concerning pneumonia of unknown origin. As of 3 January 2020, 44 pneumonia cases had been reported to the WHO by China's national authorities. The cluster first came to light after the Chinese government determined that a novel coronavirus (COV)—officially known as COVID-19, which stands for "coronavirus disease 2019"—was the cause of SARS-CoV2.²

Currently, the entire world is experiencing COVID-19, a highly contagious disease that has no geographical boundaries untouched.³

The World Health Organization has classified the novel coronavirus outbreak a pandemic (WHO). This disease can spread from an asymptomatic person even throughout the incubation period, which poses a major hazard and has the potential to kill thousands of people. The search for a natural reservoir, an intermediary host, and vaccinations is ongoing. There are also a lot of unanswered concerns with COVID-19, such as the reason of the outbreak, the mode of transmission, effective treatments, methods of prevention, the length of the transmission, etc. The coronaviruses that cause MERS and SARS have demonstrated that these viruses can infect people of other species. According to recent virological investigations, coronaviruses are pathogens that infect a variety of mammals that frequently come into touch with people, laying the groundwork for future zoonotic outbreaks.⁴Coronavirus is an enveloped particle that measures 120–160 nm. contain unsegmented single-stranded positive genome meaning RNA. The sequence of the viral RNA genes is: the four typical dependent RNA polymerase the spike (S), envelope, and structural proteins (E), proteins for membranes and nucleocapsids.⁵

Emerging coronaviruses have become a new public health concern in the twenty-first century due to the zoonotic origins of two highly pathogenic coronaviruses, Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV), which caused fatal respiratory illness in humans in 2002 and 2012, respectively.⁶ Scientists are still working to find a suitable drug or vaccine to stop the present outbreak despite many setbacks. Combination drug therapy may have once been the only effective method to identify coronavirus treatment. The antiviral targets RNA-dependent RNA polymerase (RdRp) enzymes, which are necessary for thetranscription and replication of viral genomes. Dexamethason,Favipiravir, Remdesivir has been investigated for the treatment of COVID-19.^7,8 In order to create innovative libraries for the creation of biologically active molecules with enhanced pharmacokinetic properties, the pharmaceutical industry heavily relies on the utilisation of various heterocyclic moieties as a building block when producing drugs.⁹

When a molecule is being investigated for potential drug use, drug discovery and development is a challenging, multidisciplinary endeavour.¹⁰ The largest and most diverse family of organic compounds is made up of heterocyclic compounds. Today, there are many heterocyclic compounds that have been found, and as a result of extensive synthetic research as well as their usefulness in synthetic processes, this number is growing daily.¹¹ A heterocyclic molecule is formed when an oxygen, nitrogen, sulphur, or atom of a similar element is included in place of a carbon atom.¹² According to data from the World Health Organization as of October 25, 2020, viruses are the most common infectious diseases in the world. Because of the coronavirus pandemic that lasted for almost a year, this contact between viruses and people is still going on today.¹³

Heterocyclic moities including triazole, Thiadiazole, thiazole, pyrrole, pyridine, quinolone, etc., and their derivatives, are the adaptable scaffolds in medicinal chemistry and exhibit significant therapeutic potential, including antitumor, EGFR inhibitory, antioxidant, antianalgesic, antiinflammatory, antibacterial, antifungal, and antimicrobial properties.¹⁴

Due to their numerous biological applications, heterocyclic compounds with both nitrogen and sulphur atoms are a significant family of molecules in medicinal chemistry. The five-membered heterocyclic compound thiadiazole has two nitrogen atoms and one sulphur atom. Thiadiazole comes in four isomeric forms (for example, 1, 2, 3, 1, 2, 4, 1, 2, 5, and 1,3,4-thiadiazole), with the 1,3,4-thiadiazole ring being the most common in various medical importance. Several medications that contain the 1,3,4-thiadiazole ring are now on the market, including the antibacterial medications cefazolin, cefazedone, and sulfamethizole, as well as the known antitrypanosomal medication megazol.¹⁵Thiadiazole also act as a constrained pharmacophore. Modern methods utilising computer approaches, such as Docking and Pharmacophore modelling, PreADMET analysis, which are frequently used in virtual screening studies, have been applied in the hunt for innovative drugs in recent years.¹⁶

A serious issue on a global scale is the resistance to medicines that are now available. One of the most crucial areas of research nowadays is the requirement to create novel drugs to combat this resistance. The versatile moiety thiadiazole has a wide range of biological effects. The thiadiazole moiety functions as a "two-electron donor system" and a "hydrogen binding domain." Additionally, it serves as a restricted pharmacophore.^17,18

Thus, the aim of the current research is to collect and present recent advances in the research fields connected to heterocyclic compounds specially Thiadiazole to develop potential drug against the novel corona virus.

2. MATERIAL AND METHOD:

2.1 Studied compounds:

The structures of the Thiadiazole derivatives examined in this paper are presented in Figure 1, and their names are shown in Table 1. These compounds contain several functional groups which differ in polarity: hydroxyl, methyl, acetyl group, Chloro, Iodo, nitro, Bromo, Amino etc.

Data set of compounds used for docking study:

Fig 1 Structure of substituted Thiadiazole

Where R= Cl, OH, OCH₃, NO₂, NH₂, NHCOCH₃, CH₃ etc

2.2 Molecular Properties using Online program (http://www.scfbio-iitd.res.in/ software/drugdesign/lipinski.jsp#anchortag) and Molinspiration

Lipinski's rule of five calculations:

The Lipinski rule is a variable that illustrates a compound's oral bioavailability. If a chemical has a maximum molecular weight of 500, a log P of less than 5, a hydrogen bond donor of less than 5, and a hydrogen bond acceptor of less than 10, it will satisfy the Lipinski rule (Lipinski et al., 2012). Table 1 displays the results of calculations made using Lipinski's Rule of Five utilizing an online server (http://www.scfbio-iitd.res.in/software/drugdesign/lipinski.jsp#anchortag). ^19-21

2.3 Prediction of drug-likeness and biological activity for substituted Thiadiazole using Molinspiration:

Pharmacological properties of the compounds are used to check the pharmaceutical fidelity of the drug candidates by using online tool Molinspiration, Preadmet study.²² Any developed chemical must possess a few characteristics shared by nearly all of the authorized medications in order to qualify as a potential drug candidate. As a result, the key checkpoints that the drug encounters on its way from its source of entry to the site of action are what determine the drug-like qualities. The compound must, above all else, be capable of exhibiting higher biological activity and lower toxicity. Therefore, it is crucial to foresee the drug-like characteristics of developed compounds in order to assess their potential as drug candidates. Utilizing the Molinspiration tool, it was possible to estimate the drug-like characteristics and bioactivity score for substituted Thiadiazole.^23-25 Prediction of drug-likeness for substituted Thiadiazole shown in Table 1.

Activity of the designed compounds and standard drug was rigorously analyzed under four criteria of known successful drug activity in the areas of GPCR ligand activity, ion channel modulation, Kinase inhibition activity, and nuclear receptor ligand activity.^[26-27] Results are shown in Table 2 by means of numerical assignment. Thus, these compounds are expected to have near similar activity to the standard drug used based upon these four rigorous criteria (GPCR ligand, ion channel modulator, Kinase inhibitor and nuclear receptor ligand).^28-29

Table 1: Result of Molecular Properties using Online program (Molinspiration)

COMP	miLogP	TPSA	Natoms	MW	nON	Nohnh	Nviolations	nrotb	volume
C1	4.27	83.55	29	400.46	6	2	0	4	338.41
C2	4.11	92.78	31	430.49	7	2	0	5	363.96
C3	4.44	129.37	32	445.46	9	2	0	5	361.74
C4	5.86	63.32	29	510.36	5	1	2	4	354.38
C5	5.11	109.14	32	443.49	8	1	1	5	370.29
C6	5.30	63.32	33	474.41	5	1	1	4	355.05
C7	4.55	113.34	34	475.55	5	1	1	4	365.05
C8	4.90	83.55	30	434.91	6	2	0	4	351.95
C9	4.40	91.02	34	474.54	8	1	0	7	407.03
C10	5.11	109.14	32	443.49	8	1	1	5	370.29
C11	5.34	109.14	32	463.91	8	1	1	5	367.26
C12	4.01	103.78	30	416.46	7	3	0	4	346.43
C13	4.94	63.32	29	402.45	5	1	0	4	335.32
C14	4.14	135.17	32	444.48	9	3	0	5	365.01
C15	3.40	118.44	33	456.53	8	4	0	5	389.63
C16	4.63	89.34	30	413.51	6	3	0	4	358.24
C17	4.63	89.34	30	413.51	6	3	0	4	358.24
C18	5.83	63.32	29	510.36	5	1	2	4	354.38
C19	5.31	109.14	32	463.91	8	1	1	5	367.26
C20	6.06	63.32	30	453.35	5	1	1	4	357.46

Table 2: Result of Bioactivity score of the ligand

Comp.	GPCR ligand	Ion channel modulator	Kinase inhibitor	Nuclear receptor ligand	Protease inhibitor	Enzyme inhibitor
C1	-0.44	-0.78	0.02	-0.55	-0.74	-0.28
C2	-0.46	-0.80	-0.01	-0.60	-0.77	-0.30
C3	-0.56	-0.95	-0.12	-0.65	-0.84	-0.36
C4	-0.46	-0.81	-0.02	-0.63	-0.78	-0.36
C5	-0.57	-0.83	-0.15	-0.67	-0.82	-0.42
C6	-0.41	-0.69	0.02	-0.57	-0.62	-0.26
C7	-0.56	-0.82	0.00	-0.65	-0.73	-0.40
C8	-0.43	-0.83	-0.01	-0.52	-0.77	-0.29
C9	-0.45	-0.77	-0.04	-0.65	-0.71	-0.31
C10	-0.62	-0.88	-0.21	-0.81	-0.86	-0.41
C11	-0.56	-0.85	-0.14	-0.70	-0.85	-0.40
C12	-0.40	-0.87	0.00	-0.65	-0.73	-0.29
C13	-0.45	-0.82	-0.01	-0.63	-0.74	-0.33
C14	-0.55	-0.78	-0.17	-0.86	-0.73	-0.37
C15	-0.47	-0.82	-0.10	-0.89	-0.64	-0.35
C16	-0.47	-0.83	-0.09	-0.80	-0.69	-0.33
C17	-0.49	-0.83	-0.10	-0.81	-0.70	-0.35
C18	-0.49	-0.84	0.01	-0.66	-0.77	-0.33
C19	-0.56	-0.84	-0.18	-0.77	-0.87	-0.40
C20	-0.47	-0.85	-0.05	-0.65	-0.79	-0.33

Table 4: In silico ADME properties of designed compounds

Code	AlogP98 value	BBB	Caco2	HIA	Plasma Protein Binding	Skin Permeability
C1	4.0951	1.22239	9.34066	95.5009	95.35535	-2.7299
C2	4.0951	0.328046	12.1718	95.70897	93.69482	-2.73716
C3	4.8417	0.044021	0.628018	95.02414	94.03196	-2.9278
C4	5.5901	1.73306	24.4712	98.23237	100	-2.24582
C5	5.5901	0.105662	1.11423	98.4766	92.92904	-2.23124
C6	5.5061	0.066734	39.2218	96.74898	93.27192	-2.9118
C7	5.5061	0.400152	19.855	96.18754	89.3382	-2.71519
C8	5.5061	0.5051	20.242	95.89752	96.85657	-2.69404
C9	3.3485	0.595459	38.7441	97.67625	96.49856	-2.64366
C10	6.1705	0.132936	1.12094	98.4766	100	-2.23026
C11	4.6305	0.113793	5.75124	98.7369	94.55191	-2.30393
C12	6.7325	0.701275	5.07269	93.57739	92.6154	-3.43589
C13	4.5743	1.29334	36.4797	96.73704	93.35961	-2.54331
C14	3.6911	0.082196	0.646678	94.91243	93.38736	-2.96249
C15	5.4199	0.101386	6.90448	94.68749	88.19617	-3.4552
C16	4.8253	0.968238	9.20661	96.01554	90.81824	-2.48973
C17	4.8253	1.06929	9.20661	96.01552	88.49729	-2.47813
C18	5.3279	1.73919	24.4712	98.23237	100	-2.2446
C19	5.3279	0.105886	5.41394	98.7369	94.72359	-2.2836
C20	5.3279	0.652431	33.1334	97.39162	100	-2.24704

2.5 Docking Study:

The protein-ligand interaction is important in the design of drugs with a structural basis. In structural molecular biology and computer-assisted drug creation, molecular docking is a crucial tool.^31,32 Molecular modeling studies were performed to investigate the potential interactions between target compound and Targeted Protein active sites residues to produce Targeted Protein inhibitory activity by using Molegro virtual docker 6.0.1. The docking protocol was validated by re-docking the co-crystallized ligand into the Targeted Protein binding pocket.

The COVID-19 main protease of the Corona virus species is one of the attractive targets in corona associated diseases.³³3D structure of protein targets Covid-19 main Protease (PDB: 6LU7) was downloaded from protein data bank. Among all designed compounds, C1, C3, and C14 exhibited the most significant affinity score and H-bond interactions against Covid-19 main Protease (PDB: 6LU7).compound C1 having -154.238 dock score with 7 H-bond interactions i.e. Glu166, His164, Cys145, Cys44, Tyr54, Met49, Asp187 which is significant as compared to standard drug Azithromycin having dock score of -152.362 and with 6 H-bond interactions i.e. Glu166, Cys145, Asn142, Leu141, Ser 144, Gly143. The docking interactions are illustrated in figure 2-6.

Figure 2: H-Bond Interactions of Co-crystallized ligand

Figure 3: H-Bond Interactions of C14

H-bond interactions of most significant ligand against Covid-19 main Protease:

Figure 4: H-Bond Interactions of C3

Figure 5: H-Bond Interactions of C1

Fig 2-6: Representation of most active compound C1, C3, C14 (C3 having most H-bond interaction and C14 having highest dock score) and Azithromycin for Covid-19 main protease (PDB: 6lu7). Hydrogen bond Interactions are represented as dotted lines

3.0 RESULT AND DISCUSSION:

From the results of present study a series of novel biologically active substituted thiadiazole compounds c1 to c20 were designed and screened for antiviral activities against Covid-19 main protease. From the molecular docking study of Covid-19 main protease (PDB: 6lu7, docking score -154.238) it was observed that the top ranked conformation of the most active compound C3 for Covid-19 main protease (PDB: 6lu7) established seven hydrogen bonds through amine and hydroxyl group with the binding site residues Glu166, His164, Cys145, Cys44, Tyr54, Met49, Asp187. Based on results of Molecular Properties using Online program (http://www.scfbio-iitd.res.in/software/drugdesign/lipinski.jsp#anchortag) and Molecular Properties using Online program (Molinspiration) and Lipinski's Rule of Five calculations, all of substituted thiadiazole derivatives conform Lipinski's rule. Bioactivity score values of C1, C6, C7, C12 shows positive values indicate greater affinity towards kinase receptor. At the Ames test endpoint of PreADMET, there are 16 mutagenic compounds and 04 other compounds are non-mutagenic compounds. The positive test results on Ames test indicate that the compound is mutagenic and has the possibility as carcinogenic. In the prediction of carcinogenicity in rat produced 02 carcinogenic positive compounds and 18 other compounds are negative carcinogenic. While in the prediction of carcinogenicity in mouse 14 compounds are not carcinogenicity. At the hERG Inhibition 11 compounds show low risk while others are ambiguous.

4.0 CONCLUSION:

In conclusion, our study aimed to investigate the potential role of substituted thiadiazole in anti-viral activity of corona virus by targeting Covid-19 main protease. The observations from our docking results suggested that substituted thiadiazole may be a better ligand for Covid-19 main protease in comparison to Azithromycin in terms of binding affinity and interactions. Further based upon the prediction of the druglike qualities of substituted thiadiazole we observed that it can be a potential drug candidate. The bioactivity prediction also suggested that substituted thiadiazole may exhibit a promising activity for kinase receptor ligands. Altogether, substituted thiadiazole may be proposed as a potential ligand for Covid-19 main protease and based on their bioactivity score and may also be suggested to be used as a future drug candidate as antiviral agents for corona virus.

5.0 ACKNOWLEDGMENTS:

The authors are thankful to the School of Pharmacy, DAVV Indore (MP), India, for providing facility and resources for this work.

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Received on 12.10.2022 Modified on 25.02.2023

Research J. Pharm. and Tech 2023; 16(12):5802-5807.

DOI: 10.52711/0974-360X.2023.00939

Toxicity		Compounds
Ames_test	Mutagen	C3,C4,C5,C6,C7,C9,C10,C11,C12,C13,C14,C15,C16,C17, C18,C19
Ames_test	Non-Mutagen	C1,C2,C8,C20
Carcino_Mouse	Negative	C1, C2,C3,C5,C7, C8,C9, C10,C11,C14, C15, C16, C17, C19
Carcino_Mouse	Positive	C4,C6,C12,C13,C18,C20
Carcino_Rat	Negative	C1, C2,C3, C5,C6, C7, C8,C9, C10,C11,C12,C13, C14, C15, C16, C17, C19,C20
Carcino_Rat	Positive	C4, C18
hERG_inhibition	Ambiguous	C1, C2,C3, C7, C8, C14, C15, C16, C17
hERG_inhibition	Low-risk	C4, C5,C6,C9, C10,C11,C12,C13, C18, C19,C20
Drug Likeness		Compounds
CMC_like_Rule	Qualified	C1,C2,C3,C5,C7,C8,C10,C11,C12,C13,C14,C15,C16,C17,C19
CMC_like_Rule	Not qualified	C4,C6,,C9,C18,C20
MDDR_like_Rule	Mid Structure	C1,C2,C3,C4,C5,C6,C7,C8, C10, C11, C12, C13, C14, C15, C16, C17,C18,C19
MDDR_like_Rule	Drug Like	C9
Rule_of_Five	Suitable	C1,C2,C3, C5,C6,C7,C8,C9, C10, C11, C12, C13, C14, C15, C16, C17,C19,C20
Rule_of_Five	Not Suitable	C4,C18